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Jul.29.2021

Diabetes Mellitus Type 2 in Adults

Synopsis

Key Points

  • Type 2 diabetes mellitus is a metabolic disease in which hyperglycemia results from insulin resistance and reduced insulin; it accounts for 90% to 95% of cases of diabetes in adultsr1
  • Most cases are diagnosed with laboratory tests during routine screening or incidentally during another illness
  • Diagnosis is confirmed by fasting plasma glucose level of 126 mg/dL (7 mmol/L) or higher, 2-hour oral glucose tolerance test result of 200 mg/dL (11.1 mmol/L) or higher, hemoglobin A1C level of 6.5% or higher, and/or random plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher in the presence of the classic signs and symptoms of hyperglycemia (eg, polyuria, polydipsia, polyphagia, unexplained weight loss, weakness, blurred vision) r1
  • Therapeutic lifestyle modifications (eg, diet, exercise, weight loss) are the cornerstone of therapy; pharmacotherapy is added to reach glycemic targets
  • Acute glycemic complications include hypoglycemia and hyperglycemic hyperosmolar state
  • Chronic microvascular complications are prevented by strict glycemic control; the role of glycemic control in macrovascular disease prevention is complex
  • Mortality rate is 1.5 times higher for patients with type 2 diabetes than for the general population, largely because of cardiovascular complications r2

Urgent Action

  • Severe hypoglycemia and hyperglycemic hyperosmolar state are life-threatening complications of type 2 diabetes and must be treated emergently

Pitfalls

  • Type 2 diabetes can be undiagnosed for many years because of gradual development of hyperglycemia over time
  • Treating the common comorbidities of diabetes mellitus often leads to polypharmacy; medication regimens and dosages may need to be adjusted as the disease progresses and cardiovascular function and renal function decline r3

Terminology

Clinical Clarification

  • Diabetes mellitus type 2 is a chronic, heterogeneous metabolic disorder that manifests as hyperglycemia and is characterized by impaired insulin secretion, insulin resistance, and increased hepatic glucose production; most cases begin in adulthood, and type 2 accounts for 90% to 95% of cases of diabetes in adultsr4
  • Overt hyperglycemia of type 2 diabetes results from a combination of underlying insulin resistance and progressive pancreatic β-cell dysfunction, ultimately leading to defects in insulin secretion
  • Prediabetes is impaired fasting glucose level and/or impaired glucose tolerance, indicating a state of increased risk for development of diabetes r4

Classification

  • General classification scheme for diabetes mellitus r4
    • Type 1
      • Type 1A: immune mediated
      • Type 1B: idiopathic
    • Type 2
      • Accounts for 90% to 95% of cases of diabetes in adults r4
      • Type 2 diabetes is not subclassified further
    • Other specific types of diabetes due to other less common causes
      • Genetic defects of β-cell function
      • Genetic defects in insulin action
      • Diseases of the exocrine pancreas
      • Endocrinopathies
      • Drug- or chemical-induced diabetes
      • Posttransplantation diabetes
      • Cystic fibrosis–related diabetes
      • Infections
      • Uncommon forms of immune-mediated diabetes (eg, stiff man syndrome)
      • Other unusual genetic syndromes associated with diabetes (eg, Down syndrome, Klinefelter syndrome)
    • Gestational diabetes

Diagnosis

Clinical Presentation

History

  • Most patients are initially asymptomatic, then identified through routine screening or by an incidental finding on laboratory tests in the context of another illness c1
  • Type 2 diabetes can be undiagnosed for many years owing to gradual development of hyperglycemia over time r4
  • Symptoms develop as hyperglycemia worsens, including:
    • Polyuria c2
    • Polydipsia c3
    • Polyphagia c4
    • Unexplained weight loss c5
    • Weakness c6
    • Blurred vision c7
  • Patients with known, established type 2 diabetes often relate a history of hypertension, dyslipidemia, or cardiovascular disease c8c9c10
  • History of frequent infections (eg, candidiasis, urinary tract infections) or slow-healing wounds (eg, foot ulcers) suggests poor metabolic control c11c12c13c14c15c16c17c18

Physical examination

  • Overweight or obese body habitus in approximately 80% of patients r5c19c20
  • Signs of insulin resistance
    • Increased abdominal adiposity c21
    • Acanthosis nigricans (cutaneous velvety hyperpigmented patches most prominent in intertriginous areas) when insulin resistance is extreme c22c23
  • Elevated blood pressure (in most patients) c24
  • Signs of complications in long-standing and/or poorly controlled disease
    • Microaneurysms, exudates, and/or macular edema on funduscopic examination c25c26c27c28c29c30
    • Decreased lower extremity sensation, pedal pulses, and/or reflexes c31c32c33c34c35c36
    • Foot ulcers, deformities, or wounds on inspection c37c38c39c40
    • Heart rate variability on deep inspiration, position change, and/or Valsalva maneuver c41c42c43c44c45c46

Causes and Risk Factors

Causes

  • Multifactorial pathogenesis in which metabolic, behavioral, lifestyle, and environmental factors precipitate disease in genetically predisposed persons r6c47c48c49
    • Combination of insulin resistance, increased hepatic gluconeogenesis, and relative defects in insulin secretion promote metabolic dysfunction
    • Overweight or obese body habitus is a major factor contributing to insulin resistance, which is a precursor to development of glucose intolerance and diabetes
    • Hypercaloric diet and sedentary lifestyle also worsen insulin resistance
    • Hyperglycemia develops when progressive impairments in insulin secretion render pancreatic β-cells unable to maintain euglycemia
  • Strong hereditary component contributes to manifestation of the disease, with complex polygenic inheritance pattern underlying most cases

Risk factors and/or associations

Age
  • Incidence increases with age, owing in part to age-related reduced glucose tolerance but also to reduced physical activity and increased adiposity c50c51
Sex
  • Women with history of the following are at greater risk for diabetes:
    • Polycystic ovary syndrome c52
    • Delivery of an infant weighing more than 4 kg c53
    • Previous diagnosis of gestational diabetes c54
Genetics
  • Most cases of type 2 diabetes have a complex multifactorial polygenic basis, with over 100 loci identified as contributing to higher risk r7c55
  • Most genes identified by genome-wide association studies individually confer modest risk of diabetes; when combined, they enable development and progression of the disease
    • Single nucleotide polymorphisms within the following set of genes are robustly associated with type 2 diabetes: TCF7L2, GCK, HNF1B, WFS1, KCNJ11, PPARG, and IRS1r7c56c57c58c59c60c61c62
    • Presence of multiple at-risk polymorphisms in a patient substantially increases the risk of developing diabetes
  • Genetic risk for type 2 diabetes is largely expressed in the setting of environmental factors such as obesity and sedentary lifestyle
Ethnicity/race
  • Increased prevalence in African American, Latino, Native American, Pacific Islander, and Asian American populations r4c63c64c65c66c67c68
Other risk factors/associations
  • Risk factors
    • Prediabetes (hemoglobin A1C level, 5.7%-6.4%; 5-fold elevated risk) r8c69
    • Overweight or obesity (2-fold elevated risk if overweight; risk rises proportionately with higher class of obesity) r5c70c71
    • Sedentary lifestyle c72
    • Medications that worsen glucose tolerance or exacerbate hyperglycemia, such as: r4
      • Glucocorticoids c73
      • Thiazide diuretics c74
      • Atypical antipsychotics c75
    • Sleep disorders (eg, obstructive sleep apnea, chronic sleep deprivation, night shift work schedule) in conjunction with glucose intolerance c76c77c78c79

Diagnostic Procedures

Primary diagnostic tools

  • Elements of history and physical examination findings can suggest the disorder, but biochemical parameters are essential for the diagnosis c80
  • Issues to consider in the selection of the diagnostic testing method r6
    • Fasting glucose level
      • Advantage: easy, inexpensive measurement
      • Disadvantage: relatively insensitive, levels fluctuate, and test requires patient to fast overnight
    • Oral glucose tolerance test
      • Advantage: most sensitive as a metabolic test
      • Disadvantage: inconvenient and time-consuming for the patient
    • Hemoglobin A1C level
      • Advantage: convenient, best measure of chronic glycemia, closely associated with complications, and less biologic variability compared with glucose-based tests
      • Disadvantage: results are confounded in certain situations of increased RBC turnover and hemoglobinopathies
  • Laboratory confirmation of diabetes mellitus can be achieved with any of the following: r4
    • Fasting plasma glucose measurement of at least 126 mg/dL (7 mmol/L)
    • Random glucose measurement of at least 200 mg/dL (11.1 mmol/L) when symptoms of hyperglycemia (eg, polyuria, polydipsia, polyphagia) are present
    • 2-hour glucose measurement of at least 200 mg/dL (11.1 mmol/L) from an oral glucose tolerance test
    • Hemoglobin A1C measurement of at least 6.5%
  • Confirmation of the diagnosis requires 2 of the above abnormal test results unless accompanied by a clear clinical diagnosis of hyperglycemia r4
  • Condition of prediabetes is met with 1 or both of the following states, or with hemoglobin A1C testing: r4
    • Impaired fasting glucose level: fasting glucose value of 100 to 125 mg/dL (5.6-6.9 mmol/L)
    • Impaired glucose tolerance: 2-hour post–oral glucose tolerance test value of 140 to 199 mg/dL (7.8-11 mmol/L)
    • Hemoglobin A1C level: 5.7% to 6.4%
  • Additional clinical or laboratory tests to assess comorbidities and complications at time of diagnosis
    • Measure blood pressure, comprehensive metabolic panel (includes electrolytes, renal and liver function), fasting lipid panel, and assessment of urinary albumin excretion r9
    • Refer for baseline dilated eye examination r10
    • Obtain resting ECG in patients with hypertension or suspected cardiovascular disease r11
    • Assess osteoporosis risk factors and obtain fracture history in older patients with diabetes and recommend measurement of bone mineral density if appropriate for the patient's age and sex r9
    • Refer patients with symptoms suggestive of obstructive sleep apnea (eg, excessive daytime sleepiness, snoring, witnessed apnea) for screening of sleep apnea r12
    • Consider measurement of early morning serum testosterone level in men with diabetes and signs and symptoms of hypogonadism (eg, decreased libido, erectile dysfunction) r9
    • Encourage regular visits to the dentist to screen for and treat periodontal disease r13r14

Laboratory c81c82

  • Fasting glucose measurement r4c83
    • Fasting requires no caloric intake for at least 8 hours; in absence of unequivocal hyperglycemia, repeated testing is required to confirm
    • Diagnostic thresholds are as follows:
      • Fasting glucose reference range: less than 100 mg/dL (less than 5.6 mmol/L)
      • Impaired fasting glucose level: 100 to 125 mg/dL (5.6-6.9 mmol/L)
      • Diabetes mellitus: 126 mg/dL (7 mmol/L) or higher
        • In absence of unequivocal hyperglycemia, another abnormal test result from either the same specimen or a separate specimen is required to confirm diagnosis r4
  • Random glucose measurement r4c84
    • Diagnostic threshold is 200 mg/dL (11.1 mmol/L) or higher when signs or symptoms of hyperglycemia are present
    • In absence of unequivocal signs or symptoms of hyperglycemia, repeated testing is required to confirm
  • Oral glucose tolerance test r4c85
    • Performed 2 hours after oral ingestion of 75 g of glucose dissolved in water
    • Diagnostic threshold for 2-hour glucose measurements:
      • Glucose tolerance reference range: less than 140 mg/dL (less than 7.8 mmol/L)
      • Impaired glucose tolerance level: 140 to 199 mg/dL (7.8-11.1 mmol/L)
      • Diabetes mellitus: 200 mg/dL (11.1 mmol/L) or higher
        • In absence of unequivocal hyperglycemia, another abnormal test result from either the same specimen or a separate specimen is required to confirm diagnosis r4
  • Hemoglobin A1C level r4c86
    • Diagnostic threshold
      • Diabetes mellitus: 6.5% or greater
        • In absence of unequivocal hyperglycemia, another abnormal test result from either the same specimen or a separate specimen is required to confirm diagnosis
      • Prediabetes: suggested by 5.7% to 6.4% (requires confirmatory fasting plasma glucose measurement or oral glucose tolerance test for definitive diagnosis)
    • Accuracy is reduced in certain conditions r4
      • Hemoglobinopathies (eg, sickle cell anemia, thalassemias, spherocytosis)
      • Iron deficiency
      • Hemolytic anemia
      • Chronic kidney disease
      • Severe hepatic disease
      • Severe renal disease
      • HIV treated with certain medications
      • Pregnancy and postpartum period
      • Erythropoietin therapy
      • Recent blood loss or transfusion
    • Less accurate in Black patients (hemoglobin A1C measurement is higher than in White patients despite similar glucose levels) r15
  • Pancreatic autoantibodies test r4c87
    • Aids in classification when uncertainty exists about type 1 versus type 2 diabetes but not routinely indicated for most patients
    • Autoantibodies include those against insulin, glutamic acid decarboxylase 2, certain islet cell antigens, zinc transporter 8, and protein tyrosine phosphatase receptor type N
    • Results are negative in most patients with type 2 diabetes
  • C-peptide level c88
    • Normal or elevated C-peptide level is usually indicative of type 2 diabetes, whereas a frankly low or completely absent C-peptide level is indicative of type 1 diabetes r16
    • Can be low in the setting of glucotoxicity; may be most helpful when delayed until several months after metabolic control has been established
  • Additional laboratory tests recommended at diagnosis to screen for associated diseases and complications include: r9
    • Fasting lipid panel c89
    • Renal function tests for nephropathy c90
      • Estimated GFR c91
      • Urine albumin to creatinine ratio c92
    • Liver function tests c93

Differential Diagnosis

Most common

  • Type 1 diabetes c94d1
    • Often presents overtly rather than through screening, with moderate to severe hyperglycemia and accompanying symptoms of polyuria, polydipsia, polyphagia, and unexplained weight loss
    • Typically (although not always) distinguished by younger age at onset (younger than 40 years), BMI within reference range, and history of ketoacidosis r17
    • Diagnosis is confirmed by positive pancreatic autoantibodies (against insulin, glutamic acid decarboxylase 2, certain islet cell antigens, zinc transporter 8, and protein tyrosine phosphatase receptor type N)
  • Diabetes insipidus c95d2
    • Spectrum of diseases that display hypotonic polyuria and inability to concentrate urine owing to inadequate secretion of or impaired renal responsiveness to arginine vasopressin
    • Presenting symptoms of polyuria, polydipsia, and nocturia overlap with those of diabetes mellitus when the latter is associated with symptomatic hyperglycemia
    • Diagnosis of diabetes insipidus is suggested by 24-hour urine volume more than 3 Lr18 and low urinary osmolality; a definitive diagnosis requires a water deprivation test
    • Most easily differentiated from diabetes mellitus on the basis of laboratory testing (ie, plasma glucose level, oral glucose tolerance test, or hemoglobin A1C level)
  • Monogenic diabetes/maturity-onset diabetes of youth r19r20c96
    • Autosomal dominant disorders that cause β-cell dysfunction and impaired insulin secretion, with onset of hyperglycemia at young age (younger than 25 years)
    • Features include young age at presentation and strong family history of diabetes, without typical features of type 2 diabetes (eg, nonobese, low-risk ethnic group)
    • Other clinical situations that may suggest monogenic diabetes include: r21
      • Mild fasting hyperglycemia that is stable and easy to control over the long-term
      • Gestational diabetes in women without typical risk factors
      • BMI is within reference range at onset without ketosis or pancreatic antibodies
      • Unusual sensitivity to low-dose sulfonylureas or meglitinides
    • Can be formally differentiated from type 2 diabetes by genetic testing, most commonly with identification of mutations in HNF1A gene (HNF1 homeobox A) or GCK gene (glucokinase) r22
  • Medication-induced diabetes r23c97
    • Drugs promoting hyperglycemia may also induce type 2 diabetes in a genetically susceptible person r24
    • Common triggers include glucocorticoids, thiazide diuretics, atypical antipsychotics, statins, and calcineurin inhibitors
    • Identified by temporal association of hyperglycemia that develops after the inciting drug is used
    • Resolution of hyperglycemia after discontinuation of the introduced medication confirms medication-induced diabetes; however, when it is not practical to discontinue the medication, hyperglycemia is treated with pharmacotherapy as needed
  • Endocrinopathies
    • Some rare neuroendocrine tumors secrete or cause the secretion of hormones that antagonize insulin action or reduce insulin secretion, leading to hyperglycemia c98
    • Cushing syndrome, acromegaly, glucagonoma, and pheochromocytomas are associated with glucose intolerance, and a subset of people with such conditions develop overt type 2 diabetes during the course of the disease c99c100c101c102

Treatment

Goals

  • Aim for optimal glycemic control
    • Glycemic targets differ among professional organizations; however, all organizations agree that target goals should be individualized r25
      • Take into account the following factors: life expectancy, disease duration, presence or absence of micro- and macrovascular complications, cardiovascular risk factors, comorbid conditions, and risk for hypoglycemia r25r26r27
      • For recent-onset type 2 diabetes mellitus in nonpregnant women without cardiovascular disease, normal (or near normal) glycemia is the goal to prevent or delay the progression of micro- and macrovascular complications
    • Hemoglobin A1C targets
      • For most nonpregnant adults, a target hemoglobin A1C of less than 7% is reasonable (American Diabetes Association) r28
      • More stringent target of less than 6.5% is suggested for selected patients if this can be achieved without significant hypoglycemia (American Diabetes Association, American Association of Clinical Endocrinologists, National Institute for Health and Care Excellence). These selected patients include those with: r26r28r29r30
        • Short duration of diabetes
        • Type 2 diabetes treated with lifestyle modifications or metformin only
        • Long life expectancy
        • No significant cardiovascular disease
      • Less stringent hemoglobin A1C goals (eg, less than 8%) are appropriate for selected patients with: r28r31
        • History of severe hypoglycemia
        • Limited life expectancy
        • Advanced microvascular or macrovascular complications
        • Extensive comorbid conditions (including renal and liver failure)
        • Long-standing diabetes in which glycemic goal is difficult to attain
    • Self-monitoring of blood glucose level: targets
      • Fasting plasma glucose target of 80 to 130 mg/dL (American Diabetes Association)r28 or less than 110 mg/dL (American Association of Clinical Endocrinologists)r32
      • 2-hour postprandial glucose target of less than 180 mg/dL (American Diabetes Association)r28 or less than 140 mg/dL (American Association of Clinical Endocrinologists)r32
    • Ambulatory glucose profile targets (continuous glucose monitoring)
      • Greater than 70% of time in range 70 to 180 mg/dL r28r33
    • Inpatient glucose targets vary by setting
      • A glucose target between 140 and 180 mg/dL is recommended for most critically and noncritically ill patients r34
      • Glucose target between 110 and 140 mg/dL may be appropriate for selected individual patients (eg, those who have undergone cardiac surgery or have history of stroke or acute ischemic cardiac events) provided that the targets can be achieved without significant hypoglycemia r34
  • Control cardiovascular risk factors
    • Blood pressure goals
      • American College of Cardiology/American Heart Association guidelines recommend blood pressure target of lower than 130/80 mm Hg for patients with or without diabetes r35
      • American Diabetes Association recommends blood pressure target of lower than 140/90 mm Hg for patients with a 10-year atherosclerotic cardiovascular disease risk of less than 15%; lower target of 130/80 mm Hg may be appropriate for certain people (eg, younger patients, patients with albuminuria, patients with existing atherosclerotic cardiovascular disease or a 10-year atherosclerotic cardiovascular disease risk of 15% or higher) if they can be safely achieved r36
        • Less aggressive goals may be considered for patients who are older, have functional limitations, take multiple medications (polypharmacy), and have multiple comorbidities
        • During pregnancy, blood pressure goals of less than 135/85 mm Hg are recommended to optimize maternal health and minimize fetal harm r36
      • American Association of Clinical Endocrinologists recommends an individualized target but states that blood pressure should be approximately 130/80 mm Hg; a more intensive goal (eg, lower than 120/80 mm Hg) can be considered if this target can be reached safely without adverse effects from medication r26
      • Uncertainty exists regarding optimal blood pressure targets for patients with hypertension and type 2 diabetes
        • Some evidence suggests that tight blood pressure control may be favorable for reducing cardiovascular events and stroke r37
        • Other evidence suggests that the benefits of blood pressure reduction in decreasing cardiovascular events plateau after attainment of a lower systolic blood pressure of 140 mm Hg,r38 and some evidence suggests that lowering systolic blood pressure below 140 mm Hg is associated with an increased risk of cardiovascular deathr39
      • Individualization of blood pressure targets is emphasized in all guidelines, with consideration of other factors such as age and presence of kidney disease and/or coronary artery disease
    • Lipid goals
      • American Diabetes Association and American Heart Association do not specify a numeric LDL-C goal, but they comment that epidemiologic evidence suggests that an LDL-C level higher than 100 mg/dL is associated with increased cardiovascular disease risk r36r40r41
      • American Association of Clinical Endocrinologists does specify numeric LDL-C goals according to degree of atherosclerotic cardiovascular disease risk r26r42
        • High risk: for patients with diabetes and no atherosclerotic cardiovascular disease or major cardiovascular risk factors, LDL-C goal is less than 100 mg/dL and non–HDL-C goal is less than 130 mg/dL
        • Very high risk: for patients with diabetes and at least 1 additional major atherosclerotic cardiovascular disease risk factor (eg, hypertension, family history, low HDL-C level, smoking), LDL-C goal is less than 70 mg/dL and non–HDL-C goal is less than 100 mg/dL
        • Extreme risk: patients with diabetes and a prior atherosclerotic cardiovascular disease event or chronic kidney disease stage 3 or 4: LDL-C goal is less than 55 mg/dL and non–HDL-C goal is less than 80 mg/dL

Disposition

Admission criteria r43

DKA r44d3

  • Plasma glucose level greater than 250 mg/dL
  • Arterial pH less than 7.3
  • Serum bicarbonate level less than 15 mEq/L
  • Moderate ketonuria and/or ketonemia
  • Volume depletion
  • Acute kidney injury

Hyperglycemic hyperosmolar state r45

  • Plasma glucose level greater than 600 mg/dL
  • Elevated serum osmolality greater than 320 mmol/kg
  • Altered mental status

Hypoglycemia with neuroglycopenia r43

  • Blood glucose level less than 50 mg/dL refractory to treatment
  • Coma, seizures, or altered behavior due to hypoglycemia

Uncontrolled diabetes r43

  • Hyperglycemia with volume depletion
  • Persistent hyperglycemia associated with metabolic deterioration
  • Hemoglobin A1C level that is 100% or more above upper reference limit
  • Recurrent fasting plasma glucose level greater than 300 mg/dL, refractory to outpatient treatment
  • Frequent episodes of hypoglycemia with blood glucose level less than 50 mg/dL, refractory to outpatient treatment
  • Metabolic instability as evidenced by frequent swings between fasting hyperglycemia and hypoglycemia
  • Recurrent DKA not precipitated by infection or injury
  • Severe psychosocial issues causing uncontrolled metabolic function that cannot be managed in the community
Criteria for ICU admission
  • Critical illness and mental obtundation with DKA or hyperosmolar hyperglycemic state; continuous IV insulin is the standard of care r46
  • Need for IV insulin infusion, such as in DKA, very poorly controlled diabetes despite subcutaneous insulin (blood glucose level greater than 350 mg/dL for more than 12 hours), or total parenteral nutrition r47

Recommendations for specialist referral

  • Certified diabetes educator for diabetes self-management education and ongoing support
  • Registered dietitian for medical nutrition therapy
  • Ophthalmologist for dilated eye examination
  • Endocrinologist for uncertain diagnosis, teaching and supervising insulin therapy, treatment of labile glycemia (eg, recurrent hypoglycemia, persistent hyperglycemia, ketoacidosis), or when the complexity of care exceeds the capacity of the primary care setting r6
  • Nephrologist for persistent proteinuria, decreased GFR, labile blood pressure, or hyperkalemia
  • Cardiologist for associated cardiovascular disease management
  • Podiatrist for orthotic footwear and prevention or treatment of diabetic foot ulcers
  • Dentist for periodontal examination
  • Mental health specialist for depression, self-harm, blatant disregard for self-care, severe anxiety, diabetes-related distress, or cognitive impairment

Treatment Options

Comprehensive diabetes management encompasses several components, including therapeutic lifestyle changes, pharmacotherapy, glucose monitoring, diabetes education, and strategies to reduce cardiovascular risk factors

All patients should engage in lifestyle modifications directed at weight loss and increased physical activity r48r49

  • Such interventions improve measures of glycemia and cardiovascular risk factors and reduce the need for medications in established type 2 diabetes

General guidance on pharmacologic therapy

  • Professional societies have proposed guidelines and treatment algorithmsr49r50r27 to assist with drug selection
  • Metformin is the consensus first line drug of choice, provided that no contraindications exist r1r49
    • Start at time of diagnosis, provided that no contraindications exist
  • If hemoglobin A1C level is 1.5 percentage points or more above target, combination therapy with 2 antihyperglycemic agents may be required r1r51r52
  • If marked hyperglycemia is present (eg, plasma glucose levels are more than 300-350 mg/dL or hemoglobin A1C level is 10% or more), consider using insulin therapy from the outset (at least temporarily) r27
  • All glucose-lowering medications have advantages and disadvantages that require consideration, both within and between classes, including factors such as: r27r49
    • Efficacy (ability to lower hemoglobin A1C level to less than 7% or absolute reduction in hemoglobin A1C level)
    • Macrovascular and/or microvascular disease risk reduction
    • Durability
    • Safety and adverse effects (particularly with respect to hypoglycemia, renal effects, and effect on body weight)
    • Tolerability
    • Patient acceptance (particularly with respect to route of administration and dosing schedules)
  • Clinicians are encouraged to evaluate and compare the categories of antihyperglycemic agents using the patient-oriented STEPS criteria (safety, tolerability, effectiveness, price, and simplicity of use) r53

Antihyperglycemic medications

  • Monotherapy: metformin is drug of choice r1r26r49
    • Guidelines and experts universally agree that metformin is the preferred first line agent in the absence of contraindications or intolerance
    • Alternative first line therapies include 1 of 6 options: sulfonylurea, thiazolidinedione, dipeptidyl-peptidase IV inhibitor, glucagon-like peptide 1 receptor agonist, sodium-glucose cotransporter 2 inhibitor, or basal insulin r27
    • Less commonly used classes of drugs (eg, α-glucosidase inhibitors, bile acid sequestrants [colesevelam], dopamine agonists [bromocriptine]) can be considered, but these agents have very modest glucose-lowering effects and more bothersome adverse effects
  • Dual therapy: add second oral or noninsulin injectable if hemoglobin A1C target is not achieved or maintained over 3 months of monotherapy r1
    • After metformin, there is no universally accepted protocol, in part because of a lack of comparative outcome data among the various classes of glucose-lowering medications available to guide choice of drugs
      • Several potential sequences of escalating medications are available, but usually this regimen includes metformin plus another agent
      • On average, addition of any second agent is typically associated with a reduction in hemoglobin A1C level of approximately 0.7% to 1% r1r54
      • Until comparative datar55 become available, individualization of therapy is encouraged, based on drug-specific effects and patient factors
    • For patients without atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, consider a combination of metformin and any 1 of the preferred 6 treatment options: sulfonylurea, thiazolidinedione, dipeptidyl-peptidase IV inhibitor, glucagon-like peptide 1 receptor agonist, sodium-glucose cotransporter 2 inhibitor, or basal insulin r1r56
    • For a patient with atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, or high risk for atherosclerotic cardiovascular disease, recommended to use drug proven to reduce major cardiovascular events, cardiovascular mortality, or both r1r57r58
      • For patients older than 18 years with atherosclerotic cardiovascular disease, heart failure, chronic kidney disease, or high risk for atherosclerotic cardiovascular disease, use a sodium-glucose cotransporter 2 inhibitor r56r57r59
        • Empagliflozin, canagliflozin, or dapagliflozin are appropriate
          • Sotagliflozin also resulted in a lower risk of cardiovascular mortality and heart failure exacerbations in patients with diabetes and chronic kidney disease r60r61
          • Ertugliflozin reduced hospitalization for heart failure but did not significantly reduce major cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) r62
      • For patients older than 18 years with atherosclerotic cardiovascular disease or high risk for atherosclerotic cardiovascular disease, use a glucagon-like peptide 1 receptor agonist r57
        • Dulaglutide, liraglutide, or semaglutide are appropriate
    • Insulin therapy by injection or insulin pump, with or without other agents; may be used either alone or in combination at any point in therapy r63
  • Triple therapy: add third oral or noninsulin injectable if hemoglobin A1C target is not achieved after about 3 months of dual therapy (usually this regimen includes metformin plus 2 other agents from separate drug classes) r6r54
    • Addition of a third agent enhances treatment efficacy but to a lesser extent than when the agent is used first or second line r1
    • Patients who are already taking 2 oral antihyperglycemic agents and have hemoglobin A1C level greater than 9% and symptomatic hyperglycemia would likely benefit more from the addition of insulin rather than a third noninsulin agent r26
  • Insulin therapy r64
    • Treatment with insulin becomes necessary if therapy with 2 or more oral agents or noninsulin injectable drugs fails to maintain adequate glycemic control
      • Other indications for insulin include severe hyperglycemia (as indicated by fasting plasma glucose levels higher than 250 mg/dL), hemoglobin A1C levels higher than 10%, or symptoms of hyperglycemia
    • Aim is to create a near normal glycemic profile while minimizing weight gain and avoiding hypoglycemia
    • As initial therapy, the addition of once daily basal insulin is often sufficient unless the patient is markedly hyperglycemic and/or symptomatic; it also provides relatively uniform coverage over a 24-hour period
    • Many oral or other injectable agents may be continued, provided that contraindications have not developed
      • Combination of metformin and basal insulin is commonly used, as data show reduced weight gain when the 2 drugs are used simultaneously
      • Combination of a glucagon-like peptide 1 receptor agonist and basal insulin is another option, forestalling the need for prandial insulin dosing r65
      • Discontinue insulin secretagogues (eg, sulfonylureas, meglitinides) either at time of starting basal insulin (optional) or after start of prandial insulin regimens r27
    • After start of basal insulin, further therapy can consist of addition of either a glucagon-like peptide 1 receptor agonist (if not already started) or prandial insulin (in incremental doses)
      • Postprandial glucose levels contribute more to overall glycemic control than fasting blood glucose levels with lower hemoglobin A1C levels; therefore, adding prandial insulin is more effective than simply increasing basal insulin doses further
      • Adding rapid-acting analogues to reduce postprandial glucose levels lowers hemoglobin A1C levels with less weight gain and less hypoglycemia, compared with increasing basal insulin doses
      • Addition of a daily glucagon-like peptide 1 receptor agonist to basal insulin improves glycemia and has the advantage of limiting weight gain that often occurs with insulin r65r66

Self-monitoring of blood glucose level r67

  • Provides a profile of daily glycemic fluctuations that reflect meals, physical activity, and actions of specific insulin components
  • Usually performed with a glucometer in patients with type 2 diabetes; continuous glucose monitoring is reserved for unusual cases in which insulin-treated patients experience severe nocturnal hypoglycemia or hypoglycemia unawareness

Bariatric surgery

  • Bariatric surgery is highly effective for attaining significant and durable weight loss in obesity; it is a treatment option that improves glycemia and reduces cardiovascular risk factors for patients with type 2 diabetes who are unable to achieve lasting weight loss and improvement in glycemia with nonsurgical measures r68
    • Rate of resolution for diabetes (defined as becoming nondiabetic with normal hemoglobin A1C level without medications) after bariatric surgery is approximately 78% r69
    • Compared with nonsurgical treatment of obesity, bariatric surgery leads to greater weight loss, greater improvement in cardiovascular risk factors (eg, dyslipidemia, hypertension), and higher remission rates of type 2 diabetes r70

Management of comorbidities

  • Treatment of hypertension and dyslipidemia is as important as treatment of glycemia in type 2 diabetes, to reduce the risk of complications r71r72
    • ACE inhibitors and angiotensin receptor blockers are recommended for treatment of hypertension and diabetic nephropathy
    • Statins are recommended as first line therapy for treatment of dyslipidemia in most patients with type 2 diabetes

Drug therapy

  • Oral agents
    • Metformin c103
      • First line monotherapy for most patients with diabetes; may be continued as other agents are added
        • Recent revised FDA labeling permits use in patients with renal impairment, based on safety and mortality data as used in patients with chronic kidney disease, congestive heart failure, and chronic liver disease
        • Before starting, estimated GFR should be greater than 45 mL/minute/1.73 m²; patient may remain on metformin until estimated GFR falls to 30 mL/minute/1.73 m², when it must be stopped
      • Decreases hepatic glucose production and increases glucose uptake in muscle tissue; may benefit cardiovascular healthr73
      • Low risk for hypoglycemia with long-lasting antihyperglycemic effect
      • May cause gastrointestinal adverse effects (eg, cramping, diarrhea) and vitamin B₁₂ deficiency
      • Comparison with other oral drugs r49
        • Metformin reduces weight to a greater extent than all agents except the sodium-glucose cotransporter 2 inhibitors
      • Metformin Hydrochloride Oral tablet; Adults: Initially, 500 mg PO twice daily or 850 mg PO once daily, given with meals. If patient 80 years or older, do not initiate unless normal renal function documented. May increase by 500 mg/week or 850 mg every 2 weeks or from 500 mg PO twice daily to 850 mg PO twice daily after 2 weeks. Doses above 2,000 mg/day are better tolerated if divided and given 3 times/day with meals. Adult Max: 2,550 mg/day PO. There is modest additional A1C benefit with doses more than 2,000 mg/day; consider tolerance/benefit. For geriatric adults, use caution with doses higher than 1,000 mg/day.
      • Metformin Hydrochloride Oral tablet, extended-release; Adults: USUAL DOSE: 500 mg PO once daily with the evening meal. May increase by 500 mg every week as needed. Max; 2,000 mg PO once daily, or if glycemic control not achieved, consider 1,000 mg PO twice daily.
    • Sulfonylureas c104
      • Stimulate insulin secretion
      • May cause weight gain and/or hypoglycemia, especially with concurrent renal insufficiency; may lose efficacy after several years of treatment
      • Retrospective data suggest a possible cardiovascular risk with use of this class of drugs, compared with metformin r74
      • Glimepiride c105
        • Glimepiride Oral tablet; Adults: Initially, 1 mg or 2 mg PO once daily with breakfast or the first main meal of the day. Use 1 mg PO once daily in those with risk factors for hypoglycemia, such as the elderly. After achieving a dose of 2 mg/day, titrate by 1 mg or 2 mg/day no more frequently than every 1 to 2 weeks. Usual dose range: 1 to 4 mg PO once daily. Max: 8 mg/day PO.
      • Glipizide c106
        • Glipizide Oral tablet; Adults: Initially, 5 mg PO once daily given 30 minutes before breakfast. Geriatric patients or those at risk for hypoglycemia may be started on 2.5 mg/day. Adjust in increments of 2.5 to 5 mg. Several days should elapse between dosage adjustments. Usual maintenance dose: 10 to 15 mg PO once daily. Max once daily dose: 15 mg PO once daily. Some patients may have better response with twice daily dosing. Daily doses more than 30 mg/day should be divided into 2 doses. Max: 40 mg/day, given in divided doses.
      • Glyburide c107
        • Glyburide Oral tablet; Adults: Initially, 2.5 to 5 mg PO once daily with breakfast or the first main meal of the day. In the geriatric adult or those predisposed to hypoglycemia, consider an initial dose of 1.25 mg PO once daily. Titrate the daily dose by no more than 2.5 mg per week based on the blood glucose response. Usual range: 1.25 to 20 mg/day PO, given in single or divided doses. For some patients, particularly those taking more than 10 mg/day, better glucose control may be achieved with twice daily dosing. Max: 20 mg/day PO, in single or divided doses. If converting from insulin or another antidiabetic agent, consult the manufacturer's recommendations.
    • Dipeptidyl-peptidase IV inhibitors c108
      • Increase glucose-dependent insulin secretion and decrease glucagon secretion
      • Comparison with other oral agents r49
        • Favored over sulfonylureas for long-term all-cause mortality, long-term cardiovascular mortality, and cardiovascular morbidity
        • Favored over pioglitazone for short-term cardiovascular morbidity
        • Favored over sulfonylureas or thiazolidinediones for weight control
        • Inferior to metformin and sulfonylureas for hemoglobin A1C reduction
      • Dose adjustment is needed for patients with chronic kidney disease (except linagliptin)
      • Neutral effect on cardiovascular risk, but increased risk of hospitalization for heart failure; use with caution in patients with concurrent heart failure r71
      • May cause upper respiratory tract infections, pancreatitis, or immune-related dermatologic effects (eg, angioedema, urticaria)
      • Alogliptin c109
        • Alogliptin Oral tablet; Adults: 25 mg PO once daily is the usual daily dose. If used with sulfonylurea or insulin, a lower sulfonylurea or insulin dose may be needed to decrease risk for hypoglycemia.
      • Linagliptin c110
        • Linagliptin Oral tablet; Adults: 5 mg PO once daily. Used as monotherapy or in combination with other drugs used to treat type 2 diabetes mellitus, with the exception of GLP-1 agonists. When used with a sulfonylurea or insulin, a lower dose of the sulfonylurea or insulin may be necessary to minimize the risk of hypoglycemia.
      • Sitagliptin c111
        • Sitagliptin Phosphate Oral tablet; Adults: 100 mg PO once daily. May use as monotherapy or in combination with other hypoglycemic agents including insulin, but not GLP-1 agonists. If used with sulfonylurea or insulin, a lower sulfonylurea or insulin dose may be needed to decrease hypoglycemia.
      • Saxagliptin c112
        • Saxagliptin Oral tablet; Adults: 2.5 to 5 mg PO once daily; limit to 2.5 mg/day if used with a strong CYP 3A4/5 inhibitor. May use as monotherapy or in combination with other antidiabetic agents, with the exception of GLP-1 agonists. If used with sulfonylurea or insulin, lower doses of these agents may be needed to decrease risk for hypoglycemia.
    • Sodium-glucose cotransporter 2 inhibitors c113
      • Increase urinary excretion of glucose
      • May cause dehydration, hypotension, minimal increases in LDL-C level, weight loss, urinary tract infections, fungal genital tract infections, bone loss, and fractures
      • Clinical benefits in addition to improved glycemic control include reduced risk of hospitalization due to heart failure (in patients with and without existing cardiovascular disease), reduced risk of major cardiovascular events in patients with atherosclerotic cardiovascular disease or chronic kidney disease, and improved renal outcomes in patients with kidney disease r57r75
      • Favored over sulfonylureas as an add-on to metformin therapy in terms of cardiovascular mortality, hemoglobin A1C lowering, weight reduction, systolic blood pressure reduction, and heart rate response r49
      • Canagliflozin c114
        • Canagliflozin Oral tablet; Adults: 100 mg PO once daily in the morning before the first meal of the day. May increase to 300 mg PO once daily for additional glycemic control as long as eGFR is 60 mL/minute/1.73 m2 or more.
      • Dapagliflozin c115
        • Dapagliflozin Oral tablet; Adults: 5 mg PO once daily. May increase dose to 10 mg PO once daily in those who require additional glycemic control.
      • Empagliflozin c116
        • Reduces relative risk of cardiovascular and all-cause mortality to 38% and 32%, respectively r76
        • Slows progression of renal disease in diabetes r77
        • Reduces risk of nonfatal myocardial infarction and heart failure but does not show benefit with stroke r76
        • Empagliflozin Oral tablet; Adults: 10 mg PO once daily in the morning with or without food. May increase to 25 mg PO once daily for additional glycemic control.
      • Ertugliflozin c117
        • Ertugliflozin Oral tablet; Adults: 5 mg PO once daily, taken in the morning, with or without food. May increase in patients who require additional glycemic control, if tolerated. Max: 15 mg PO once daily.
      • Sotagliflozin
    • Meglitinides c118
      • Increase insulin secretion, similar to sulfonylureas
      • May cause hypoglycemia or weight gain
      • Nateglinide c119
        • Nateglinide Oral tablet; Adults: 120 mg PO 3 times daily given within 30 minutes before each meal. If patients are near their goal A1C at treatment initiation, 60 mg PO 3 times daily before meals may be used.
      • Repaglinide c120
        • Repaglinide Oral tablet; Adults: If A1C less than 8%, start with 0.5 mg PO given within 30 minutes prior to each meal, 2, 3, or 4 times a day. If A1C is greater than 8%, start with 1 or 2 mg PO within 30 minutes prior to each meal, 2, 3, or 4 times a day. May titrate by doubling the dose until satisfactory blood glucose levels are achieved; do not exceed 4 mg/dose. Allow at least 1 week to elapse between dose adjustments. Max: 16 mg/day PO, not to exceed 4 mg/dose.
    • Thiazolidinediones c121
      • Increase glucose uptake by fat and muscle tissue and decrease hepatic glucose production
      • Useful in patients with nonalcoholic steatohepatitis
      • May benefit some aspects of cardiovascular health and improve lipid profile, but incidence of heart failure is increased r78r79
      • Safe in patients with renal insufficiency and renal failure
      • May cause weight gain, fluid retention, peripheral edema, bone loss, and fractures
      • Contraindicated in New York Heart Association class 3 and 4 heart failure
      • Whether pioglitazone increases risk of bladder cancer is controversial r80
      • Pioglitazone c122
        • Pioglitazone Hydrochloride Oral tablet; Adults: Initially, 15 mg or 30 mg PO once daily. For an inadequate response, increase by 15 mg increments as needed. Max: 45 mg/day PO. Consider combination therapy for inadequate response to monotherapy. PATIENTS RECEIVING POTENT INHIBITORS OF CYP2C8 (e.g., gemfibrozil): Max pioglitazone dose is 15 mg/day PO. ADDING TO METFORMIN: The current metformin dose can be continued. ADDING TO A SULFONYLUREA: The current sulfonylurea dose can be continued. Decrease sulfonylurea dose if the patient reports hypoglycemia.
      • Rosiglitazone c123
        • Rosiglitazone Maleate Oral tablet; Adults: 4 mg/day PO once daily or divided bid. After 12 weeks, may titrate up to 8 mg/day.
    • Bile acid sequestrant r81c124
      • May work by decreasing hepatic glucose production and increasing incretin levels
      • Lowers LDL-C level
      • May cause constipation
      • Colesevelam hydrochloride c125
        • Colesevelam Hydrochloride Oral tablet; Adults: 3 tabs PO twice daily or 6 tabs PO once daily. Administer with liquid and a meal.
    • α-glucosidase inhibitors c126
      • Slows carbohydrate digestion and absorption from the intestines; may improve cardiovascular health
      • May cause gastrointestinal adverse effects (eg, flatulence, diarrhea)
      • Acarbose c127
        • Acarbose Oral tablet; Adults weighing more than 60 kg: Initially, 25 mg PO 3 times daily with first bite of each main meal; may increase to 50 mg 3 times daily after 4 to 8 weeks. Usual maintenance dose: 50 to 100 mg 3 times daily. Max: 100 mg PO 3 times daily.
      • Miglitol c128
        • Miglitol Oral tablet; Adults: Initially, 25 mg PO 3 times daily given with the first bite of each main meal. After 4 to 8 weeks, the dose may be increased to 50 mg PO 3 times daily and maintained for 3 months; this is the usual maintenance dose for most patients. If at 3 months the A1C level is not satisfactory, the dose may be further titrated to 100 mg PO 3 times daily. Max: 300 mg/day PO.
    • Dopamine 2 agonist c129
      • Activates dopaminergic receptors; may improve cardiovascular health
      • May cause nausea, orthostatic hypotension, fatigue, or rhinitis
      • Contraindicated in patients taking antipsychotic medications
      • Bromocriptine mesylate c130
        • Bromocriptine Mesylate Oral tablet [Diabetic Therapy]; Adults: Initially, 0.8 mg PO once daily in the morning within 2 hours of waking (with food); titrate by 0.8 mg/day weekly to the maximum tolerated dose within the usual dose range. Usual dose range: 1.6 mg to 4.8 mg/day PO. Max: 4.8 mg/day PO. Limit dose to 1.6 mg/day PO during concomitant use of a moderate CYP3A4 inhibitor (e.g., erythromycin). Avoid potent CYP3A4 inhibitors during use.
  • Noninsulin injectables
    • Glucagon-like peptide 1 receptor agonists c131
      • Increase glucose-dependent insulin secretion, decrease glucagon secretion, slow gastric emptying, and increase satiety
      • Frequently cause gastrointestinal adverse effects (eg, nausea, vomiting, diarrhea) and weight loss
      • Use with caution in patients with a history of pancreatitis; discontinue if pancreatitis develops
      • In addition to improved glycemic control, reduces risk of major cardiovascular events in patients with atherosclerotic cardiovascular disease r57
      • Contraindicated in patients with personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia type 2 (except twice daily exenatide)
      • Dulaglutide c132
        • Dulaglutide Solution for injection; Adults: 0.75 mg subcutaneously once weekly (every 7 days), initially. Give at any time of day, with or without meals. May increase to 1.5 mg once weekly if response inadequate. Then, may increase to 3 mg once weekly after at least 4 weeks on the 1.5 mg/week dose if needed. May further increase the dose to 4.5 mg once weekly, after at least 4 weeks on the 3 mg/week dose, if needed for glycemic control. Max: 4.5 mg/week.
      • Exenatide c133
        • Exenatide Solution for injection; Adults: 5 mcg subcutaneously twice daily. May increase after 1 month to 10 mcg subcutaneously twice daily.
        • Contraindicated in patients with creatinine clearance less than 30 mg/mL
        • Exenatide (extended-release)
          • Exenatide Suspension for injection, Extended Release; Adults: 2 mg subcutaneously once every 7 days (once weekly).
          • Contraindicated in patients with creatinine clearance less than 30 mg/mL
      • Liraglutide c134
        • Use of liraglutide is associated with reduced risk of death due to cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in patients at elevated cardiovascular risk r82
        • Liraglutide Solution for injection; Adults: Initially, 0.6 mg subcutaneously once daily for 1 week to reduce GI symptoms; must titrate to a higher dose for glycemic control. Then, increase to 1.2 mg subcutaneously once daily. If inadequate response, increase to 1.8 mg subcutaneously once daily. For a missed dose, resume with the next scheduled dose; do not take double or extra doses. If more than 3 days have elapsed since the last dose, reinitiate at 0.6 mg once daily and retitrate.
      • Lixisenatide c135
        • Lixisenatide Solution for injection; Adults: Initially, 10 mcg subcutaneously once daily within 1 hour before the morning meal. If a dose is missed, administer within 1 hour prior to the next meal. Continue 10 mcg once daily for 14 days. Starting on day 15, increase the dose to the maintenance dose of 20 mcg subcutaneously once daily.
      • Semaglutide c136
        • Semaglutide Solution for injection; Adults: Initially, 0.25 mg subcutaneously once every 7 days (weekly) at any time of day, with or without meals. Must titrate for effective glycemic control. After 4 weeks, increase to 0.5 mg subcutaneously once weekly. If needed, may increase again after 4 weeks. Max: 1 mg/week subcutaneously.
    • Amylin mimetic/analogue c137
      • Decreases glucagon secretion, slows gastric emptying, and increases satiety
      • May cause gastrointestinal adverse effects (eg, nausea, vomiting) and weight loss
      • Pramlintide c138
        • Pramlintide Acetate Solution for injection; Adults: 60 mcg subcutaneously immediately before meals (at least 250 kcal or 30 grams of carbohydrates); if no nausea has occurred for at least 3 days, increase to 120 mcg/dose pre-meals subcutaneously. Max: 120 mcg/dose. If nausea or vomiting persists at 120 mcg/dose, decrease to 60 mcg/dose. Reduce pre-prandial, rapid- or short-acting insulin, or fixed-mix insulin dose by 50% when pramlintide is initiated. Once at a maintenance dose of pramlintide, adjust insulin to achieve optimal glycemic control.
    • Other injectables for type 2 diabetes mellitus.GLP-1, glucagon-like peptide 1; MACE, major adverse cardiovascular events; MEN-2, multiple endocrine neoplasia type 2. * Studied in patients with preexisting atherosclerotic cardiovascular disease.Adapted from Wallia A et al: Insulin therapy for type 2 diabetes. JAMA. 311:2315-25, 2014.
      Drug classHemoglobin A1C–lowering effectHypoglycemia riskCardiovascular effectsEffect on body weightComments
      GLP-1 receptor agonist1%-1.5%NeutralLiraglutide associated with reduction in major adverse cardiovascular events,* myocardial infarction, and reductions in cardiovascular and all-cause mortality; semaglutide associated with reduction in MACE (but not mortality)*LossContraindicated in chronic kidney disease stages 4-5, or in personal or family history of medullary thyroid carcinoma or MEN-2; renal function should be checked at baseline and periodically throughout therapy
      Combined insulin- GLP-1 receptor agonist>1.5%Moderate, due to insulin componentAllows less weight gain (or even promotes minor weight loss) that otherwise occurs with insulinSame contraindications as with GLP-1 receptor agonist; renal function should be checked at baseline and periodically throughout therapy
      Pramlintide0.5%Neutral alone, but increased risk of hypoglycemia when used with insulin (as indicated)Slight loss; may limit weight gain that occurs with use of insulinIndicated for use in conjunction with basal-bolus insulin regimens
  • Insulin c139
    • Overall insulin regimen is highly individualized and based on patient age, duration of diabetes, comorbidities, and risk of hypoglycemia
    • Barriers with insulin
      • Hypoglycemia is the major limiting factor and can occur as a result of multiple issues (eg, decreased caloric intake, delayed meals, mismatches between insulin injections and meals, alcohol intake, exercise, use of other medications, kidney disease)
      • Weight gain is a frequent valid concern; average weight gain after 1 year is approximately 1.75 kg for a person starting insulin r83
    • Selection of basal insulin r84
      • Both isophane insulin suspension and basal insulin analogues are capable of lowering hemoglobin A1C level to a similar extent, but the insulin analogues have the advantages of less frequent and severe hypoglycemia and reduced weight gain, and they provide basal coverage for up to 24 hours or longer with a single injection
      • Basal analogue duration of action (longer to shorter): degludec, longest; glargine, longer; detemir, shorter
    • Initial strategy is to start with a single daily injection of a long-acting basal insulin analogue and add prandial control if necessary (basal-bolus strategy) r64
      • Step 1: start basal insulin analogue (eg, glargine, detemir, degludec) c140c141c142
        • If hemoglobin A1C level is less than 8%, start with 0.1 to 0.2 units/kg/day (or 10 units/day)
        • If hemoglobin A1C level is more than 8%, start with 0.2 to 0.3 units/kg/day
      • Step 2: titrate insulin approximately every 2 to 3 days until glycemic targets are reached (usually fasting blood glucose level is less than 110 mg/dL)
        • If fixed regimen is used, increase by 2 units per day
        • If adjustable regimen is used, titration is based on fasting blood glucose level
          • If fasting blood glucose level is more than 180 mg/dL, add 4 units
          • If fasting blood glucose level is between 140 and 180 mg/dL, add 2 units
          • If fasting blood glucose level is between 110 and 139 mg/dL, add 1 unit
      • Step 3: monitor for hypoglycemia
        • If blood glucose level is less than 70 mg/dL, reduce basal insulin by 10% to 20%
        • If blood glucose level is less than 40 mg/dL, reduce basal insulin by 20% to 40%
      • Insulin Glargine
        • Insulin Glargine Solution for injection; Adults: 10 units or 0.1 to 0.2 units/kg/day subcutaneously once daily in patients not controlled on an oral antidiabetic medicine; increase dosage by 2 units every 3 days until blood glucose goals are achieved. If the patient experiences hypoglycemia, determine the cause, and decrease the corresponding dose by 10% to 20%; the total daily dosage ranges from 1 to 80 units (Toujeo SoloStar) and from 2 to 160 units (Toujeo Max SoloStar). Give the dose at the same time every day, at any time. Patients previously controlled on Lantus, Basaglar, or Semglee will require a higher daily dose of Toujeo to maintain the same level of glycemic control. No dose change is necessary for conversion from once daily NPH insulin. For conversion from twice-daily NPH, reduce the total daily dose of NPH insulin (or other twice daily basal insulin) by 20% and give once daily. Thereafter, adjust to patient response.
      • Insulin Detemir
        • Insulin Detemir (Recombinant) Solution for injection; Adults: 10 units or 0.1 to 0.2 units/kg/day subcutaneously once daily in the evening or divided into a twice daily regimen in patients not controlled on an oral antidiabetic medicine or GLP-1 receptor agonist; increase dosage by 2 units every 3 days until blood glucose goals are achieved. If hypoglycemia occurs, determine the cause, and decrease the corresponding dose by 10% to 20%. In patients established on basal insulin, the same total daily dose of basal insulin is not changed; adjust to response. For once-daily dosing, give at dinnertime or bedtime; for twice-daily dosing, administer every 12 hours or in the morning and dinner/at bedtime. Adjust concurrent rapid- or short-acting insulins or oral hypoglycemics as needed.
      • Insulin Degludec
        • Insulin Degludec Solution for injection; Adults: In adults naive to insulin, initiate with 10 units subcutaneously once daily. Insulin degludec may be given at any time of day; however, doses must be given at least 8 hours apart. Titrate every 3 to 4 days to achieve blood glucose and A1C goals. When transferring from long or intermediate-acting insulin therapy (e.g., NPH insulin, insulin glargine), initiate insulin degludec at the same total daily insulin dose and adjust based on patient response.
    • Intensification of insulin regimens
      • If the basal insulin regimen accomplishes fasting and preprandial blood glucose targets, but hemoglobin A1C level is still above target, modify the insulin regimen to cover postprandial blood glucose excursions using rapid-acting analogues (eg, lispro, aspart, glulisine) c143c144c145c146
      • Various stepwise approaches may be used to start prandial insulin
        • Weight-based, given at each meal r32
          • Calculate total daily dose of insulin: 0.3 to 0.5 units/kg/day
          • Half of the total units are given as basal insulin and half are given as prandial insulin, divided equally among the 3 meals
          • If 2-hour postprandial glucose or preprandial glucose level is greater than 180 mg/dL, increase the prandial dose for the next meal by 10%
          • If hypoglycemia occurs between meals after prandial insulin, the next prandial insulin dose is reduced; if nighttime hypoglycemia occurs, reduce basal insulin or reduce prandial insulin taken before dinner
        • 1 prandial dose added, given before largest meal of day r64
          • Start with an initial dose of 2 to 4 units, increased by 1 to 2 units every 3 days if glucose level at the next meal is not within the goal range (typically 70-130 mg/dL)
            • Single injection of rapid-acting insulin before the main meal improves glucose control r85
            • Daily long-acting basal insulin and a prandial rapid-acting insulin with the largest meal is preferred approach rather than using premixed insulins r64
          • Add prandial doses to the second and third meals at 8- to 12-week intervals if hemoglobin A1C targets are not met
        • Titration of prandial insulin
          • On an ongoing basis, prandial doses can be fixed or can be adjusted for meal size using carbohydrate counting
            • Fixed prandial doses have the advantage of being simple and easier to adhere to; an individualized algorithm can be created to provide guidance on how to adjust doses based on preprandial blood glucose levels r86
            • Doses based on carbohydrate content of meals have the advantage of allowing flexibility with meal content, but this method is more complex
          • Prandial doses may be increased by 1 to 2 units once or twice weekly until targets (which are usually based on the fasting blood glucose level at subsequent meals) are reached r28
          • If hypoglycemia occurs, determine and address the cause
            • If there is no obvious explanation for hypoglycemia, reduce the corresponding dose by 2 to 4 units r1
      • Insulin Lispro
        • Insulin Lispro Solution for injection; Adults: 4 units or 10% of the usual basal dose given subcutaneously once daily before the largest meal of the day as an initial dose. If A1C is less than 8% at the time of insulin lispro initiation, consider reducing the daily basal insulin dose by the same amount. Increase insulin lispro dosage by 1 to 2 units (or 10% to 15%) twice weekly until goals are achieved. If the patient experiences hypoglycemia, determine the cause, and decrease the corresponding dose by 10% to 20%. If goals are not achieved, consider switching to a basal-bolus regimen with 2 or more insulin lispro injections per day given before meals. Administer insulin lispro 15 minutes before or immediately after a meal.
      • Insulin Aspart
        • Insulin Aspart (Recombinant) Solution for injection; Adults: 4 units or 10% of the usual basal dose given subcutaneously once daily before the largest meal of the day as an initial dose. If A1C measurement is less than 8% at the time of insulin aspart initiation, consider reducing the daily basal insulin dose by the same amount. Increase insulin aspart dosage by 1 to 2 units (or 10% to 15%) twice weekly until goals are achieved. If the patient experiences hypoglycemia, determine the cause and decrease the corresponding dose by 10% to 20%. If goals are not achieved, consider switching to a basal-bolus regimen with 2 or more insulin aspart injections per day given before meals. Administer insulin aspart immediately before a meal (i.e., meal starts within 5 to 10 minutes after injection).
      • Insulin Glulisine
        • Insulin Glulisine Solution for injection; Adults: 4 units or 10% of the usual basal dose given subcutaneously once daily before the largest meal of the day as an initial dose. If A1C measurement is less than 8% at the time of insulin glulisine initiation, consider reducing the daily basal insulin dose by the same amount. Increase insulin glulisine dosage by 1 to 2 units (or 10% to 15%) twice weekly until blood glucose goals are achieved. If the patient experiences hypoglycemia, determine the cause, and decrease the corresponding dose by 10% to 20%. If blood glucose goals are not achieved, consider switching to a basal-bolus regimen with 2 or more insulin glulisine injections per day given before meals. Administer insulin glulisine within 15 minutes before or 20 minutes after starting a meal.
    • Alternative options for insulin therapy include short-acting (regular), intermediate-acting (NPH insulin, that is, isophane insulin suspension/neutral protamine Hagedorn), and premixed insulins; these are less expensive but also less effective for postprandial blood glucose excursions r64c147c148
      • Isophane insulin suspension
        • Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Adults: 10 units or 0.1 to 0.2 units/kg/day subcutaneously given once daily in the evening or divided into a twice daily regimen in patients not controlled on an oral antidiabetic medicine; increase dosage by 2 units every 3 days until blood glucose goals are achieved. If hypoglycemia occurs, determine the cause, and decrease the corresponding dose by 10% to 20%. For patients who are initially given bedtime NPH, but are still above A1C target, consider converting to a twice-daily NPH regimen. The conversion is based on individual needs and current glycemic control, but 1 approach is to give 80% of the current bedtime NPH dose. About two-thirds of the daily insulin dose is given in the morning, and about one-third is given at bedtime. Titrate dosage according to blood glucose and A1C goals.
      • Regular insulin
        • Insulin Regular (Recombinant) Solution for injection; Adults: 0.4 to 1 unit/kg/day is the typical total daily insulin requirement. In general, 50% of the daily insulin is given as basal insulin (intermediate-acting or long-acting), usually at night. The other 50% is divided and given as prandial insulin (rapid-acting or short-acting) before a meal. When used for intermittent subcutaneous injection, regular 100 units/mL insulin is typically administered 30 minutes before meals. Regular 500 units/mL insulin has a longer duration of action (up to 24 hours) compared to regular 100 units/mL insulin, and is usually administered 2 to 3 times per day.
      • Premixed insulin (50/50, 70/30, 80/20)
        • Increased rate of hypoglycemia and inferior glycemic control versus basal insulin alone r87
        • Insulin Aspart (Recombinant), Insulin Aspart Protamine (Recombinant) Suspension for injection; Adults: Premixed insulins are generally not recommended in type 1 diabetes. Total daily insulin requirements typically range from 0.4 to 1 units/kg/day. Insulin aspart; insulin aspart protamine is typically administered twice daily within 15 minutes prior to the start of the meal. A common regimen is to initially give about two-thirds of the daily insulin dose before breakfast and about one-third before the evening meal. Adjust dosage as necessary based on the patient's blood glucose concentrations.
        • Insulin Lispro Protamine (NPL), Insulin Lispro Suspension for injection; Adults: Premixed insulins are generally not recommended in type 1 diabetes. Total daily insulin requirements typically range from 0.4 to 1 units/kg/day. Insulin lispro; insulin lispro protamine is typically administered twice daily within 15 minutes prior to the start of the meal. A common regimen is to initially give about two-thirds of the daily insulin dose before breakfast and about one-third before the evening meal. Adjust dosage as necessary based on the patient's blood glucose concentrations.
        • Insulin Regular (Recombinant), Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Adults, Adolescents, and Children: Equipotent to other insulin mixtures; commonly given as 2 injections/day. Insulin requirement range: 0.1 to 2.5 units/kg/day. Most patients require 0.5 to 1.2 units/kg/day. Average initial dose: Type 1 DM, 0.5 to 0.6 units/kg/day; Type 2 DM, 0.2 to 0.6 units/kg/day. Initially, give about 2/3 daily dose before breakfast and 1/3 before evening meal. Administer 30 to 60 minutes before food.
      • Concentrated regular insulin, U-500 (500 units/mL) r88
        • Available form of insulin for those patients requiring more than 200 units/day
        • Total daily dose is given as 2 to 4 injections per day, typically administered 30 to 60 minutes before meals
        • Works as both a basal and a bolus insulin
        • Regular insulin is available in 2 concentrations: 100 units/mL and 500 units/mL. It is essential that clinicians and patients ensure that the correct concentration of regular insulin is used
        • A conversion chart should always be used when administering doses from the Humulin R U-500 vial with U-100 insulin syringes or 1 mL tuberculin syringes; no dose conversion is required with the Humulin R U-500 KwikPen
      • Concentrated long-acting insulin analogues r84
        • Insulin glargine U-300
          • Glargine formulation with smaller injection volume, prolonged insulin activity, and similar efficacy to glargine U-100
          • Available in a prefilled pen calibrated for the higher concentration, so no dose conversion calculations are required
          • Lower rates of nocturnal hypoglycemia compared directly versus insulin glargine U-100 and insulin detemir r89
        • Insulin degludec U-200
          • Degludec formulation with smaller injection volume and similar efficacy to U-100 basal analogues
          • Available in a prefilled pen also calibrated for the higher concentration
          • Similar ability to lower hemoglobin A1C level as glargine with lower rates of hypoglycemia r90
    • Insulin therapy for type 2 diabetes mellitus.Pharmacokinetic properties of various insulin formulations.Adapted from Wallia A et al: Insulin therapy for type 2 diabetes. JAMA. 311:2315-25, 2014.
      Type of insulinNamesTime of action: onset, peak, and duration of effectsComments
      BasalNPHOnset: 2-4 hours
      Peak: 4-10 hours
      Duration: 10-18 hours
      Variable action profile; can mix with rapid-acting insulins
      Basal analogGlargineOnset: 1.5 hours
      Peak: none
      Duration: 24 hours
      Glargine also comes in a concentrated form of U-300
      DetemirOnset: 1-3 hours
      Peak: 6-8 hours
      Duration: 18-20 hours
      Basal analog insulins provide similar hemoglobin A1C levels, better evening glucose levels, and less hypoglycemia compared to NPH
      DegludecOnset: 1 hour
      Peak: 12 hours
      Duration: >42 hours
      Ultra-long-acting, once daily basal analog with peakless activity
      Bolus regularHumulin ROnset: 30 minutes
      Peak: 1.5-3.5 hours
      Duration: 5-7 hours
      Longer duration compared to rapid- acting analogs makes regular insulin useful in gastroparesis
      Bolus rapid-acting analogLispro, aspart, glulisineOnset: 5-15 minutes
      Peak: 0.5-2 hours
      Duration: 3-5 hours
      Rapid-acting analog insulin provides better control of postprandial glucose levels and less hypoglycemia compared with regular insulin; may be taken during or after meals. Lispro also available in U-200
      Pre-mixed insulin (50/50, 70/30, 75/25, 80/20)Humalog 75/25 or 50/50 mix, Novolog 70/30 mix, Novolin 70/30, Humulin 70/30Onset: 5-15 minutes
      Peak: 0.5-2 hours
      Duration: 3-5 hours
      Titration of both basal and prandial must occur simultaneously; compared with use of basal insulin or basal bolus insulin regimens, there is an Increased rate of hypoglycemia with inferior achievement of glycemic goals
      U-500 insulinHumulin R U500Onset: 30 minutes
      Peak: 1.5-3.5 hours
      Duration: 5-7 hours
      Use for insulin-resistant patients who need >200 total units per day, given 3 times per day
  • Fixed-ratio combination of insulin plus glucagon-like peptide 1 receptor agonist
    • Basal insulin/glucagon-like peptide 1 receptor agonist combinations are more potent (in lowering of hemoglobin A1C level) than all comparators, including insulin degludec, insulin glargine, liraglutide, and placebo
      • Major advantage of this combination is its ability to minimize weight gain with insulin therapy; disadvantage is limited dosing flexibility r84
    • Insulin degludec; liraglutide (Xultophy, IDegLira)
      • Formulation contains 100 units/mL of insulin degludec and 3.6 mg/mL of liraglutide, so that each dosing unit increment contains 1 unit of insulin degludec with 0.036 mg of liraglutide up to a maximum dose of 50 units of insulin degludec with 1.8 mg of liraglutide
      • Insulin Degludec, Liraglutide Solution for injection; Adults: This product is administered as dose units. The pre-filled pen can provide 10 to 50 dose units in a single injection in increments of 1 dose unit. RECOMMENDED STARTING DOSE: Naive to basal insulin or a GLP-1 RA: Give 10 dose units (10 units of insulin degludec and 0.36 mg of liraglutide) subcutaneously once daily. If currently on basal insulin or a GLP-1 RA: Give 16 dose units (16 units of insulin degludec and 0.58 mg of liraglutide) subcutaneously once daily. TITRATION: Titrate (up or down) by 2 dose units (2 units of insulin degludec and 0.072 mg of liraglutide) once weekly or twice weekly (every 3 to 4 days) to glycemic goals. May temporarily titrate below 16 dose units if needed. However, if the dose is persistently below 16 dose units use alternative therapy. MAX: 50 dose units (50 units insulin degludec and 1.8 mg liraglutide) subcutaneously once daily. MISSED DOSE: Resume with the next scheduled dose. If more than 3 days have elapsed, reinitiate at the starting dose to mitigate GI symptoms. LIMIT OF USE: Do not use in combination with any other product containing liraglutide or any other GLP-1 RA.
    • Insulin glargine; lixisenatide (Soliqua, LixiLan) c149
      • Formulation contains 100 units/mL of insulin glargine and 33 mcg/mL of lixisenatide, so that each dosing unit increment contains 1 unit of insulin glargine with 0.33 mcg of lixisenatide up to a maximum daily dose of 60 units of insulin glargine with 20 mcg of lixisenatide
      • Very potent hemoglobin A1C effect: During treatment in clinical trials, hemoglobin A1C level is lowered an average of 0.5% more versus use of insulin glargine alone r91
      • Insulin Glargine, Lixisenatide Solution for injection; Adults: This product is administered as dose units. The pre-filled pen can provide from 15 up to 60 dose units in a single injection in increments of 1 dose unit. RECOMMENDED STARTING DOSE: In patients naive to basal insulin or to a GLP-1 receptor agonist, currently on a GLP-1 RA, or currently on less than 30 units of basal insulin daily: give 15 dose units (15 units insulin glargine and 5 mcg lixisenatide) subcutaneously once daily. In patients inadequately controlled on 30 to 60 units of basal insulin with or without a GLP-1 RA: give 30 dose units (30 units insulin glargine and 10 mcg lixisenatide) subcutaneously once daily. Give all doses within the hour prior to the first meal of the day. TITRATION: Titrate (up or down) by 2 to 4 units every week to glycemic control goals. LIMITS: If less than 15 dose units or more than 60 dose units per day are needed, use alternative antidiabetic therapy. MAX: 60 dose units (60 units insulin glargine and 20 mcg lixisenatide) subcutaneously once daily.
  • Oral pharmacotherapy for type 2 diabetes mellitus.DPP4, dipeptidyl-peptidase 4; eGFR, estimated GFR; GLP1, glucagon-like peptide 1; SGLT2, sodium-glucose cotransporter 2; UKPDS, United Kingdom Prospective Diabetes Study.Adapted from Wallia A et al: Insulin therapy for type 2 diabetes. JAMA. 311:2315-25, 2014.
    Drug classHemoglobin A1C–lowering effectHypoglycemia riskMicro- or macrovascular benefitWeight changeUse in renal diseaseWarningsComments
    Biguanide (metformin)1%-1.5%NeutralReduction in cardiovascular events noted in UKPDSMostly neutral, but potential for slight losseGFR should be more than 45 mL/minute/1.73 m² at the time drug is started; thereafter, contraindicated if eGFR falls below 30 mL/minute/1.73 m²Lactic acidosis riskVitamin B₁₂ deficiency can occur, and levels should be checked annually; drug should be discontinued on hospital admission, before administration of radiocontrast agents, or in the setting of hypoxia or volume disturbance
    Sulfonylureas1%-1.5%Moderate to severeReduction in microvascular complications noted in UKPDSGainHypoglycemia risk increases with declining renal function; contraindicated in chronic kidney disease stage 4Glyburide not recommended with renal failureRetrospective data suggest a possible cardiovascular risk with use of this class of drugs, as compared with metformin
    Meglitinides1%ModerateGainHypoglycemia risk increases with declining renal function; may be used in chronic kidney disease stages 3 to 5 with dosing adjustmentsDosed multiple times per day at meals
    DPP4 inhibitors0.6%-0.8%NeutralMicrovascular benefit of reducing albuminuria; Potential risk for heart failure hospitalizations with saxagliptin

    Neutral
    Requires renal dosing adjustments, except linagliptinRenal function should be checked at baseline and periodically throughout therapy; only linagliptin does not require adjustments for renal insufficiency
    SGLT2 inhibitors0.5%-1%NeutralEmpagliflozin has been shown to reduce cardiovascular and all-cause mortality and to slow progression of renal disease in nephropathy; canagliflozin has been shown to slow nephropathyLossRequires renal dosing adjustments at chronic kidney disease stage 3 or greater; contraindicated
    if eGFR is less than 45 mL/minute/1.73 m²
    Increased risk of bone fractures and increased risk of lower extremity amputations for canagliflozin; increased potential for DKA with all SGLT2 inhibitorsReductions in blood pressure; risk for volume contraction; renal function should be checked at baseline and periodically throughout therapy
    Thiazolidinediones1%NeutralReduction in cardiovascular events noted in PROactive trial with pioglitazone, but drugs of this class increase incidence of heart failureGainRisk of congestive heart failure (contraindicated in class III and IV heart failure), fracture risk, and possible risk of bladder cancer with pioglitazonePossible benefit in nonalcoholic steatohepatitis; elevated risk of bone fractures; slight elevation in LDL cholesterol
    α-glucosidase inhibitors0.5%NeutralNeutralNonsystemic absorption
    Dopamine-2 agonists0.5%NeutralNeutral

Nondrug and supportive care

Therapeutic lifestyle modifications r32r48c150

  • Medical nutrition therapy r48r92c151
    • Counseling and education sessions for development of an individualized eating plan according to the metabolic needs of the individual patient, preferably provided by a registered dietitian r93
    • Incorporates weight loss goals, caloric needs, and distribution of macronutrients r93
    • Addresses lifestyle, preferences, eating patterns, culture, and comorbidities of the individual patient
    • Guidance is available with regard to management of diabetes during fasting for Ramadan and during intercurrent illness r94r95
    • Capable of reducing hemoglobin A1C level by 1% to 2% r93
    • Various eating patterns, including the DASH diet (Dietary Approaches to Stop Hypertension) and the Mediterranean diet,r96 are effective for controlling glycemia and lowering cardiovascular risk factors r48
      • In general, diets should emphasize nonstarchy vegetables, minimize added sugars and refined grains, and avoid highly processed foods r97
    • General recommendations consist of emphasizing nutrient-dense foods in appropriate portion sizes; consumption of fruits, vegetables, and low-fat dairy products; limiting added sugars; and substituting healthy fats for saturated and trans fats r98
    • Part of medical nutrition involves instruction in how to use carbohydrate, fat, and protein counting for patients who have advanced to flexible insulin therapy
    • Macronutrient consideration r48
      • Ideal distribution of calories among carbohydrates, fats, and proteins for patients with type 2 diabetes to optimize glycemic control is unknown
      • Individualize macronutrient distribution based on the dietary reference intake recommendations for healthy eating, metabolic goals, and total caloric needs r93
      • Carbohydrates
        • Evidence is insufficient to support a specific amount of carbohydrate intake for all people with diabetes
        • Monitoring carbohydrate intake, by carbohydrate counting or experience-based estimation, is an especially important strategy for patients who use insulin r93
        • Certain sources of carbohydrates are preferred over others for patients with type 2 diabetes
          • Whole grains, vegetables, fruits, legumes, and dairy products are foods that are higher in fiber and lower in glycemic load; these sources are preferable over others, especially those containing sugars
        • Reduce consumption of sugar-sweetened and nonnutritive sweetened beverages and encourage water as an alternative r48
      • Fats
        • Recommended total fat intake is equal to 20% to 35% of total calories (same as in general population) r48
        • Emphasize consumption of healthy fats (eg, long-chain ω-3 fatty acids, eicosapentaenoic acid, docosahexaenoic acid, α-linolenic acid) from food sources, such as fish, nuts, and avocados
        • Limit consumption of saturated fats (such as those from full-fat dairy, red meat, and tropical oils) and trans fats
      • Proteins
        • Emphasize sources of protein that are low in saturated fat, such as fish, egg whites, and beans; avoid processed meats
        • Ideal amount of protein intake
          • Usual protein intake: 15% to 20% of total energy r48
          • For patients without diabetic nephropathy, the evidence is inconclusive regarding the ideal amount of protein intake for optimizing glycemic control or improving cardiovascular risk; therefore, protein intake should approximate the recommended daily allowance for the general population (0.8 g/kg body weight) r99
          • For people with diabetic nephropathy (either micro- or macroalbuminuria), dietary protein restriction is not recommended, because it does not alter glycemic measures, cardiovascular risk measures, or the course of GFR decline r10
            • For patients with non–dialysis-dependent diabetic kidney disease, the recommended daily dietary protein intake is the same as that of the general population (0.8 g/kg body weight)
            • For patients receiving dialysis, consider higher levels of dietary protein intake
    • Micronutrients r98
      • Routine supplementation is not recommended, because there is no clear evidence of benefit in patients with diabetes who do not have underlying deficiencies
      • A healthful diet can usually provide sufficient micronutrients
    • Alcohol r48
      • Alcohol should be consumed in moderation, if at all (1 or fewer drinks per day for women, 2 or fewer drinks per day for men)
      • Ingestion of alcohol increases the risk of delayed hypoglycemia, especially for patients who use insulin or insulin secretagogues
    • Sodium r48
      • Recommended total sodium is 2300 mg/day or less (same as in general population)
      • Further sodium reduction (1500 mg/day or less) is recommended for concurrent hypertension
  • Physical activity c152
    • Prescribe exercise program with individualized goals r100
      • Begin exercise slowly and gradually build up
      • Goal duration for optimal health benefit is at least 150 minutes of moderate intensity (50%-70% of maximum heart rate) aerobic exercise per week, spread out over at least 3 days per week; avoid more than 2 consecutive days without exercise
      • Encourage balance, strength, and flexibility training at least 2 days per week in addition to aerobic training
      • Participation in both resistance and aerobic training is associated with reduction in hemoglobin A1C level r101
      • Participation in high-intensity interval trainingr102 is associated with improved insulin sensitivity and reduction in hemoglobin A1C level
    • Advise reduction in overall sedentary time and discourage periods of extended sitting (beyond 30 minutes) r103
    • Insulin dosing may need to be modified with exercise to prevent hypoglycemia
    • Pre-exercise medical clearance is unnecessary for asymptomatic persons before beginning low- or moderate-intensity physical activity not exceeding the demands of brisk walking or everyday living r104
    • Pre-exercise screening for coronary artery disease is recommended for patients who are currently sedentary and will undertake exercise that is more intense than brisk walking
      • American College of Sports Medicine exercise preparticipation health screening guidelines focus on assessing: r105
        • Patient's current level of physical activity
        • Presence of signs or symptoms and/or known cardiovascular, metabolic, or renal disease
        • Desired exercise intensity
  • Weight management c153
    • Primary approach to weight management is through lifestyle modification, which includes dietary change focused on caloric restriction, increased energy expenditure through physical activity, and behavioral modification (monitoring of food, exercise, and weight) r106
    • Weight loss goals r107
      • For overweight patients (BMI 25-29.9 kg/m²)r108, weight loss goal is to achieve BMI within reference range (18.5-24.9 kg/m²)r108
      • For obese patients (BMI 30 kg/m² or higher),r108 initial weight loss goal is 5% to 10% of body weight
    • Intensive lifestyle interventions, targeting weight reduction through caloric restriction and increased physical activity, are effective for modest weight loss (3%-5%) r107
      • Clinically meaningful health benefits include improved physical fitness and HDL-C levels, reductions in hemoglobin A1C level, and lower requirements for medication for glucose, blood pressure, and lipid control r107
      • Weight loss achieved through lifestyle modification improves cardiovascular risk factors, although available data do not demonstrate that this translates into reduction in cardiovascular events r109
    • Pharmacotherapy can be considered when lifestyle interventions do not achieve desired goals r68d4
    • Bariatric surgery may be considered for patients whose BMI remains more than 30 kg/m² despite lifestyle and/or pharmacologic treatment r110

Diabetes self-management education and support r48c154

  • Ongoing processes of facilitating the knowledge, skill, and ability necessary for the patient to participate in diabetes self-care
  • Focus is on helping patients make informed self-management decisions
  • Core educational topics include: r111
    • Diabetes disease process and treatment options
    • Incorporating nutritional changes and physical activity into lifestyle
    • Monitoring blood glucose, then interpreting and using the results for day to day management decisions
    • Using medications safely for greatest effectiveness

Blood glucose monitoring

  • Self-monitoring of blood glucose r67r112c155
    • Point of care testing technology in which a small volume of capillary blood is placed on a test strip and inserted into a glucometer, providing a real-time digital display of blood glucose level
    • Rationale for blood glucose monitoring, regardless of insulin use, is to encourage patients to play a more active role in their diabetes management and to maximize the efficacy and safety of glucose-lowering therapies
      • Glucose data are used by the patient to make immediate decisions regarding coordination of insulin dosing with food intake and physical activity
        • Instruct patients to record and store blood glucose data so that it may be reviewed by clinicians to assist in drug therapy titration
      • Glucose data are trended and analyzed by the health care professional to tailor the treatment plan
        • If the decline in bedtime to morning glucose level is more than 55 mg/dL (3.1 mmol/L), this suggests an excessive basal insulin dose r67
        • Overnight rise in glucose levels may indicate a need to increase basal insulin dose
    • Recommended frequency of blood glucose testing depends on medication regimen r67
      • If using multiple daily injections of insulin, test glucose level before meals, at bedtime, and (if needed) periodically in the middle of the night
      • If using basal insulin only, without prandial doses, test glucose level in the morning when fasting and at bedtime
      • If using noninsulin medications:
        • Use self-monitoring only when patients and/or caregivers have the knowledge, skills, and willingness to incorporate glucose monitoring and any therapeutic adjustments into their diabetes care plan
        • If using an insulin secretagogue (eg, sulfonylurea, meglitinide), test fasting blood glucose level once daily and periodically at other times to confirm effectiveness of therapy and detect possible hypoglycemia
        • If using medications with low risk of hypoglycemia, test at least weekly; initial daily testing at meals and bedtime may be helpful for patient understanding of the effects of medical nutrition therapy and lifestyle modifications on glucose levels
        • If using lifestyle therapy only, daily testing is not recommended; initial daily testing at meals and bedtime may be helpful for patient understanding of the effects of medical nutrition therapy and lifestyle modifications on glucose levels
      • More frequent monitoring is required for frequent hypoglycemia, recurrent episodes of severe or nocturnal hypoglycemia, or persistently elevated hemoglobin A1C level
  • Continuous glucose monitoring r32r113c156
    • Testing technology uses a catheter with a glucose oxidase sensor, which is placed subcutaneously to measure and record interstitial glucose levels
    • Downloadable metrics from devices (eg, time in range, glycemic variability, patterns of hypoglycemia and hyperglycemia) are used to make adjustments to the insulin regimen
    • Personal-use continuous devices, which are owned and used over the long-term by patients, display glucose data in real time so that the patient can make immediate or retrospective adjustments to diabetes management
    • Professional-use devices are used on a short-term basis (eg, 72 hours) to assess glycemic patterns for therapeutic decision making by a health care professional
      • Short-term, intermittent, real-time continuous glucose monitoring is appropriate for persons who use basal insulin alone and have hemoglobin A1C levels above 7% r114
    • Traditionally used by patients with type 1 diabetes, because evidence has shown benefit in this population
      • However, current expert opinion holds that continuous glucose monitoring is likely to assist other patients, regardless of diabetes type, and therefore should be offered to patients who use insulin, are compliant with self-monitoring their glucose level, and also have the following: r115
        • Hypoglycemia unawareness
        • Higher risk of hypoglycemia (including patients older than 65 years, patients with renal impairment, and/or athletes)
    • Contraindication: physical or cognitive impairment precluding ability to effectively use the technology
    • Small crossover trial conducted in patients with type 2 diabetes showed significant reduction in hemoglobin A1C level for patients using a continuous glucose monitoring device versus self-monitoring of blood glucose level r116

Smoking cessation r48c157

  • Smokers (and those exposed to secondhand tobacco smoke) with type 2 diabetes are at greater risk for microvascular complications of diabetes, cardiovascular disease, and sudden death
  • Offer counseling and/or medications to assist with cessation
  • Encourage avoidance of tobacco smoke for those who have been exposed

Immunizations r9r32

  • Hepatitis B vaccine is recommended for all adults with type 2 diabetes who are aged 19 to 59 years; consider for patients aged 60 years or older, depending on risk assessment and projected immune response c158c159
  • Pneumococcal vaccination with PPSV23 is recommended for adults with type 2 diabetes aged up to 64 years; give additional PPSV23 vaccine to patients aged 65 years or older regardless of prior vaccination history c160c161
  • Annual influenza vaccine is recommended for all patients with diabetes c162
  • Administer other vaccines in accordance with age-specific CDC recommendations r117
Procedures
Continuous subcutaneous insulin infusion (insulin pump) therapy r32r118r119c163c164c165
General explanation
  • Mechanically driven insulin delivery technology in which a catheter is placed subcutaneously to provide a continuous infusion of short-acting insulin
  • Provided as a preset basal rate with operator-driven periodic boluses
  • Most often used in patients with type 1 diabetes, but some patients with type 2 diabetes (particularly those with insulinopenia) can benefit with very modest improvements in glycemic control r120
  • A sensor-augmented pump is a continuous subcutaneous insulin infusion device combined with a continuous glucose monitoring feature r119
    • A pump with threshold suspension functionality temporarily halts delivery of insulin when interstitial glucose levels fall below a set threshold
    • A system is available that integrates an insulin pump and continuous glucose monitor and uses an algorithm to determine insulin needs based on sensor values without requiring intervention from user
Indication
  • Intensively managed insulin-treated patients with type 2 diabetes can be considered for insulin pump therapy under the following sets of circumstances:
    • Absolute insulin deficiency, as confirmed with undetectable C-peptide level r118
    • Good adherence to monitoring and dosing insulin, yet poor glycemic control despite multiple interventions (eg, oral agent insulin, glucagon-like peptide 1 receptor agonist); currently administers 4 or more insulin injections daily r114
Contraindications
  • Physical or cognitive impairment precluding the rigors of insulin pump therapy during initiation and maintenance r118
  • Inability to manage the complexity of therapy, which can require carbohydrate counting, calculating insulin bolus and correction doses, and adjusting basal settings
Complications
  • Unrecognized pump malfunction can lead to hyperglycemia
Interpretation of results
  • Overall, the use of insulin pump therapy in place of multiple daily injections of insulin does not lead to better glycemic control in patients with type 2 diabetes on the basis of achieving a lower hemoglobin A1C level r118
  • May decrease overall insulin requirements in insulin-treated patients with type 2 diabetes r118
Bariatric surgery c166c167c168c169
General explanation
  • Comprises a set of surgical procedures performed in obese persons to achieve and sustain substantial weight loss
  • Most common bariatric procedures include Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, vertical sleeve gastrectomy, and biliopancreatic diversion with duodenal switch
  • Most bariatric surgical procedures are performed through a laparoscopic approach; only rarely is open surgery necessary
  • Weight loss and diabetes resolution are greatest for biliopancreatic diversion with duodenal switch, followed by gastric bypass; least success is achieved by banding procedures r69
  • Postoperative improvements in metabolic control occur rapidly and are out of proportion to weight loss
Indication
  • Second Diabetes Surgery Summit recommend bariatric surgery for patients who have type 2 diabetes and any of the following: r110
    • Class III obesity (BMI of 40 kg/m² or more), regardless of the level of glycemic control or complexity of glucose-lowering regimens
    • Class II obesity (BMI of 35-39.9 kg/m²), with inadequately controlled hyperglycemia despite lifestyle and optimal medical therapy
    • Class I obesity (BMI of 30-34.9 kg/m²), with inadequately controlled hyperglycemia despite optimal medical therapy by either oral or injectable medications (including insulin) r121
    • BMI thresholds are adjusted down by 2.5 kg/m² for patients with Asian ethnicity
Contraindications
  • Absolute
    • Diseases associated with poor long-term life expectancy
    • Poor myocardial reserve
    • Significant chronic obstructive pulmonary disease or respiratory dysfunction
    • Uncontrolled or untreated major depression or other psychiatric illnesses
    • Active substance use/misuse
    • Severe portal hypertension
  • Relative
    • History of nonadherence to medical care
    • Borderline personality disorder or bipolar disease
    • Moderate portal hypertension
Complications r122
  • All bariatric procedures
    • Mortality rates are typically 0.1% to 0.5% for laparoscopic procedures and 2% for open procedures
    • Thromboembolism
    • Staple line leak
    • Stomach ulcer
    • Internal hernia
    • Gallstones
    • Nutritional deficiencies
    • Nephrolithiasis
    • Bone loss
  • Biliopancreatic diversion procedure
    • Associated with highest perioperative complication rate
    • Additional complications of hypoalbuminemia, fat malabsorption, and liver dysfunction
Interpretation of results
  • Bariatric surgery shows superior efficacy in reducing weight and improving glycemia compared with pharmacologic or lifestyle interventions in trials with postoperative observation extending from 1 to 5 years in duration r123r124
  • Data suggest an erosion of diabetes remission over time; more than 35% to 50% of patients who initially achieve remission of diabetes eventually experience recurrence r68
  • Median disease-free period after Roux-en-Y gastric bypass is about 8 years r68
  • With or without diabetes relapse, most patients who undergo surgery maintain substantial improvement of glycemic control from baseline for at least 5 years and up to 15 years r124
  • Analysis of 11 trials comparing surgery with lifestyle modifications or pharmacotherapy for diabetes shows median hemoglobin A1C reduction of 2% for surgery and 0.5% for conventional therapies r110
  • Microvascular complications of nephropathy, neuropathy, and retinopathy appear to improve, but definitive proof awaits studies in progress r125
  • Major complication rate is approximately 5% and reoperation rate is approximately 8% r123

Comorbidities

  • Hypertension d5
    • Hypertension affects most patients with type 2 diabetes and greatly increases the risk of micro- and macrovascular complications
    • There is strong evidence supporting treatment of patients with diabetes and blood pressure of 140/90 mm Hg or higher with a goal to lower blood pressure to less than 140/90 mm Hg r126
    • Overall, available evidence suggests that blood pressure targets lower than 140/90 mm Hg yield cardiovascular benefits for some populations but increase adverse events (elevations in serum creatinine level and electrolyte disturbances) r126
      • More intensive treatment, with lower blood pressure targets, also provides lower risk of stroker37 and reduction in albuminuria r126
      • Patients with higher baseline cardiovascular risk and higher baseline blood pressure appear to derive greater benefits; patient characteristics that impart higher risk for adverse events of aggressive blood pressure lowering have not been identified r127
    • Optimal blood pressure targets in patients with hypertension and type 2 diabetes are uncertain; suggested targets vary by professional society r127c170
    • American Diabetes Association generally recommends blood pressure goals less than 140/90 mm Hg for patients with diabetes, but lower targets (less than 130/80 mm Hg) may be appropriate for certain people (eg, younger patients, patients with albuminuria, those with known atherosclerotic cardiovascular disease or 10-year atherosclerotic cardiovascular disease risk of 15% or higher r36
      • In older adults, pharmacologic therapy to achieve treatment goals of less than 130/70 mm Hg is not recommended; treating to lower systolic blood pressure below 130 mm Hg has not been shown to improve cardiovascular outcomes, and treating to lower diastolic blood pressure below 70 mm Hg has been associated with higher mortality r128
    • American College of Cardiology/American Heart Association recommend a uniform target blood pressure less than 130/80 mm Hg r35
    • Treatment
      • Advise all patients with blood pressure greater than 120/80 mm Hg to undertake lifestyle changes for reducing blood pressure, such as: r36
        • Weight loss, if patient is overweight or obese
        • DASH diet or DASH-like diet (Dietary Approaches to Stop Hypertension), which includes reduced sodium and increased potassium intake
        • Moderation of alcohol intake
        • Increased physical activity
      • Start pharmacotherapy in addition to lifestyle changes for patients with blood pressure higher than 140/90 mm Hg r36
        • For patients with diabetes and hypertension but without albuminuria for whom cardiovascular disease prevention is the primary goal, any of the following drug classes may be considered: ACE inhibitor, angiotensin receptor blocker, thiazide diuretic, or dihydropyridine calcium channel blocker
        • For patients with diabetes, albuminuria, and hypertension, start either an ACE inhibitor or an angiotensin receptor blocker, but not both
        • Multidrug therapy (ie, thiazide diuretic and ACE inhibitor/angiotensin receptor blocker at maximal doses) is often required to achieve blood pressure targets
          • If blood pressure is 160/100 mm Hg or more, start pharmacotherapy with 2 agents
  • Dyslipidemia c171d6
    • Patients with type 2 diabetes have a specific type of dyslipidemia that promotes atherosclerosis and contributes to an elevated risk of atherosclerotic cardiovascular disease r129
      • Most prevalent pattern in type 2 diabetes: hypertriglyceridemia, low HDL-C level, moderately increased LDL-C level, and elevated levels of small, dense LDL particles r78r129
    • There is a lack of consensus among medical societies regarding the use of numeric lipid goals
      • American Heart Association does not specify a numeric LDL-C goal r130
      • American Association of Clinical Endocrinologists recommends an LDL-C goal less than 100 mg/dL for patients with diabetes and no atherosclerotic cardiovascular disease or major risk factors, less than 70 mg/dL for patients with diabetes and at least other 1 major risk factor, and less than 55 mg/dL for patients with diabetes with established atherosclerotic cardiovascular disease r26r42
    • Lifestyle modifications for dyslipidemia are recommended for all patients with diabetes, regardless of whether pharmacotherapy is used, including: r129
      • Medical nutrition therapy (low saturated fat, low trans fat, low cholesterol, increased omega-3 fatty acids, increased fiber)
      • Weight loss if necessary
      • Increased physical activity
      • Smoking cessation
    • Pharmacotherapy for treatment of dyslipidemia
      • Statin therapy is first line drug therapy for dyslipidemia; type of therapy is adjusted based on assessment of cardiovascular risk and age
      • Joint guidelines of American College of Cardiology and American Heart Association recommend the following: r130
        • Moderate-intensity statin therapy is indicated for adults aged 40 to 75 years with diabetes mellitus, regardless of estimated 10-year risk of atherosclerotic cardiovascular disease
        • It is reasonable to assess the 10-year risk of a first atherosclerotic cardiovascular event in adults aged 40 to 75 years with diabetes mellitus and an LDL-C level of 70 to 189 mg/dL
        • High-intensity statin therapy with the aim to reduce LDL-C levels by 50% or more is reasonable for adults with diabetes mellitus who have multiple risk factors for atherosclerotic cardiovascular disease
        • Addition of ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more may be reasonable for adults with diabetes mellitus and 10-year risk of 20% or higher for atherosclerotic cardiovascular events
        • It is reasonable to consider initiation of statin therapy in adults older than 75 years with diabetes mellitus based on individual risks and benefits; and it is reasonable for those who are already on statin therapy to continue beyond age 75 years
        • Initiation of statin therapy may be reasonable in adults aged 20 to 39 years with type 1 diabetes mellitus for 20 years or longer, albuminuria (30 mcg or more of albumin per milligram of creatinine), estimated GFR less than 60 mL/minute/1.73 m², retinopathy, neuropathy, or ankle-brachial index less than 0.9
  • Chronic kidney disease r131c172
    • Drug therapy is challenging because of potential for various adverse effects, such as lactic acidosis and hypoglycemia r132
    • Contraindications and dose adjustments of all medication classes are required for patients with chronic kidney disease stages 2 to 5
    • Metformin
      • Therapy is appropriate if GFR is more than 45 mL/minute/1.73 m²
      • Patient may remain on metformin down to an estimated GFR of 30 mL/minute/1.73 m²
    • Dipeptidyl-peptidase IV inhibitor
      • Can be used in all stages of renal impairment
      • Most require dosage adjustment, except linagliptin
    • Sulfonylureas
      • Undesirable to use this class in general, particularly glipizide, because of the risk of hypoglycemia
      • Most sulfonylureas are contraindicated in patients with stage 4 chronic kidney disease
    • Meglitinides
      • May be used in stage 3 to 5 chronic kidney disease, but requires careful dose adjustments
    • Glucagon-like peptide 1 receptor agonists
      • All such agonists are currently contraindicated in stages 4 and 5 chronic kidney disease (GFR less than 30 mL/minute/1.73 m²)
    • Sodium-glucose cotransporter 2 inhibitors r131
      • At stage 3 or greater, these drugs require dose adjustment or are contraindicated
      • Empagliflozin and canagliflozin are contraindicated if estimated GFR persistently falls below 45 mL/minute/1.73 m²
      • Dapagliflozin is contraindicated if estimated GFR persistently falls below 60 mL/minute/1.73 m²
    • Thiazolidinediones
      • Only pioglitazone is advisable, owing to safety concerns with other agents in this class r131
      • Do not use pioglitazone in patients using dialysis, owing to lack of information about use in this setting
  • Coronary artery disease c173d7
    • Use American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease risk calculator to assess 10-year atherosclerotic cardiovascular disease risk and to guide therapy
    • Promote lifestyle modifications to reduce cardiovascular risk, including: r36r40
      • Smoking cessation
      • Maintaining body weight within reference range
      • Regular physical activity
      • Consumption of a balanced diet replete with fruits and vegetables, low in saturated fat and sodium, and enriched with whole grains
    • Most patients with coronary artery disease should be treated with metformin plus a drug proven to reduce major cardiovascular events and/or cardiovascular mortality: r57
      • Strongest evidence for cardiovascular benefit has been demonstrated with liraglutide, dulaglutide, semaglutide, empagliflozin, dapagliflozin, and canagliflozin r27r57
    • Treat risk factors such as hypertension and dyslipidemia
    • Antiplatelet therapy with low-dose aspirin is recommended for secondary prevention in patient with a history of cardiovascular disease and may be considered for primary prevention in patients at increased risk of cardiovascular events r36
      • Use of aspirin in patients with diabetes is associated with approximately 9% relative risk reduction for cardiovascular events but 2-fold or higher relative risk of bleeding r106
      • Not generally recommended for adults older than 70 years or those younger than 50 years with no other risk factors for atherosclerotic cardiovascular disease
    • Also consider ACE inhibitor or angiotensin receptor blocker in patients with known cardiovascular disease
    • Obtain resting ECG in patients with hypertension or suspected cardiovascular disease r11
    • Routine screening for coronary artery disease is not recommended in asymptomatic patients r36
    • Exercise ECG may be considered for cardiovascular risk assessment in patients with cardiac symptoms or an abnormal resting ECG r36
    • Coronary artery calcium measurement may be considered for patients 40 years of age or older r36
  • Congestive heart failure c174
    • Sodium-glucose cotransporter 2 inhibitors are recommended for patients with clinical heart failure r27r133
      • Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin have been shown to reduce the risk of heart failure hospitalizations in patients: r134
        • Who have type 2 diabetes mellitus and established cardiovascular disease
        • Who are at high cardiovascular risk
    • Thiazolidinedione class is contraindicated in class III and class IV heart failure
    • Some studies (not all) have reported an association between dipeptidyl-peptidase IV inhibitors and worsening heart failure; use with caution, if at all r27r135
  • Obesity r68c175d4
    • Obesity (BMI of 30 kg/m² or more) is associated with insulin resistance r136
    • Abdominal adiposity (waist circumference greater than 102 cm in men and greater than 88 cm in women) in overweight patients (BMI of 25-30 kg/m²) is also associated with insulin resistance r32
    • Efforts to achieve modest and sustained weight loss are a priority r137
      • Sustained weight loss of 3% to 5% results in clinically meaningful reductions in triglyceride levels, fasting blood glucose level (20 mg/dL), and hemoglobin A1C level (0.2%-0.3%) r107
      • Greater amounts of weight loss will further reduce hemoglobin A1C level (0.6%-1%), reduce blood pressure (approximately 3 mm Hg), improve LDL-C and HDL-C levels, and reduce the need for medications to control blood pressure, blood glucose level, and lipid levels r107
    • First line therapy is lifestyle modification to achieve weight loss of 5% or more r68
      • Consists of reduced calorie diet in conjunction with physical activity and behavioral therapy
      • Individual counseling sessions occur frequently (16 or more in 6 months) with goal of producing a 500 to 750 kcal/day energy deficit
      • Prescribe long-term (1 year or longer) comprehensive weight maintenance programs for patients who achieve short-term weight loss goals
      • Use of very-low-calorie diets (800 kcal/day or less) and total meal replacements are reserved for patients in whom careful medical monitoring is possible
    • Second line therapy is pharmacotherapy, indicated for a person who has diabetes and a BMI of 27 kg/m² or more r107
      • Agents include phentermine, orlistat, lorcaserin, phentermine–topiramate extended-release, naltrexone-bupropion, and liraglutide
      • Reassess medications for comorbid conditions and minimize those that cause weight gain, including atypical antipsychotics, antidepressants, glucocorticoids, anticonvulsants, antihistamines, and anticholinergics r68
    • Select a regimen for diabetes management to include drugs that have favorable effects on body weight where possible r68
      • Diabetes medication classes associated with weight gain include sulfonylureas, meglitinides, thiazolidinediones, and insulin
      • Diabetes medication classes that promote modest weight loss are metformin, glucagon-like peptide 1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, and amylin mimetics
      • Diabetes medication classes that are weight neutral include dipeptidyl-peptidase IV inhibitors
    • Bariatric surgery is a recommended option to treat type 2 diabetes in patients with: r68
      • BMI of 40 kg/m² or more (37.5 kg/m² or more in Asian Americans)
      • BMI of 35 to 39.9 kg/m² (32.5-37.4 kg/m² in Asian Americans) if unable to achieve durable weight loss and improvement in comorbidities (including hyperglycemia) with nonsurgical methods
    • Bariatric surgery may be also considered in patients with a BMI of 30 to 34.9 kg/m² (27.5-32.4 kg/m² in Asian Americans) if unable to achieve durable weight loss and improvement in comorbidities (including hyperglycemia) with nonsurgical methods r68
  • Obstructive sleep apnea r9c176c177c178c179
    • Associated with obesity (particularly central obesity), male sex, and older age; affects approximately two-thirds of men who have diabetes and are older than 65 years r32
    • Increases risk for heart disease owing to increased insulin resistance, hyperglycemia, hypertension, dyslipidemia, and inflammation
    • Assess sleep pattern and duration in all patients with type 2 diabetes r138
    • Treat with weight loss, CPAP, adjustable airway pressure devices, oral appliances, and/or surgery
    • Treatment of sleep apnea improves quality of life and positively affects blood pressure
  • Nonalcoholic fatty liver disease r9c180d8
    • Excess of fat in the liver (steatosis) that is not a result of excessive alcohol consumption or other secondary causes
    • Type 2 diabetes is a risk factor for development of the disease
    • Among the available medications to treat type 2 diabetes, pioglitazone improves nonalcoholic fatty liver disease activity and resolves nonalcoholic steatohepatitis in about half of treated patients r139
  • Liver failure and cirrhosis c181c182
    • Treatment of diabetes in these patients is complex, because many diabetes drugs can promote hypoglycemia and lactic acidosis r140
    • In most cases, insulin therapy, including the insulin analogues, is the safest choice
    • Oral diabetes medications are contraindicated in patients with advanced liver diseases who have cirrhosis, ascites, or encephalopathy r141
    • Glucagon-like peptide 1 receptor agonists exenatide and liraglutide have been shown to be safe in patients with liver disease r140
    • Dipeptidyl-peptidase IV inhibitors appear to be safe for use in patients with liver cirrhosis r140
  • Osteoporosis r9c183
    • Use thiazolidinediones and the sodium-glucose cotransporter 2 inhibitor canagliflozin with caution
  • HIV c184
    • Fasting glucose levels are the preferred method of diagnosis r4
      • Hemoglobin A1C test should not be used to diagnose diabetes in patients with HIV, because it underestimates glycemia in this population r142
    • Risk of developing diabetes is increased with treatment with some protease inhibitors and nucleoside reverse transcriptase inhibitors r9
  • Psychosocial disorders r143
    • Depression c185d9
      • Highly prevalent in patients with type 2 diabetes; 20% to 25% of patients with diabetes are affected by depressionr144
      • Associated with increased risk of myocardial infarction and mortality
      • Depression and diabetes-related distress are associated with poor self-care, nonadherence, and poor glycemic control
      • Refer to a mental health specialist for assessment and treatment r48
    • Anxiety c186d10
      • Anxiety over aspects of the disease or diabetes care (eg, complications, injections, hypoglycemia) is common and can lead to maladaptive behavior, such as avoidance, withdrawal, or excessive repetitive habits r48
      • Fears of hypoglycemia can lead to self-relaxing of glycemic goals and reducing the intensity of measures to treat the disease
      • Refer patients to diabetes education for blood glucose awareness training or to a mental health specialist for more severe forms of anxiety
    • Diabetes-related distress is the experience of people who become overly burdened by the ongoing behavioral demands of managing the disease r144c187
      • Refer such patients to diabetes education, or to a mental health specialist if areas of diabetes care are adversely impacted

Special populations

  • Older adults r145r146
    • Older adults with type 2 diabetes have higher rates of premature death, disability, and comorbidities than their counterparts without diabetes
    • Geriatric syndromes are also more common in older adults with type 2 diabetes
      • Cognitive impairment
      • Polypharmacy
      • Urinary incontinence
      • Falls (with associated fractures)
      • Chronic pain
    • If cognitive or functional impairment limits diabetes self-care, enlist and educate caregivers about diabetes management
      • Intensive treatment to achieve strict glycemic control does not remediate cognitive deficits;r147 instead, modify treatment to avoid hypoglycemiar146r145
    • Glucose targets for older adults with type 2 diabetes depend on comorbidities, complications, life expectancy, and functional status; in general, the healthier the patient, the more aggressive the glycemic target r146
      • In healthy older adults (few comorbidities, fully functional)
        • Hemoglobin A1C level: 7% to less than 7.5%
        • Fasting blood glucose level: 90 to 150 mg/dL
        • Bedtime blood glucose level: 100 to 180 mg/dL
      • In somewhat unhealthy older adults (multiple comorbidities, some functional or cognitive impairment)
        • Hemoglobin A1C level: 7.5% to less than 8%
        • Fasting blood glucose level: 100 to 150 mg/dL
        • Bedtime blood glucose level: 150 to 180 mg/dL
      • In very unhealthy older adults (eg, in long-term care, with end-stage chronic illness, significant physical impairment, moderate to severe dementia)
        • Hemoglobin A1C level: 8% to less than 8.5%
        • Fasting blood glucose level: 100 to 180 mg/dL
        • Bedtime blood glucose level: 110 to 250 mg/dL
    • Older adults with type 2 diabetes are at increased risk for hypoglycemia owing to decreased insulin and increased renal insufficiency, requiring closer monitoring when treated with medications that can cause hypoglycemia r145r146
    • Metformin is the first line agent for treatment of type 2 diabetes for older adults r145
    • Drug therapy may need to be adjusted for older adults, especially in the setting of comorbidities r146
      • Metformin is contraindicated in renal failure and heart failure
      • Use thiazolidinediones with caution in congestive heart failure
      • Saxagliptin may increase the risk of hospitalization for heart failure
      • Simplify drug regimens (eg, combination drug pills) where possible for elderly patients with cognitive impairments
      • Once-daily injection of basal insulin may be a reasonable option for some older adults
  • Pregnant women
    • Glucose targets for pregnant women with pregestational type 2 diabetes are more aggressive than for the general population of patients with type 2 diabetes
      • American Association of Clinical Endocrinologists: r32
        • Hemoglobin A1C less than 6% during pregnancy
        • Preprandial, bedtime, and overnight glucose levels: 60 to 99 mg/dL
        • Peak postprandial blood glucose level: 100 to 129 mg/dL
      • American Diabetes Association r148
        • Hemoglobin A1C level: 6% or lower
        • Fasting blood glucose of less than 95 mg/dL
        • 1-hour postprandial blood glucose less than 140 mg/dL or 2-hour postprandial blood glucose less than 120 mg/dL
    • Insulin is the preferred medication for managing glycemia during pregnancy r148
      • Long-term safety profile is superior compared with noninsulin agents
      • Insulin can easily be titrated to match changing insulin demand in pregnancy
        • First trimester insulin requirements are typically lower, whereas second and third trimester requirements are typically higher owing to increasing insulin resistance
    • Oral agents considered to be relatively safe alternatives to insulin during pregnancy include metformin and glyburide r32
    • Pregnant women with type 2 diabetes are more likely to be overweight or obese r148
      • Suggested weight gain for an overweight pregnant woman with diabetes is 6.8 to 11.3 kg
      • Suggested weight gain for an obese pregnant woman with diabetes is 4.5 to 9 kg
    • In pregnancy complicated by both diabetes and hypertension, blood pressure targets and treatment may differ compared with those of prepregnancy care r148
      • Target blood pressure of 135/85 mm Hg or lower is recommended r36
    • Diabetes is associated with an increased risk of preeclampsia: prescribe low-dose aspirin during second and third trimester to reduce risk r148
  • Hospitalized patients
    • Inpatient glucose targets vary per setting and circumstance
      • Glucose target between 140 and 180 mg/dL is recommended for most critically and noncritically ill patients r34
      • Glucose target between 110 and 140 mg/dL may be appropriate for select patients (eg, those with previous cardiac surgery, stroke, or acute ischemic cardiac events) provided that the target can be achieved without significant hypoglycemia r34
    • ICU r34
      • Administer IV insulin infusions using validated written or computerized protocols (where available) that allow for predefined adjustments in the insulin infusion rate based on glycemic fluctuations and insulin dose
    • Non-ICU
      • A basal plus bolus correction insulin regimen is the preferred treatment for noncritically ill patients with poor oral intake or those who have NPO status. An insulin regimen with basal, nutritional, and correction components is optimal for patients with good nutritional intake r34
    • Perioperative care
      • Target glucose range for perioperative period is 80 to 180 mg/dL; attempts to achieve tighter perioperative glucose control lead to unacceptable rates of hypoglycemiar149r34
      • Withhold metformin 24 hours before surgery, and withhold all other oral hypoglycemic drugs beginning on the morning of surgery r34
      • Use regular insulin or rapid-acting insulin analogues to correct higher glycemic excursions
      • Resume oral medications 1 to 2 days before discharge, when possible
    • Enteral/parenteral feedings r34
      • Give insulin in portions designated as basal, nutritional, and correctional
      • Dosing can be determined by preadmission basal insulin dose; if no insulin was used, a dose of 10 units glargine every 24 hours may be used
      • Tube feedings: use 1 unit of insulin for 10 to 15 g of carbohydrate
      • Enteral bolus feeding: give 1 unit of regular or immediate-acting insulin per 10 to 15 g of carbohydrate before the feeding
      • Continuous peripheral or central parenteral delivery: add 1 unit of regular insulin per 10 g of dextrose
      • Correctional doses, based on point of care blood glucose measurements, should be administered every 6 hours in all cases, using regular insulin or an immediate-acting insulin
    • Avoid iatrogenic hypoglycemia (less than 70 mg/dL) r34
      • Inpatient hypoglycemia is associated with higher complication rates and greater mortality
      • Triggers include emesis, reduced oral intake, reduction in glucocorticoid doses, misalignment between administration of rapid-acting insulin and meals, interruption of change in enteral/parenteral feedings, or new NPO status

Monitoring

  • Periodic evaluation of several clinical and laboratory parameters is part of the ongoing comprehensive management of type 2 diabetes
  • Glycemic control
    • Acute (day to day) control
      • Capillary blood glucose measurements performed by patient, obtained via glucometer c188
      • Self-monitoring of blood glucose level is suggested for patients using insulin
      • Frequency of blood glucose monitoring is individualized and determined by glucose lability, frequency of hypoglycemia, presence of hypoglycemia unawareness, and insulin requirements
      • Review patient records of self-monitored blood glucose levels every 3 months c189
    • Long-term control
      • Hemoglobin A1C level provides a 2- to 3-month estimation of glycemia, although it does not provide a measure of glycemic variability or hypoglycemia r9
      • Measure hemoglobin A1C level every 3 months until it is stable, or goals are met r9c190
      • With the evaluation of hemoglobin A1C levels, it is appropriate to revise treatment strategies on the basis of changes in general health, patient preferences, and life expectancy that alter the balance of benefits and harms r31
      • Consider de-escalation of therapy (by reducing dosage or number of drugs) in patients that reach hemoglobin A1C target less than 6.5% r31
    • A discrepancy between preprandial self-monitored blood glucose levels and hemoglobin A1C level can be caused by high postprandial blood glucose levels
  • Lifestyle and behavior r9
    • Inquire at least annually about eating patterns and weight; advise or refer to dietitian as needed c191c192
    • Inquire at least annually about sleep patterns and physical activity, and advise on optimal sleep duration and engagement in exercise c193c194
    • Discourage tobacco use and advise limited alcohol intake
  • Medications
    • Metformin
      • Obtain serum creatinine level, GFR, and vitamin B₁₂ levels annually, at a minimum c195c196c197
      • Before starting, estimated GFR should be greater than 45 mL/minute/1.73 m²; patient may remain on metformin until estimated GFR falls to 30 mL/minute/1.73 m², when it must be stopped
    • Dipeptidyl-peptidase IV inhibitors, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists
      • Before starting, measure baseline renal function, and recheck periodically throughout therapy c198c199c200
  • Monitoring of comorbidities
    • Hypertension
      • Monitor blood pressure at each office visit (3-4 times annually at a minimum) r36c201
      • If ACE inhibitors, angiotensin receptor blockers, or diuretics are used, monitor estimated GFR and serum levels of creatinine and potassium c202c203c204c205c206c207c208c209c210
    • Dyslipidemia
      • Monitor lipid profile at time of first diagnosis and periodically (every 1-2 years) thereafter r36c211c212
      • Once a patient is using lipid-lowering therapy, measuring lipid profile may be considered on an individual basis to monitor adherence and efficacy
    • Obesity
      • Calculate and document BMI at each patient encounter r68c213
    • Psychosocial issues
      • Screen for depression, anxiety, and disordered eating at least annually r48c214c215c216
      • Consider assessment for cognitive impairment in older adults c217
  • Surveillance for complications r10
    • Retinopathy d11
      • Refer to retinal specialist for initial dilated eye examination at time of diagnosis c218
      • Dilated eye examination every 2 years if there is no evidence of retinopathy for 1 or more annual eye examinations c219
      • Dilated eye examination annually if any level of retinopathy is present c220
    • Nephropathy d12
      • Measure both urine albumin-creatinine ratio and creatinine clearance/estimated GFR annually; if urinary albumin over 30 mg/g of creatinine and/or estimated GFR is less than 60 mL/minute/1.73 m², measure every 6 months c221c222
      • Refer to nephrologist for further management if GFR less than 30 mL/minute/1.73 m²
    • Neuropathy d13
      • Assess all patients for peripheral neuropathy at time of diagnosis and at least annually thereafter c223
      • Assessment includes thorough history, 10-g monofilament testing, and at least 1 of the following tests: pinprick, temperature, or vibration sensation
    • Hypoglycemia
      • Inquire about timing of episodes, awareness, frequency, and potential causes
    • Cognitive impairment
      • Screen annually for early detection of cognitive impairment in adults aged 65 years or older r145

Complications and Prognosis

Complications

  • Acute
    • Hypoglycemia r28c224
      • Common treatment-related complication of diabetes caused by an imbalance among food intake, physical activity, pharmacologic effects, organ function, and counterregulation with glucagon and/or epinephrine
      • Hypoglycemia thresholds: r150
        • Hypoglycemia below 70 mg/dL is low enough to require fast-acting carbohydrate and adjustment of insulin doses
        • Hypoglycemia below 54 mg/dL indicates serious, clinically important hypoglycemia
        • Any hypoglycemia (no specific threshold) that causes cognitive impairment and requires external assistance for recovery is considered severe
      • Treatment in alert and conscious patient consists of consumption of glucose (eg, juice, soft drink, milk, glucose tablet), reassessment of blood glucose level after 15 minutes, and repeated glucose intake if blood glucose level remains low
      • Confused or unconscious patients should receive an injection of glucagon subcutaneously or intramuscularly from medical personnel or a trained family member/caregiver and then be referred for emergency medical care
      • If untreated, can lead to loss of consciousness, seizure, coma, and death
      • Severe or frequent hypoglycemia is associated with cognitive decline in older adults, increased risk for cardiovascular events, and increased mortality
    • Hyperglycemic hyperosmolar state r151c225
      • Presents with altered mental status, profound dehydration, and hyperglycemia without ketoacidosis
      • Signs and symptoms include polyuria, polydipsia, polyphagia, weight loss, weakness, blood glucose level greater than 600 mg/dL, and serum osmolality greater than 320 mOsm/kg
      • Occurs more frequently in patients with type 2 diabetes than DKA because insulin production is sufficient to prevent ketoacidosis but insufficient to prevent severe hyperglycemia with accompanying dehydration; onset is slower than that of DKA
      • Relatively high mortality rate owing to higher incidence in older patients with comorbidities and severe dehydration
      • Treat with fluid resuscitation, insulin, electrolyte replacement, and correction of precipitating factors
    • DKA r151c226d3
      • Seldom occurs spontaneously in patients with type 2 diabetes, but on rare occasions can occur in association with illness or infection; onset is abrupt
        • DKA has been associated with use of sodium-glucose cotransporter 2 inhibitors; heightened awareness for DKA should be maintained in patients taking this class of medications r30
      • Presents with the biochemical triad of hyperglycemia, ketonemia, and metabolic acidosis
      • Signs and symptoms include polyuria, polydipsia, polyphagia, weight loss, weakness, abdominal pain, nausea, vomiting, Kussmaul respirations, acetone breath, and blood glucose level more than 250 mg/dL r45
      • Treat with fluid resuscitation, insulin, electrolyte replacement, and correction of the precipitating factors (including discontinuation of sodium-glucose cotransporter 2 inhibitors, if relevant)
  • Chronic
    • Cardiovascular disease c227
      • Major macrovascular complication of type 2 diabetes
      • Impact of strict glycemic control on reducing risk of cardiovascular disease in type 2 diabetes is uncertain owing to mixed results from clinical trials
        • 2 clinical trials with long-term follow-up have shown a 15% to 17% reduction in cardiovascular disease with intensive glycemic therapy,r152r153 whereas others have shown no benefitr154 or harmr155
        • Composite analysis of trials of intensive glycemic control suggests that glucose lowering has an overall modest reduction in major cardiovascular disease outcomes, which likely emerge after many years of intensive therapy and strict control r156
      • Antiplatelet therapy with low-dose aspirin, statin therapy, and aggressive blood pressure and glycemic control is recommended; also consider the addition of an ACE inhibitor
    • Peripheral vascular disease r36c228
      • Atherosclerotic occlusive disease of the medium and small vessels of the lower extremities; initially characterized by intermittent claudication
      • Progression to limb-threatening ischemia is characterized by pain at rest, tissue loss, and gangrene
      • Major cause of lower extremity amputations
      • Presence of peripheral vascular disease is indicative of systemic vascular disease (eg, coronary, renal, cerebral) and is an associated risk for myocardial infarction, cerebral vascular events, and death
      • Treatment focuses on smoking cessation, exercise therapy, foot care, glycemic control, control of dyslipidemia and hypertension, antiplatelet therapy, and symptom control with pentoxifylline or cilostazol
    • Retinopathy c229d11
      • Present in 25% to 45% of patients with type 2 diabetes; leading cause of blindness in adults r32r157
      • Begin annual assessment for diabetic retinopathy at time of type 2 diabetes diagnosis
      • Diabetic retinopathy includes macular edema, nonproliferative diabetic retinopathy, and proliferative diabetic retinopathy
      • Progression of diabetic retinopathy may be slowed with aggressive blood pressure, lipid, and glycemic control
      • Treatment may include laser photocoagulation therapy and anti–vascular endothelial growth factor therapy
    • Nephropathy c230d12
      • Present in 40% of patients with diabetes; cause of 40% to 50% of end-stage renal disease cases r32
      • Begin annual assessment for diabetic nephropathy at time of type 2 diabetes diagnosis; include assessment of urinary albumin-to-creatinine ratio and serum creatinine level for estimated GFR r10
      • Progression of diabetic nephropathy may be slowed with aggressive control of blood pressure, lipids, and glycemia r128
      • Treatment with an ACE inhibitor or an angiotensin receptor blocker is recommended for a urinary albumin-creatinine ratio of more than 30 mg/g creatinine r10r128
        • Both drug classes have the dual effects of controlling blood pressure and slowing the progression of kidney damage
        • Avoid combined use of an ACE inhibitor and an angiotensin receptor blocker, owing to higher risks of hyperkalemia and acute kidney injury r158
      • Supportive care measures are also important components of care (eg, maintaining a low-protein/low-fat diet, performing physical exercise, reducing alcohol consumption, and smoking cessation)
    • Neuropathy r10c231d13
      • Affects approximately 50% of patients with diabetes; cause of 50% to 75% of all nontraumatic amputations r32
      • Begin annual neurologic assessment at time of type 2 diabetes diagnosis
      • Encompasses an array of heterogeneous conditions; most common are diabetic peripheral neuropathy and autonomic neuropathy
        • Diabetic peripheral neuropathy
          • Signs and symptoms include decreased sensation, pain, paresthesia, decreased reflexes, decreased pulses, abnormalities in foot structure, impaired skin integrity, and decreased skin temperature; occurs primarily in the feet, legs, and ankles
          • Painful neuropathy may be treated with tricyclic antidepressants, selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and/or anticonvulsants
          • Large fiber neuropathies cause ataxia and increase the risk of falls; management consists of physical therapy, orthotics, tendon lengthening, casting, and/or surgery
          • Small fiber neuropathies may be diagnosed with a skin punch biopsy; management consists of measures to protect the feet (eg, prevention of heat injury, padded socks, daily inspection, skin emollients)
        • For neuropathic pain, first line treatments include pregabalin, gabapentin, or duloxetine r10r159
        • Autonomic neuropathy c232
          • Signs and symptoms vary by the system affected
            • Cardiovascular autonomic neuropathy: orthostatic hypotension; exercise intolerance; resting tachycardia; and heart rate variability on Valsalva maneuver, deep inspiration, or position change
            • Gastrointestinal autonomic neuropathy: gastroparesis, constipation, fecal incontinence, nausea, vomiting, and erratic glucose control
            • Genitourinary autonomic neuropathy: erectile dysfunction; vaginal dryness; nocturia; and urinary frequency, urgency, retention, or incontinence
            • Vasomotor autonomic neuropathy: anhidrosis, hyperhidrosis, heat intolerance, impaired visceral sensation, hypoglycemic unawareness
          • Cardiovascular autonomic neuropathy is significant as a risk factor for cardiovascular mortality
          • Treatment depends on the system affected and is aimed at symptom management

Prognosis

  • Mortality rate for adults with diabetes (any type) is approximately 1.5 times higher than that of the general population, largely because of cardiovascular events r2
  • People with type 2 diabetes have excess mortality compared with the general population r160
    • Overall mortality hazard ratio is 1.27 (95% confidence interval, 1.26-1.28) r160
    • Cardiovascular death hazard ratio is 1.33 (95% confidence interval, 1.31-1.34) r160
    • Excess risk of death increases with increasing mean hemoglobin A1C level r160
  • For each increase of 1 percentage point in hemoglobin A1C level, there is a corresponding average increase in risk of 12% for all-cause mortality and 14% for cardiovascular mortality r160
  • Excess mortality in type 2 diabetes appears to be greater with worsening glycemic control, severe renal complications, and impaired renal function r160
  • Intensive glycemic control resulting in hemoglobin A1C level less than 7% is associated with 25% reduction in risk of microvascular complications (eg, retinopathy, nephropathy, neuropathy); intensive glycemic control does not have as great an effect on cardiovascular complications r161

Screening and Prevention

Screening

At-risk populations

Screening tests

  • Screening tests are similar to diagnostic testing and include any of the following: r4
    • Fasting plasma glucose level c314
    • Oral glucose tolerance test c315
    • Hemoglobin A1C level c316

Prevention

  • In patients with impaired glucose tolerance, type 2 diabetes can be delayed or prevented through lifestyle modification and pharmacologic intervention r162r163r164
    • Lifestyle modification includes: c317c318
      • Weight loss of 5% to 10% of body weight if overweight or obese at baseline r107c319c320c321c322
      • Dietary changes c323c324
        • Various eating patterns, including low-fat, low-calorie diets; DASH diet (Dietary Approaches to Stop Hypertension); and the Mediterranean diet, are appropriate r165r166c325c326
        • Ideal, most effective macronutrient composition to achieve weight loss varies by person
      • Exercise to include at least 150 minutes per week of moderate intensity activity r32c327c328c329c330
    • Intensive lifestyle interventions that target the risk factors of obesity and sedentary activity reduce progression from impaired glucose tolerance to overt type 2 diabetes by 58% r32
    • Pharmacologic therapy (eg, metformin, acarbose,r167 thiazolidinediones) has been shown to be effective in slowing the progression from impaired glucose tolerance to type 2 diabetes c331c332c333c334c335c336
      • Metformin has the strongest evidence base and safety record as pharmacologic therapy for diabetes prevention r168r169
        • Use of metformin reduced or delayed risk of progression to diabetes in those at increased risk when compared to placebo or diet and exercise, but not when compared to intensive lifestyle intervention r169r170
        • Consider for patients with prediabetes, especially those with BMI more than 35 kg/m², those younger than 60 years, and women with history of gestational diabetes r166
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