Diabetes Mellitus Type 2 in Adults

History

• Most patients are initially asymptomatic, then identified through routine screening or by an incidental finding on laboratory tests in context of another illness ^c1
• Type 2 diabetes can be undiagnosed for many years owing to gradual development of hyperglycemia over time
• 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 ^c22
• Elevated blood pressure (common) ^r6c23
  • Patients found to have blood pressure of 140/90 mm Hg or higher should have blood pressure confirmed with multiple readings, including measurements on a separate day, to diagnose hypertension
  • Patients with blood pressure of 180/110 mm Hg or higher and known cardiovascular disease can receive hypertension diagnosis in a single visit
• Signs of complications in long-standing and/or poorly controlled disease:
  • Microaneurysms, exudates, and/or macular edema on funduscopic examination ^{c24c25c26c27c28c29}
  • Decreased lower extremity sensation, pedal pulses, and/or reflexes ^{c30c31c32c33c34c35}
  • Foot ulcers, deformities, or wounds on inspection ^c36c37c38c39
  • Heart rate variability on deep inspiration, position change, and/or Valsalva maneuver ^{c40c41c42c43c44c45}

Causes

• Multifactorial pathogenesis in which metabolic, behavioral, lifestyle, and environmental factors precipitate disease in genetically predisposed persons ^r7c46c47c48
  • 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 increase 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

Primary diagnostic tools

• Elements of history and physical examination findings can suggest the disorder, but biochemical parameters are essential for diagnosis ^c79
• Issues to consider in selection of diagnostic testing method: ^r7
  • Fasting glucose level
    • Advantage: easy, inexpensive measurement
    • Disadvantages:
      • Relatively insensitive
      • Levels fluctuate
      • Test requires patient to fast overnight
  • Oral glucose tolerance test
    • Advantage: most sensitive as a metabolic test
    • Disadvantage: inconvenient and time-consuming for patient
  • Hemoglobin A1C level
    • Advantages:
      • Convenient
      • Best measure of chronic glycemia
      • Closely associated with complications
      • 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: ^r1
  • 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 diagnosis requires 2 of the above abnormal test results unless accompanied by clear clinical diagnosis of hyperglycemia ^r1
• Condition of prediabetes is met with 1 or both of the following states, or with hemoglobin A1C testing: ^r1
  • 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 ^r11
  • Measure the following:
    • Blood pressure
    • Comprehensive metabolic panel (includes electrolytes, renal and liver function)
    • Fasting lipid panel
    • Urinary albumin excretion
  • Refer for baseline dilated eye examination
  • Obtain resting ECG for patients with hypertension or suspected cardiovascular disease ^r12
  • For older adult patients with diabetes, assess osteoporosis risk factors and obtain fracture history; recommend measurement of bone mineral density if appropriate for patient's age and sex
  • Refer patients with symptoms suggestive of obstructive sleep apnea (eg, excessive daytime sleepiness, snoring, witnessed apnea) for screening for sleep apnea ^r13
  • Consider measurement of early morning serum testosterone level in males with diabetes and signs and symptoms of hypogonadism (eg, decreased libido, erectile dysfunction)
  • For patients with elevated liver enzyme levels, obtain liver ultrasonography and evaluate for presence of nonalcoholic steatohepatitis and liver fibrosis
  • Recommend dental assessment for periodontal disease ^r14r15

Laboratory ^c80c81

• Fasting glucose measurement ^r1c82
  • 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
• Random glucose measurement ^r1c83
  • 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 ^r1c84
  • Performed 2 hours after oral ingestion of 75 g of glucose dissolved in water
  • Ensure patient has had adequate carbohydrate intake (at least 150 g/day) for 3 days before testing
  • 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
• Hemoglobin A1C level ^r1c85
  • 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 result for definitive diagnosis)
  • Accuracy is reduced in certain conditions:
    • 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 for Black patients (hemoglobin A1C measurement is higher than in White patients despite similar glucose levels) ^r16
• Pancreatic autoantibody testing ^r1c86
  • 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 for most patients with type 2 diabetes
• C-peptide level ^c87
  • Normal or elevated C-peptide level is usually indicative of type 2 diabetes, whereas low or completely absent C-peptide level is indicative of type 1 diabetes ^r17
  • Can be low in 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: ^r11
  • Fasting lipid panel ^c88
  • Renal function tests for nephropathy ^c89
    • Estimated GFR ^c90
    • Urine albumin to creatinine ratio ^c91
  • Liver function tests ^c92

Most common

• Type 1 diabetes ^c93d1
  • 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: ^r18
    • Younger age at onset (younger than 40 years)
    • BMI within reference range
    • History of ketoacidosis
  • 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 ^c94d2
  • 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 is suggested by 24-hour urine volume more than 3 L^r19 and low urinary osmolality; definitive diagnosis requires water deprivation test
  • Most easily differentiated from diabetes mellitus on basis of laboratory testing (ie, plasma glucose level, oral glucose tolerance test, or hemoglobin A1C level)
• Monogenic diabetes/maturity-onset diabetes of youth ^r20r21c95
  • 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: ^r22
    • Mild fasting hyperglycemia that is stable and easy to control over long term
    • Gestational diabetes in females without typical risk factors
    • BMI 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) ^r23
• Medication-induced diabetes ^r24c96
  • Drugs promoting hyperglycemia may also induce type 2 diabetes in a genetically susceptible person ^r25
  • Common triggers include:
    • Glucocorticoids
    • Thiazide diuretics
    • Atypical antipsychotics
    • Statins
    • Calcineurin inhibitors
  • Identified by temporal association of hyperglycemia that develops after inciting drug is used
  • Resolution of hyperglycemia after discontinuation of introduced medication confirms medication-induced diabetes
    • However, when it is not practical to discontinue medication, hyperglycemia is treated with pharmacotherapy as needed
• Endocrinopathies
  • Some rare neuroendocrine tumors secrete or cause secretion of hormones that antagonize insulin action or reduce insulin secretion, leading to hyperglycemia ^c97
  • 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 course of disease ^{c98c99c100c101}

Admission criteria ^r37

DKA ^r38d3

• 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 ^r39

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

Hypoglycemia with neuroglycopenia ^r37

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

Uncontrolled diabetes ^r37

• 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 that cause uncontrolled diabetes that cannot be managed in community

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: ^r7
  • Uncertain diagnosis
  • Teaching and supervising insulin therapy
  • Treatment of labile glycemia (eg, recurrent hypoglycemia, persistent hyperglycemia, ketoacidosis)
  • When complexity of care exceeds capacity of primary care setting
• Nephrologist for:
  • Persistent proteinuria
  • Decreased GFR
  • Labile blood pressure
  • Hyperkalemia
• Cardiologist for associated cardiovascular disease management
• Podiatrist for:
  • Orthotic footwear
  • 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
  • Cognitive impairment

Drug therapy

• Oral agents
  • Biguanides
    • Decrease hepatic glucose production and increase glucose uptake in muscle tissue
    • First line monotherapy for most patients with diabetes; may be continued as other agents are added
    • Can be used in patients with renal impairment provided estimated GFR is 30 mL/minute/1.73 m² or more ^r70
      • Dosage adjustment is required when estimated GFR is less than 45 mL/minute/1.73 m² (for some patients, required when estimated GFR is 45-59 mL/minute/1.73 m²)
    • Low risk for hypoglycemia with long-lasting antihyperglycemic effect
    • May benefit cardiovascular health ^r71
    • Metformin reduces weight to a greater extent than all other oral agents except the sodium-glucose cotransporter-2 inhibitors ^r41
    • May cause adverse gastrointestinal effects (eg, cramping, diarrhea) and vitamin B₁₂ deficiency; monitor vitamin B₁₂ levels
    • Metformin immediate-release ^c102
      • Metformin Hydrochloride Oral tablet; Adults: 500 mg PO twice daily or 850 mg PO once daily, initially. May increase dose by 500 mg/week or 850 mg every 2 weeks if needed. Doses more than 2,000 mg/day may be better tolerated in 3 divided doses. Max: 2,550 mg/day. Use doses more than 1,000 mg/day with caution in older adults.
    • Metformin extended-release
      • Metformin Hydrochloride Oral tablet, extended-release; Adults: 500 mg PO once daily, initially. May increase dose by 500 mg/week if needed. Max: 2,000 mg/day; may consider 1,000 mg PO twice daily if glycemic control is not achieved with 2,000 mg PO once daily. Use doses more than 1,000 mg/day with caution in older adults.
  • Sulfonylureas ^c103
    • Stimulate insulin secretion
    • Risk of hypoglycemia present, especially in the setting of concomitant renal insufficiency
    • Retrospective data suggest a possible cardiovascular risk with use of this class of drugs, compared with metformin ^r72
    • May cause weight gain, and efficacy may decrease after several years of treatment
    • Glimepiride ^c104
      • Glimepiride Oral tablet; Adults: 1 or 2 mg PO once daily, initially. May increase dose by 1 or 2 mg/day every 1 to 2 weeks if needed. Max: 8 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Glimepiride Oral tablet; Older Adults: 1 mg PO once daily, initially. May increase dose by 1 or 2 mg/day every 1 to 2 weeks if needed; a conservative titration scheme is recommended.  Max: 8 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Glipizide immediate-release ^c105
      • Glipizide Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose by 2.5 to 5 mg/day after several days if needed. Divide doses more than 15 mg/day into 2 doses. Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Glipizide Oral tablet; Older Adults: 2.5 mg PO once daily, initially. May increase dose by 2.5 to 5 mg/day after several days if needed; a conservative titration scheme is recommended. Divide doses more than 15 mg/day into 2 doses. Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Glipizide extended-release
      • Glipizide Oral tablet, extended-release; Adults: 5 mg PO once daily, initially. Adjust dose based on glycemic control if needed. Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Glipizide Oral tablet, extended-release; Older Adults: 2.5 mg PO once daily, initially. Adjust dose based on glycemic control if needed. Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Glyburide ^c106
      • Glyburide Oral tablet; Adults: 2.5 to 5 mg PO once daily, initially. May increase dose by 2.5 mg/day every week if needed. Consider dividing dose more than 10 mg/day into 2 doses. Usual dose range: 1.25 to 20 mg/day. Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Glyburide Oral tablet; Geriatric Adults: 1.25 mg PO once daily, initially. May increase dose by 2.5 mg/day every week if needed; a conservative titration scheme is recommended. Consider dividing dose more than 10 mg/day into 2 doses. Usual dose range: 1.25 to 20 mg/day. Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  • Dipeptidyl-peptidase IV inhibitors ^c107
    • Increase glucose-dependent insulin secretion and decrease glucagon secretion
    • Low risk of hypoglycemia
    • Neutral effect on risk of myocardial infarction or stroke but increased risk of hospitalization for heart failure; use with caution for patients with concurrent heart failure ^r69
    • May cause upper respiratory tract infections, pancreatitis, or immune-related dermatologic effects (eg, angioedema, urticaria)
    • Comparison with other oral agents ^r41
      • Favored over sulfonylureas in terms of long-term all-cause mortality, long-term cardiovascular mortality, and cardiovascular morbidity
      • Favored over pioglitazone in terms of short-term cardiovascular morbidity
      • Favored over sulfonylureas or thiazolidinediones for weight control
      • Inferior to metformin and sulfonylureas for hemoglobin A1C reduction
    • Dose adjustment (except for linagliptin) is needed for patients with chronic kidney disease
    • Alogliptin ^c108
      • Alogliptin Oral tablet; Adults: 25 mg PO once daily.
    • Linagliptin ^c109
      • Linagliptin Oral tablet; Adults: 5 mg PO once daily.
    • Saxagliptin ^c110
      • Saxagliptin Oral tablet; Adults: 2.5 or 5 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Sitagliptin ^c111
      • Sitagliptin Phosphate Oral tablet; Adults: 100 mg PO once daily.
  • Sodium-glucose cotransporter-2 inhibitors ^c112
    • Increase urinary excretion of glucose
    • 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 ^r41
    • Low risk of hypoglycemia
    • Class-wide clinical benefits in addition to improved glycemic control include reduced risk of hospitalization due to heart failure (for patients with and without existing cardiovascular disease), reduced risk of major cardiovascular events for patients with atherosclerotic cardiovascular disease or chronic kidney disease, and improved renal outcomes for patients with kidney disease ^r47r48r73
    • May cause dehydration, hypotension, minimal increases in LDL-C level, weight loss, urinary tract infections, fungal genital tract infections, bone loss, and fractures
    • Canagliflozin ^c113
      • Canagliflozin Oral tablet; Adults: 100 mg PO once daily, initially. May increase dose to 300 mg PO once daily if needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Dapagliflozin ^c114
      • Dapagliflozin Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose to 10 mg PO once daily if needed.
    • Empagliflozin ^c115
      • Empagliflozin Oral tablet; Adults: 10 mg PO once daily, initially. May increase dose to 25 mg PO once daily if needed.
    • Ertugliflozin ^c116
      • Ertugliflozin Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose to 15 mg PO once daily if needed.
  • Glucagon-like peptide-1 receptor agonists
    • Semaglutide is the only oral glucagon-like peptide-1 receptor agonist available; all others are injectable
    • Increase glucose-dependent insulin secretion, decrease glucagon secretion, slow gastric emptying, and increase satiety
    • Low risk of hypoglycemia
    • Oral semaglutide has been shown to be noninferior to placebo in a composite end point of major adverse cardiovascular event outcomes; superiority in major adverse cardiovascular event outcomes is being evaluated in the SOUL study ^r74r75
    • Frequently cause adverse gastrointestinal effects (eg, nausea, vomiting, diarrhea) and weight loss
    • Use with caution for patients with a history of pancreatitis; discontinue if pancreatitis develops
    • Contraindicated for patients with personal or family history of medullary thyroid carcinoma or patients with multiple endocrine neoplasia type 2
    • Semaglutide
      • Semaglutide Oral tablet; Adults: 3 mg PO once daily for 30 days, then 7 mg PO once daily, initially. May increase the dose to 14 mg PO once daily after at least 30 days on 7 mg/day if additional glycemic control is needed.
  • Meglitinides ^c117
    • Increase insulin secretion
    • Moderate risk of causing hypoglycemia
    • No clear evidence to support a cardiovascular benefit ^r76
    • May cause weight gain
    • May cause dizziness, diarrhea, and upper respiratory tract infections
    • Nateglinide ^c118
      • Nateglinide Oral tablet; Adults: 120 mg PO 3 times daily, or 60 mg PO 3 times daily for patients who are near glycemic goal when treatment is initiated.
    • Repaglinide ^c119
      • Repaglinide Oral tablet; Adults: 0.5 mg PO before each meal for patients whose HbA1c is less than 8% and 1 or 2 mg PO before each meal for patients whose HbA1c is 8% or more. May double the dose after at least 1 week if needed. Usual dose range: 0.5 to 4 mg PO before each meal. Max: 4 mg/dose and 16 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  • Thiazolidinediones ^c120
    • Increase glucose uptake by fat and muscle tissue and decrease hepatic glucose production
    • Low risk of hypoglycemia
    • May benefit some aspects of cardiovascular health and improve lipid profile, but incidence of heart failure is increased ^r77r78
    • Contraindicated for patients with New York Heart Association class 3 and 4 heart failure
    • May cause weight gain, fluid retention, peripheral edema, bone loss, and fractures
    • Useful for patients with nonalcoholic steatohepatitis
    • Safe for patients with renal insufficiency and renal failure
    • Whether pioglitazone increases risk of bladder cancer is controversial ^r79
    • Pioglitazone ^c121
      • Pioglitazone Hydrochloride Oral tablet; Adults: 15 or 30 mg PO once daily, initially. May increase dose by 15 mg/day based on HbA1c if needed. Max: 45 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions
    • Rosiglitazone ^c122
      • Rosiglitazone Maleate Oral tablet; Adults: 4 mg PO once daily or 2 mg PO twice daily, initially. May increase dose to 8 mg/day after 12 weeks if needed. Max: 8 mg/day. 4 mg PO once daily or 2 mg PO twice daily, initially. May increase dose to 8 mg/day after 12 weeks if needed. Max: 8 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  • α-Glucosidase inhibitors ^c123
    • Slow carbohydrate digestion and absorption from the intestines
    • Low risk of hypoglycemia
    • Treatment has been associated with decreased composite of cardiovascular outcomes for patients with prediabetes ^r80r81
    • May cause adverse gastrointestinal effects (eg, flatulence, diarrhea) and are typically considered weight neutral
    • Acarbose ^c124
      • Acarbose Oral tablet; Adults weighing more than 60 kg: 25 mg PO 3 times daily, initially, or alternately, 25 mg PO once daily to minimize gastrointestinal side effects. May increase dose to 50 mg PO 3 times daily and then 100 mg PO 3 times daily every 4 to 8 weeks based on 1-hour post-prandial glucose or HbA1c if needed. Max: 100 mg PO 3 times daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Acarbose Oral tablet; Adults weighing 60 kg or less: 25 mg PO 3 times daily, initially, or alternately, 25 mg PO once daily to minimize gastrointestinal side effects. May increase dose to 50 mg PO 3 times daily every 4 to 8 weeks based on 1-hour post-prandial glucose or HbA1c if needed. Max: 50 mg PO 3 times daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Miglitol ^c125
      • Miglitol Oral tablet; Adults: 25 mg PO 3 times daily, initially, or alternately, 25 mg PO once daily to minimize gastrointestinal side effects. May increase dose after 4 to 8 weeks to 50 mg PO 3 times daily for 3 months and then 100 mg PO 3 times daily based on HbA1c if needed. Max: 100 mg PO 3 times daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  • Bile acid sequestrants ^r82c126
    • Decrease hepatic glucose production and increase incretin levels
    • Low risk of hypoglycemia
    • Lower LDL-C level
    • May cause constipation
    • Colesevelam hydrochloride ^c127
      • Colesevelam Hydrochloride Oral tablet; Adults: 1.875 g PO twice daily or 3.75 g PO once daily.
  • Central acting dopamine-2 agonists ^c128
    • Decrease postprandial glucose due to suppression of hepatic glucose production ^r83
    • Low risk of hypoglycemia
    • May improve cardiovascular health
    • May cause nausea, orthostatic hypotension, fatigue, or rhinitis
    • Contraindicated for patients taking antipsychotic medications
    • Bromocriptine mesylate ^c129
      • Bromocriptine Mesylate Oral tablet [Diabetic Therapy]; Adults: 0.8 mg PO once daily in the morning within 2 hours of waking, initially. May increase dose by 0.8 mg/day every 7 days if needed. Usual dose: 1.6 to 4.8 mg/day. Max: 4.8 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
• Noninsulin injectables
  • Glucagon-like peptide-1 receptor agonists ^c130
    • Increase glucose-dependent insulin secretion, decrease glucagon secretion, slow gastric emptying, and increase satiety
    • Low risk of hypoglycemia
    • Reduce risk of major cardiovascular events for patients with atherosclerotic cardiovascular disease ^r47r48
    • Frequently cause gastrointestinal adverse effects (eg, nausea, vomiting, diarrhea) and weight loss
    • Use with caution for patients with a history of pancreatitis; discontinue if pancreatitis develops
    • Contraindicated for patients with personal or family history of medullary thyroid carcinoma or patients with multiple endocrine neoplasia type 2 (except twice-daily exenatide)
    • Dulaglutide ^c131
      • Dulaglutide Solution for injection; Adults: 0.75 mg subcutaneously once weekly, initially. Increase the dose to 1.5 mg subcutaneously once weekly for additional glycemic control; may increase the dose to 3 mg subcutaneously once weekly after at least 4 weeks on 1.5 mg/week and 4.5 mg subcutaneously once weekly after at least 4 weeks on 3 mg/week if additional glycemic control is needed. Max: 4.5 mg/week.
    • Exenatide immediate-release ^c132
      • Exenatide Solution for injection; Adults: 5 mcg subcutaneously twice daily, initially. May increase the dose to 10 mcg subcutaneously twice daily after 1 month if additional glycemic control is needed.
    • Exenatide extended-release
      • Exenatide Suspension for injection, Extended Release; Adults: 2 mg subcutaneously once weekly.
    • Liraglutide ^c133
      • Liraglutide Solution for injection; Adults: 0.6 mg subcutaneously once daily for 1 week, then 1.2 mg subcutaneously once daily, initially. May increase the dose after at least 1 week to 1.8 mg subcutaneously once daily if additional glycemic control is needed.
    • Lixisenatide ^c134
      • Lixisenatide Solution for injection; Adults: 10 mcg subcutaneously once daily for 14 days, then 20 mcg subcutaneously once daily.
    • Semaglutide ^c135
      • Semaglutide Solution for injection; Adults: 0.25 mg subcutaneously once weekly for 4 weeks, then 0.5 mg subcutaneously once weekly, initially. May increase the dose to 1 mg subcutaneously once weekly after 4 weeks on 0.5 mg/week and 2 mg subcutaneously once weekly after 4 weeks on 1 mg/week if additional glycemic control is needed.
  • Dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 agonists ^r84
    • Activate both the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors to increase insulin secretion and decrease glucagon levels in a glucose-dependent manner ^r84
    • Low risk of hypoglycemia
    • SURPASS-CVOT study is underway to evaluate long-term cardiovascular outcomes of tirzepatide compared with dulaglutide ^r85
    • May cause adverse gastrointestinal effects (nausea, vomiting, diarrhea); associated with weight loss
    • Tirzepatide injection
      • Tirzepatide Solution for injection; Adults: 2.5 mg subcutaneously once weekly for 4 weeks, then 5 mg subcutaneously once weekly, initially. May increase dose by 2.5 mg/week after at least 4 weeks if needed. Max: 15 mg/week.
  • Amylin mimetic/analogues ^c136
    • Decrease glucagon secretion, slow gastric emptying, and increase satiety
    • Low risk of hypoglycemia
    • Neutral cardiovascular effects ^r86
    • May cause adverse gastrointestinal effects (eg, nausea, vomiting) and weight loss
    • Pramlintide ^c137
      • Pramlintide Acetate Solution for injection; Adults: 60 mcg subcutaneously immediately before each major meal. May increase dose to 120 mcg/dose when no clinically significant nausea has occurred for at least 3 days. Max: 120 mcg/dose. If significant nausea persists at 120 mcg/dose, decrease dose to 60 mcg/dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

  • Non-insulin injectables for type 2 diabetes mellitus.

    GLP-1, glucagon-like peptide 1; MACE, major adverse cardiovascular events; MEN-2, multiple endocrine neoplasia type 2; SURPASS-CVOT, the Effect of Tirzepatide Versus Dulaglutide on Major Adverse Cardiovascular Events in Patients With Type 2 Diabetes trial. * 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 class	Hemoglobin A1C–lowering effect	Hypoglycemia risk	Cardiovascular effects	Effect on body weight	Comments
    GLP-1 receptor agonist	1%-1.5%	Neutral	Liraglutide 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)*	Loss	Contraindicated in patients with personal or family history of medullary thyroid carcinoma or MEN-2; check renal function at baseline and periodically throughout therapy
    Combined insulin- GLP-1 receptor agonist	More than 1.5%	Moderate, due to insulin component		Allows less weight gain (or even promotes minor weight loss) that otherwise occurs with insulin	Same contraindications as with GLP-1 receptor agonist; check renal function at baseline and periodically throughout therapy
    Amylin Mimetic	0.5%	Neutral alone, but increased risk of hypoglycemia when used with insulin (as indicated)		Slight loss; may limit weight gain that occurs with use of insulin	Indicated for use in conjunction with basal-bolus insulin regimens
    Dual GIP and GLP-1 agonist	1.8 - 2.07%	Neutral	SURPASS-CVOT trial underway to asses long-term cardiovascular outcomes	Loss	Same contraindications as with GLP-1 receptor agonists

• Insulin ^c138
  • Insulin regimens are 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 may 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 ^r87
  • Selection of basal insulin ^r88
    • Both isophane insulin suspension and basal insulin analogues are capable of lowering hemoglobin A1C level to a similar extent, but 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, long; detemir, shortest
    • Long-acting insulin analogues are preferable for patients on basal insulin therapy who are at high risk for hypoglycemia ^r89
  • 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) ^r58
    • Step 1: start basal insulin analogue (eg, glargine, detemir, degludec) ^c139c140c141
      • 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 degludec
      • Insulin Degludec Solution for injection; Adults: 10 units subcutaneously once daily, or alternately, 0.1 to 0.2 units/kg/day subcutaneously once daily, initially. Increase dose by 2 units every 3 days to achieve target fasting plasma glucose without hypoglycemia; reduce dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
    • Insulin detemir
      • Insulin Detemir (Recombinant) Solution for injection; Adults: 10 units subcutaneously once daily or divided twice daily, or alternately, 0.1 to 0.2 units/kg/day subcutaneously once daily or divided twice daily, initially. Increase dose by 2 units every 3 days to achieve target fasting plasma glucose without hypoglycemia; reduce dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
    • Insulin glargine
      • Insulin Glargine Solution for injection; Adults: 10 units subcutaneously once daily, or alternately, 0.1 to 0.2 units/kg/dose subcutaneously once daily, initially. Increase dose by 2 units every 3 days to achieve target fasting plasma glucose without hypoglycemia; reduce dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
  • 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) ^{c142c143c144c145}
    • Various stepwise approaches may be used to start prandial insulin
      • Weight-based, given at each meal ^r27
        • 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
        • Titrate every 2 to 3 days to reach glycemic targets
        • Increase total daily dose by 2 units/day or prandial 10% to 20% depending on type of regimen and severity of blood glucose elevation
      • 1 prandial dose added, given before largest meal of day ^r58
        • 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 ^r90
          • Daily long-acting basal insulin and a prandial rapid-acting insulin with the largest meal is preferred approach rather than use of premixed insulins ^r58
        • 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 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 ^r91
          • 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
        • Consider decreasing basal insulin dose if significant increases are made to the prandial insulin dose, particularly to evening meal dose ^r2
    • Insulin aspart
      • Insulin Aspart (Recombinant) Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily 5 to 10 minutes before the largest meal or meal with the greatest postprandial glucose excursion, initially. Consider lowering the basal insulin dose by 4 units or 10% of basal dose if HbA1c is less than 8%. Increase dose by 1 to 2 units or 10% to 15% twice weekly and proceed to full basal-bolus regimen based on blood glucose or HbA1c if further glycemic control is needed; reduce corresponding dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
    • Insulin glulisine
      • Insulin Glulisine Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily 15 minutes before or within 20 minutes after starting the largest meal or meal with the greatest postprandial glucose excursion, initially. Consider lowering the basal insulin dose by 4 units or 10% of basal dose if HbA1c is less than 8%. Increase dose by 1 to 2 units or 10% to 15% twice weekly and proceed to full basal-bolus regimen based on blood glucose or HbA1c if further glycemic control is needed; reduce corresponding dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
    • Insulin lispro
      • Insulin Lispro Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily 15 minutes before or immediately after the largest meal or meal with the greatest postprandial glucose excursion, initially. Consider lowering the basal insulin dose by 4 units or 10% of basal dose if HbA1c is less than 8%. Increase dose by 1 to 2 units or 10% to 15% twice weekly and proceed to full basal-bolus regimen based on blood glucose or HbA1c if further glycemic control is needed; reduce corresponding dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
  • Alternative options for insulin therapy include short-acting (regular), intermediate-acting (neutral protamine Hagedorn insulin, that is, isophane insulin suspension), and premixed insulins; these are less expensive but also less effective for postprandial blood glucose excursions ^r58c146c147
    • Isophane insulin suspension
      • Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Adults: 10 units subcutaneously once daily, or alternately, 0.1 to 0.2 units/kg/day subcutaneously once daily, initially. Increase dose by 2 units every 3 days to achieve target fasting plasma glucose without hypoglycemia; reduce dose by 10% to 20% if hypoglycemia of undetermined cause occurs. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Regular 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
      • Regular insulin 100 units/mL
        • Insulin Regular (Recombinant) Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily approximately 30 minutes before the largest meal or meal with the greatest postprandial glucose excursion, initially. Consider lowering the basal insulin dose by 4 units or 10% of basal dose if HbA1c is less than 8%. Increase dose by 1 to 2 units or 10% to 15% twice weekly and proceed to full basal-bolus regimen based on blood glucose or HbA1c if further glycemic control is needed; reduce corresponding dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
      • Concentrated regular insulin, U-500 (500 units/mL) ^r92
        • 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
        • Always use a conversion chart 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
    • Premixed insulin (50/50, 70/30, 80/20)
      • Increased rate of hypoglycemia and inferior glycemic control versus basal insulin alone ^r93
      • Insulin Aspart (Recombinant), Insulin Aspart Protamine (Recombinant) Suspension for injection; Adults: 10 to 12 units subcutaneously once daily, initially. Increase dose by 2 units once or twice weekly to achieve target blood glucose without hypoglycemia; reduce dose by 2 units if hypoglycemia of undetermined cause occurs. Consider dividing the dose twice daily if the dose reaches 40 to 50 units/day.
      • Insulin Lispro Protamine (NPL), Insulin Lispro Suspension for injection; Adults: 10 to 12 units subcutaneously once daily, initially. Increase dose by 2 units once or twice weekly to achieve target blood glucose without hypoglycemia; reduce dose by 2 units if hypoglycemia of undetermined cause occurs. Consider dividing the dose twice daily if the dose reaches 40 to 50 units/day.
      • Insulin Regular (Recombinant), Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Adults: 10 to 12 units subcutaneously once daily, initially. Increase dose by 2 units once or twice weekly to achieve target blood glucose without hypoglycemia; reduce dose by 2 units if hypoglycemia of undetermined cause occurs. Consider dividing the dose twice daily if the dose reaches 40 to 50 units/day.
    • Concentrated long-acting insulin analogues ^r88
      • Insulin glargine U-300
        • Glargine formulation with smaller injection volume, prolonged insulin activity, and efficacy similar to that of 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 with insulin glargine U-100 and insulin detemir ^r94
      • Insulin degludec U-200
        • Degludec formulation with smaller injection volume and efficacy similar to that of U-100 basal analogues
        • Available in a prefilled pen also calibrated for the higher concentration
        • Ability to lower hemoglobin A1C level is similar to that of glargine with lower rates of hypoglycemia ^r95

  • 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 insulin	Names	Time of action: onset, peak, and duration of effects	Comments
    Basal	NPH	Onset: 2-4 hours Peak: 4-10 hours Duration: 10-18 hours	Variable action profile; can mix with rapid-acting insulins. NPH available as 100 unit/mL
    Basal analog	Glargine	Onset: 1.5 hours Peak: none Duration: 24 hours	Glargine available as 100 unit/mL as well as concentrated 300 unit/mL
    	Detemir	Onset: 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. Determir available as 100 unit/mL
    	Degludec	Onset: 1 hour Peak: 12 hours Duration: more than 42 hours	Ultra-long-acting, once-daily basal analog with peakless activity. Degludec available as 100 unit/mL and 200 unit/mL
    Bolus regular	Humulin R	Onset: 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. Available as 100 unit/mL
    Bolus regular U-500 insulin	Humulin R U500	Onset: 30 minutes Peak: 1.5-3.5 hours Duration: 5-7 hours	Use for insulin-resistant patients who need more than 200 total units per day, given 3 times per day. Available as 500 unit/mL
    Bolus rapid-acting analog	Lispro, aspart, glulisine	Onset: 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 available as 100 unit/mL and 200 unit/mL. Aspart and glulisine available as 100 unit/mL
    Premixed insulin (50/50, 70/30, 75/25, 80/20)	Humalog 75/25 or 50/50 mix, Novolog 70/30 mix, Novolin 70/30, Humulin 70/30	Onset: 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

• 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 ^r88
  • Insulin degludec; liraglutide (Xultophy, IDegLira)
    • Formulation contains insulin degludec,100 units/mL, and liraglutide, 3.6 mg/mL, 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
    • Dosage for persons naive to basal insulin or glucagon-like peptide-1 receptor agonist
      • Insulin Degludec, Liraglutide Solution for injection; Adults: 10 units (10 units of insulin degludec and 0.36 mg of liraglutide) subcutaneously once daily, initially. Titrate dose by 2 units (2 units of insulin degludec and 0.072 mg of liraglutide) every 3 to 4 days to achieve target fasting plasma glucose. Max: 50 units/day (50 units/day of insulin degludec and 1.8 mg/day of liraglutide).
    • Dosage for persons converting from basal insulin or glucagon-like peptide-1 receptor agonist
      • Insulin Degludec, Liraglutide Solution for injection; Adults: 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) subcutaneously once daily, initially. Titrate dose by 2 units (2 units of insulin degludec and 0.072 mg of liraglutide) every 3 to 4 days to achieve target fasting plasma glucose. Max: 50 units/day (50 units/day of insulin degludec and 1.8 mg/day of liraglutide).
  • Insulin glargine; lixisenatide (Soliqua, LixiLan) ^c148
    • Formulation contains insulin glargine, 100 units/mL and lixisenatide, 33 mcg/mL, 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 ^r96
    • Dosage for persons naive to basal insulin or glucagon-like peptide-1 receptor agonist, or conversion from less than 30 units/day of basal insulin or a glucagon-like peptide-1 receptor agonist
      • Insulin Glargine, Lixisenatide Solution for injection; Adults: 15 units (15 units of insulin glargine and 5 mcg of lixisenatide) subcutaneously once daily, initially. Titrate by 2 units (2 units of insulin glargine and 0.66 mcg of lixisenatide) to 4 units (4 units of insulin glargine and 1.32 mcg of lixisenatide) every week to achieve target fasting plasma glucose. Max: 60 units/day (60 units/day of insulin glargine and 20 mcg of lixisenatide).
    • Dosage for persons who have inadequate glycemic control with 30 to 60 units of basal insulin
      • Insulin Glargine, Lixisenatide Solution for injection; Adults: 30 units (30 units of insulin glargine and 10 mcg of lixisenatide) subcutaneously once daily, initially. Titrate by 2 units (2 units of insulin glargine and 0.66 mcg of lixisenatide) to 4 units (4 units of insulin glargine and 1.32 mcg of lixisenatide) every week to achieve target fasting plasma glucose. Max: 60 units/day (60 units/day of insulin glargine and 20 mcg of lixisenatide).

• Oral pharmacotherapy for type 2 diabetes mellitus.

  DPP4, dipeptidyl-peptidase 4; eGFR, estimated GFR; GLP1, glucagon-like peptide 1; SGLT2, sodium-glucose co-transporter-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 class	Hemoglobin A1C–lowering effect	Hypoglycemia risk	Micro- or macrovascular benefit	Weight change	Use in renal disease	Warnings	Comments
  Biguanide	1%-1.5%	Neutral	Reduction in cardiovascular events noted in UKPDS	Mostly neutral, but potential for slight loss	eGFR 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 m²	Lactic acidosis risk	Vitamin 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
  SGLT2 inhibitors	0.5%-1%	Neutral	Empagliflozin 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 nephropathy	Loss	Requires 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 inhibitors	Reductions in blood pressure; risk for volume contraction; check renal function at baseline and periodically throughout therapy
  Sulfonylureas	1%-1.5%	Moderate to severe	Reduction in microvascular complications noted in UKPDS	Gain	Hypoglycemia risk increases with declining renal function; contraindicated in chronic kidney disease stage 4	Glyburide not recommended with renal failure	Retrospective data suggest a possible cardiovascular risk with use of this class of drugs, as compared with metformin
  Meglitinides	1%	Moderate		Gain	Hypoglycemia risk increases with declining renal function; may be used in chronic kidney disease stages 3-5 with dosing adjustments		Dosed multiple times per day at meals
  DPP4 inhibitors	0.6%-0.8%	Neutral	Microvascular benefit of reducing albuminuria; potential risk for heart failure hospitalizations with saxagliptin	Neutral	Requires renal dosing adjustments, except linagliptin		Check renal function at baseline and periodically throughout therapy; only linagliptin does not require adjustments for renal insufficiency
  Thiazolidinediones	1%	Neutral	Reduction in cardiovascular events noted in PROactive trial with pioglitazone, but drugs of this class increase incidence of heart failure	Gain		Risk of congestive heart failure (contraindicated in class III and IV heart failure), fracture risk, and possible risk of bladder cancer with pioglitazone	Possible benefit in nonalcoholic steatohepatitis; elevated risk of bone fractures; slight elevation in LDL-C
  α-glucosidase inhibitors	0.5%	Neutral		Neutral			Nonsystemic absorption
  Dopamine-2 agonists	0.5%	Neutral		Neutral

Nondrug and supportive care

Therapeutic lifestyle modifications ^r27r97c149

• Medical nutrition therapy ^r98c150
  • Counseling and education sessions for development of an individualized eating plan according to metabolic needs of individual patient, preferably provided by a registered dietitian ^r99
  • Incorporates weight loss goals, caloric needs, and distribution of macronutrients ^r99
  • Addresses lifestyle, preferences, eating patterns, culture, and comorbidities of individual patient
  • Guidance is available with regard to management of diabetes during fasting for Ramadan and during intercurrent illness ^r100r101
  • Capable of reducing hemoglobin A1C level by 1% to 2% ^r99
  • Various eating patterns (eg, paleolithic, low-carbohydrate, high-protein, vegetarian, nut-enriched diets; DASH diet [Dietary Approaches to Stop Hypertension]; Mediterranean diet^r102) have beneficial effects on weight loss, glycemic control, and cardiovascular risk ^r66r97
    • In general, diets should: ^r103
      • Emphasize nonstarchy vegetables
      • Minimize added sugars and refined grains
      • Avoid highly processed foods
    • Intermittent fasting or time-restricted eating may be feasible for achieving weight loss for some patients ^r97
  • General recommendations consist of: ^r104
    • Emphasizing nutrient-dense foods in appropriate portion sizes
    • Consuming fruits, vegetables, and low-fat dairy products
    • Limiting added sugars
    • Substituting healthy fats for saturated and trans fats
  • 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 ^r97
    • 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 dietary reference intake recommendations for healthy eating, metabolic goals, and total caloric needs ^r99
    • 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 ^r99
      • 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; encourage water as an alternative
    • Fats
      • Recommended total fat intake is equal to 20% to 35% of total calories (same as for general population) ^r97
      • Emphasize consumption of healthy fats (eg, long-chain ω-3 fatty acids, eicosapentaenoic acid, docosahexaenoic acid, α-linolenic acid) from food sources (eg, fish, nuts, avocados)
      • Limit consumption of saturated fats (eg, those from full-fat dairy, red meat, and tropical oils) and trans fats
    • Proteins
      • Emphasize sources of protein that are low in saturated fat (eg, fish, egg whites, beans); avoid processed meats
      • Ideal amount of protein intake
        • Usual protein intake: 15% to 20% of total energy ^r97
        • For patients without diabetic nephropathy, evidence is inconclusive regarding ideal amount of protein intake for optimizing glycemic control or reducing cardiovascular risk ^r105
          • Therefore, protein intake should approximate recommended daily allowance for general population (0.8 g/kg body weight)
        • 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 course of GFR decline
          • For patients with non–dialysis-dependent diabetic kidney disease, recommended daily dietary protein intake is the same as that for general population (0.8 g/kg body weight)
          • For patients receiving dialysis, consider higher levels of dietary protein intake
  • Micronutrients ^r104
    • Routine supplementation is not recommended because no clear evidence of benefit exists for patients with diabetes who do not have underlying deficiencies
    • Healthy diet can usually provide sufficient micronutrients
  • Alcohol ^r97
    • Should be consumed in moderation, if at all (1 or fewer drinks per day for females, 2 or fewer drinks per day for males)
    • Ingestion of alcohol increases risk of delayed hypoglycemia, especially for patients who use insulin or insulin secretagogues
  • Sodium ^r97
    • Recommended total sodium is 2300 mg/day or less (same as for general population)
    • Further sodium reduction (less than 2000 mg/day) is recommended for patients with concurrent hypertension ^r106
• Physical activity ^c151
  • Increased physical activity and exercise improve glycemic control, lipid levels, blood pressure, and insulin sensitivity and lower risk of cardiovascular disease and mortality ^r66
  • Prescribe exercise program with individualized goals ^r107
    • 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 ^r108
    • Participation in high-intensity interval training^r109 is associated with improved insulin sensitivity and reduction in hemoglobin A1C level
    • High-intensity resistance exercise training has greater beneficial effects than low- to moderate-intensity resistance training
  • Advise reduction in overall sedentary time and discourage periods of extended sitting (beyond 30 minutes); small bouts of activity to break up sitting modestly improves postprandial glucose and insulin levels ^r107r110
  • Insulin dosing may need to be modified with exercise to prevent hypoglycemia
  • Pre-exercise medical clearance is unnecessary for patients before beginning low- or moderate-intensity physical activity not exceeding demands of brisk walking, unless symptoms of cardiovascular disease or microvascular complications are present ^r107
  • Pre-exercise medical clearance is recommended for patients who are currently sedentary and will undertake exercise that is more intense than brisk walking and for those with signs or symptoms of cardiovascular disease, long duration of diabetes, older age, or diabetes-related complications ^r107
    • American College of Sports Medicine exercise preparticipation health screening guidelines focus on assessing: ^r111
      • 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 ^c152
  • Patients who are overweight and patients with obesity with type 2 diabetes require at least 5% weight loss to improve glycemic control, lipid levels, and blood pressure ^r97
    • Aiming for more intensive weight loss (eg, 15%) may yield greater benefits and may be an appropriate goal for some patients
  • Primary approach to weight management is through lifestyle modification, which includes:
    • Dietary change focused on caloric restriction
    • Increased energy expenditure through physical activity
    • Behavioral modification (monitoring of food, exercise, and weight)
  • Weight loss goals ^r112
    • For patients who are overweight (BMI 25-29.9 kg/m²)^r113, weight loss goal is to achieve BMI within reference range (18.5-24.9 kg/m²)^r113
    • For patients with obesity (BMI 30 kg/m² or higher),^r113 initial weight loss goal is 5% to 10% of body weight
  • Intensive lifestyle interventions (eg, targeting weight reduction through caloric restriction and increased physical activity) are effective for modest weight loss (3%-5%) ^r112
    • Clinically meaningful health benefits include: ^r66r112
      • Improved physical fitness and HDL-C levels
      • Reductions in hemoglobin A1C level
      • Lower requirements for medication for glucose, blood pressure, and lipid control
    • Weight loss achieved through lifestyle modification decreases cardiovascular risk factors, although available data do not demonstrate that this translates into reduction in cardiovascular events ^r114
  • Pharmacotherapy can be considered when lifestyle interventions do not achieve desired goals ^r64d4
    • Options include orlistat, liraglutide, naltrexone/bupropion, phentermine/topiramate, semaglutide, and tirzepatide ^r64r66
  • Minimally invasive approaches (eg, implanted gastric balloons) are rarely used for patients with diabetes
    • Oral hydrogel that mimics space-occupying effect of implantable gastric balloons has been approved for long-term use by patients with BMI greater than 25 kg/m² and demonstrated improved weight loss outcomes in a subgroup of patients with prediabetes or diabetes ^r64
  • Bariatric surgery may be considered for patients whose BMI remains more than 30 kg/m² despite lifestyle modifications and/or pharmacologic treatment ^r115
    • Achieves greater improvement in glycemic control and reduction of cardiovascular risk factors for patients with obesity and type 2 diabetes compared with lifestyle and pharmacologic interventions ^r66

Diabetes self-management education and support ^r97c153

• Ongoing processes of facilitating knowledge, skill, and ability necessary for patient to participate in diabetes self-care
• Focus is on helping patients make informed self-management decisions
• Core educational topics include: ^r116
  • Diabetes disease process and treatment options
  • Incorporating nutritional changes and physical activity into lifestyle
  • Monitoring blood glucose level, then interpreting and using results for day-to-day management decisions
  • Using medications safely for greatest effectiveness

Blood glucose monitoring

• Self-monitoring of blood glucose ^r63c154
  • 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 efficacy and safety of glucose-lowering therapies
    • Patient uses glucose data 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 health care professional to tailor treatment plan
      • If decline in bedtime to morning glucose level is more than 55 mg/dL (3.1 mmol/L), this suggests an excessive basal insulin dose ^r63
      • Overnight rise in glucose levels may indicate need to increase basal insulin dose
  • Recommended regimen for blood glucose testing depends on medication regimen ^r63
    • 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:
      • Home glucose monitoring may be helpful when altering diet, physical activity, and/or medications
      • Use self-monitoring only when patients and/or caregivers have 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 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 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
      • Persistently elevated hemoglobin A1C level
• Continuous glucose monitoring ^r27r117c155
  • 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 patients own and use over the long term, display glucose data in real time so that 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% ^r118
  • 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 ^r119
    • Offer to all patients who use multiple daily insulin injections who are capable of using the devices, particularly those with higher risk of hypoglycemia or hypoglycemia unawareness ^r27
      • Can also be offered to patients on basal insulin who are capable of using devices safely
    • Small trial conducted in insulin-treated 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 ^r120r121
      • Based on this, continuous glucose monitoring is recommended as an option to improve glycemic control in patients with type 2 diabetes who are treated with basal-bolus insulin therapy ^r122
  • Contraindication: physical or cognitive impairment precluding ability to effectively use the technology

Smoking cessation ^r97c156

• 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 ^r11

• Hepatitis B vaccine is recommended for all adults with type 2 diabetes aged 19 to 59 years; consider for patients aged 60 years or older, depending on risk assessment and projected immune response ^c157c158
• Pneumococcal vaccination with PPSV23 (pneumococcal polysaccharide vaccine) 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 ^c159c160
• Annual influenza vaccine is recommended for all patients with diabetes; do not give live attenuated influenza vaccine ^c161
• Administer other vaccines, including COVID-19, in accordance with age-specific CDC recommendations ^r123

Comorbidities

• Hypertension ^d5
  • Affects most patients with type 2 diabetes and greatly increases risk of micro- and macrovascular complications
  • Treatment of hypertension reduces cardiovascular events and microvascular complications; however, specific blood pressure goal for patients with diabetes has been uncertain; suggested targets vary by professional society ^{r6r66r132r133c169}
    • American Diabetes Association, American College of Cardiology/American Heart Association, and others generally recommend target blood pressure less than 130/80 mm Hg for patients with diabetes ^r6r32
      • Individualize treatment but do not target to less than 120/80 mm Hg, as this is associated with adverse events ^r6
    • Association of British Clinical Diabetologists and Renal Association UK recommend the following blood pressure targets: ^r106
      • Less than 140/90 mm Hg in patients with urine albumin to creatinine ratio less than 3 mg/mmol (less than 26.55 mg/g)
      • Less than 130/80 mm Hg in those with urine albumin to creatinine ratio greater than 3 mg/mmol (greater than 26.55 mg/g)
    • 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 ^r134
      • Association of British Clinical Diabetologists and Renal Association UK recommend blood pressure targets of no lower than 150/90 mm Hg in patients aged 75 years or older ^r106
  • Treatment
    • Advise all patients with blood pressure greater than 120/80 mm Hg to undertake lifestyle changes for reducing blood pressure, such as: ^r6
      • Weight loss, if patient is overweight or has obesity
      • DASH diet or DASH-like diet, 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 130/80 mm Hg ^r6
      • 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
        • Dihydropyridine calcium channel blocker
      • For patients with hypertension, diabetes, and early-stage heart failure, treatment with a thiazide-type diuretic or an ACE inhibitor is more effective than treatment with a calcium channel blocker in preventing progression to symptomatic heart failure ^r135
      • For patients with diabetes, albuminuria, and hypertension, start either an ACE inhibitor or an angiotensin receptor blocker, but not both; titrate to maximum tolerated dose ^r106
      • 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 higher, start pharmacotherapy with 2 agents in addition to lifestyle modifications
• Dyslipidemia ^c170d6
  • Patients with type 2 diabetes have a specific type of dyslipidemia that promotes atherosclerosis and contributes to elevated risk of atherosclerotic cardiovascular disease ^r136
    • 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 ^r78r136
  • Lack of consensus exists among medical societies regarding use of numeric lipid goals
    • American Heart Association does not specify a numeric LDL-C goal ^r137
    • American Association of Clinical Endocrinologists recommends the following LDL-C goals: ^r27r36
      • For patients with diabetes and no atherosclerotic cardiovascular disease or major risk factors: less than 100 mg/dL
      • For patients with diabetes and at least 1 other major risk factor: less than 70 mg/dL
      • For patients with diabetes with established atherosclerotic cardiovascular disease: less than 55 mg/dL
  • Lifestyle modifications to address dyslipidemia are recommended for all patients with diabetes, regardless of whether pharmacotherapy is used, including: ^r136
    • Medical nutrition therapy (low saturated fat, low trans fat, low cholesterol, increased ω-3 fatty acids, increased fiber)
    • Weight loss if necessary
    • Increased physical activity
    • Smoking cessation
  • Intensify lifestyle modifications and optimize glycemic control for patients with triglyceride levels of 150 mg/dL or greater and/or HDL-C levels lower than 40 mg/dL (for males) or lower than 50 mg/dL (for females) ^r6
  • 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
      • Moderate-intensity statin therapy is indicated for adults aged 40 to 75 years with diabetes mellitus without atherosclerotic cardiovascular disease
      • High-intensity statin therapy to reduce LDL-C level by at least 50% of baseline and to target LDL-C goal of less than 70 mg/dL is indicated for adults aged 40 to 75 years who are at higher risk (1 or more atherosclerotic cardiovascular disease risk factors) ^r6
        • Addition of ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor to maximum tolerated statin therapy is reasonable for these patients, especially if multiple atherosclerotic cardiovascular disease risk factors and an LDL-C level of 70 mg/dL or greater are present
      • High-intensity statin therapy to target an LDL-C reduction of at least 50% from baseline and an LDL-C goal of less than 55 mg/dL is recommended for patients with diabetes and atherosclerotic cardiovascular disease ^r6
        • Addition of ezetimibe or a PCSK9 inhibitor is recommended if goals are not achieved on maximum tolerated statin therapy
      • Initiation of statin therapy may be reasonable for adults aged 20 to 39 years with diabetes and additional atherosclerotic cardiovascular disease risk factors ^r6
      • Initiation of moderate-intensity statin therapy is reasonable in adults older than 75 years with diabetes based on individual risks and benefits; it is reasonable for those who are already on statin therapy to continue beyond age 75 years ^r6r137
• Chronic kidney disease ^r138c171
  • Drug therapy is challenging owing to potential for various adverse effects (eg, lactic acidosis, hypoglycemia) ^r139
  • Contraindications and dose adjustments exist for all medication classes and should be reviewed for patients with chronic kidney disease stages 2 to 5
  • Glycemic control is based on a combination of metformin and sodium-glucose cotransporter-2 inhibitors for most patients ^r140
  • Metformin
    • Appropriate, provided that estimated GFR is 30 mL/minute/1.73 m² or more ^r140
      • Dosage adjustment is required when estimated GFR is less than 45 mL/minute/1.73 m² (for some patients, required when estimated GFR is 45-59 mL/minute/1.73 m²) ^r70
    • Discontinue when estimated GFR falls below 30 mL/minute/1.73 m²
  • Sodium-glucose cotransporter-2 inhibitors
    • Recommended in addition to angiotensin receptor blocker or ACE inhibitor to reduce chronic kidney disease progression, all-cause mortality, cardiovascular mortality, and hospitalization for heart failure for patients with estimated GFR of 20 mL/minute/1.73 m² or greater and urinary albumin-creatinine ratio of 200 mg/g or greater ^r50r141
      • May also be beneficial for patients with urinary albumin-creatinine ratio ranging from normal to 200 mg/g
    • Can be continued even if estimated GFR falls below 20 mL/minute/1.73 m², unless it is not tolerated or kidney replacement therapy is initiated ^r70
  • Glucagon-like peptide-1 receptor agonists
    • Recommended for patients who have not achieved glycemic targets despite use of metformin and a sodium-glucose cotransporter-2 inhibitor (or who are unable to use those medications) ^r70
    • Dulaglutide, liraglutide, and semaglutide may be used in all stages of renal impairment
    • Exenatide immediate release is not recommended when estimated GFR is less than 30 mL/minute/1.73m²; exenatide extended release is not recommended when estimated GFR is less than 45 mL/minute/1.73 m²
    • Lixisenatide is not recommended when estimated GFR is less than 15 mL/minute/1.73 m²
  • Dipeptidyl-peptidase IV inhibitor
    • Can be used in all stages of renal impairment
    • All require dosage adjustment, except linagliptin
  • Sulfonylureas
    • Undesirable to use this class in general, particularly glipizide, owing to risk of hypoglycemia
    • Most sulfonylureas are contraindicated for patients with stage 4 chronic kidney disease
  • Meglitinides
    • May be used in stage 3 to 5 chronic kidney disease but require careful dose adjustments
  • Thiazolidinediones
    • Only pioglitazone is advisable owing to safety concerns with other agents in this class ^r138
    • Do not use pioglitazone for patients with end-stage renal disease requiring hemodialysis
  • Dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 agonists
    • Can be used in all stages of renal impairment
    • Use of tirzepatide is associated with nausea, vomiting, and diarrhea, which may lead to dehydration. This dehydration has resulted in acute kidney injury
• Coronary artery disease ^c172d7
  • 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: ^r34r66
    • 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 ^r47
    • Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists have been shown to reduce risk of all-cause and cardiovascular mortality and major cardiovascular events for patients with established atherosclerotic cardiovascular disease or multiple risk factors for atherosclerotic cardiovascular disease ^r141
      • Glucagon-like peptide-1 receptor agonists also reduce risk of nonfatal stroke
      • Sodium–glucose cotransporter-2 inhibitors also reduce risk of hospitalization for heart failure and composite of significant decline in estimated GFR, progression to end-stage kidney disease, or kidney death
    • Strongest evidence for cardiovascular benefit has been demonstrated with liraglutide, dulaglutide, semaglutide, empagliflozin, dapagliflozin, and canagliflozin ^r47
    • Combined therapy with a sodium–glucose cotransporter-2 inhibitor with a glucagon-like peptide-1 receptor agonist may be considered for additive reduction in the risk of cardiovascular events ^r6
  • Treat risk factors (eg, hypertension, dyslipidemia)
  • Antiplatelet therapy with low-dose aspirin is recommended for secondary prevention of coronary artery disease for patients with history of cardiovascular disease and may be considered for primary prevention for patients at increased risk of cardiovascular events ^r6
    • Benefits of aspirin for primary prevention of cardiovascular disease in patients with type 2 diabetes need to be weighed carefully against risks of bleeding ^r66
    • Not generally recommended for adults older than 70 years or those younger than 50 years with no other risk factors for atherosclerotic cardiovascular disease
    • Addition of low-dose anticoagulation to antiplatelet therapy may be an option for high-risk patients with diabetes ^r66
  • An ACE inhibitor or angiotensin receptor blocker is recommended for patients with known cardiovascular disease ^r6
  • Obtain resting ECG for patients with hypertension or suspected cardiovascular disease ^r12
  • Routine screening for coronary artery disease is not recommended for asymptomatic patients ^r6
  • Exercise ECG may be considered for cardiovascular risk assessment for patients with cardiac symptoms or abnormal resting ECG ^r6
  • Coronary artery calcium measurement may be considered for patients aged 40 years or older ^r6
• Congestive heart failure ^c173
  • Sodium-glucose cotransporter-2 inhibitors are recommended for patients with clinical heart failure ^r42r135r142
    • Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin have been shown to: ^r141r143
      • Reduce risk of heart failure hospitalizations for patients with type 2 diabetes mellitus when left ventricular ejection fraction is greater than 40%
      • Reduce all-cause mortality, cardiovascular mortality, and hospitalization for heart failure when left ventricular ejection fraction is 40% or less
  • If additional glycemic control is needed, use glucagon-like peptide-1 receptor agonists, metformin, or both; insulin may also be used ^r135
  • Thiazolidinediones and dipeptidyl-peptidase IV inhibitors are not recommended for patients with heart failure ^r135
• Obesity ^c174d4
  • Obesity (BMI of 30 kg/m² or more) and overweight status (BMI of 25-30 kg/m²) are associated with insulin resistance ^r144
  • Abdominal adiposity (waist circumference greater than 102 cm in males and greater than 88 cm in females) is also associated with insulin resistance ^r27
  • Alternative criteria are advocated for use in South Asian, East Asian, and Southeast Asian populations, as adverse health effects occur at lower BMI and waist circumference levels ^r27
  • Efforts to achieve modest and sustained weight loss are a priority
    • 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%) ^r112
    • Greater amounts of weight loss will: ^r112
      • Further reduce hemoglobin A1C level (0.6%-1%)
      • Reduce blood pressure (approximately 3 mm Hg)
      • Improve LDL-C and HDL-C levels
      • Reduce need for medications to control blood pressure, blood glucose level, and lipid levels
  • First line therapy is lifestyle modification to achieve weight loss of 5% or more; greater weight loss (10% or more) has disease-modifying effects ^r64
    • 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 for whom careful medical monitoring is possible
  • Second line therapy is pharmacotherapy, which is indicated for a person who has diabetes and BMI of 27 kg/m² or more ^r112
    • FDA-approved medications for treatment of obesity include phentermine, orlistat, phentermine-topiramate extended-release, naltrexone-bupropion, liraglutide, and semaglutide ^r64
    • Tirzepatide (dual glucose-like peptide 1/glucose-dependent insulinotropic polypeptide receptor agonist) is a glucose-lowering agent that can facilitate weight loss ^r64
    • Reassess medications for comorbid conditions and minimize those that cause weight gain, including atypical antipsychotics, antidepressants, glucocorticoids, anticonvulsants, antihistamines, and anticholinergics ^r64
  • Select a regimen for diabetes management to include drugs that have favorable effects on body weight where possible ^r64
    • Diabetes medication classes associated with weight gain include:
      • Sulfonylureas
      • Meglitinides
      • Thiazolidinediones
      • Insulin
    • Diabetes medication classes that promote modest weight loss include:
      • Biguanides
      • Glucagon-like peptide-1 receptor agonists
      • Sodium-glucose cotransporter-2 inhibitors
      • Dual glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonists
      • 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: ^r64
    • BMI of 40 kg/m² or more (37.5 kg/m² or more in Asian American patients)
    • BMI of 35 to 39.9 kg/m² (32.5-37.4 kg/m² in Asian American patients) if unable to achieve durable weight loss and reduction in comorbidities (including hyperglycemia) with nonsurgical methods
  • Bariatric surgery may also be considered for patients with BMI of 30 to 34.9 kg/m² (27.5-32.4 kg/m² in Asian American patients) if unable to achieve durable weight loss and reduction in comorbidities (including hyperglycemia) with nonsurgical methods ^r64
• Nonalcoholic fatty liver disease ^r11c175d8
  • 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 ^r145
  • Spectrum of the disease ranges from nonalcoholic fatty liver to steatohepatitis (nonalcoholic steatohepatitis) to cirrhosis
  • It is estimated that more than 70% of patients with type 2 diabetes have evidence of nonalcoholic fatty liver disease, and more than 50% have steatohepatitis
  • Noninvasive screening for nonalcoholic fatty liver disease with clinically significant hepatic fibrosis and risk stratification for future cirrhosis are recommended for patients with type 2 diabetes ^r145
    • Initially determine risk based on FIB-4 (fibrosis-4) index, which is derived from age, ALT, AST, and platelets; patients with an indeterminate or high FIB-4 score should then have liver stiffness measurement with transient elastography or blood biomarker ELF (enhanced liver fibrosis) scoring ^r146
  • Refer patients with indeterminate results or high risk for significant liver fibrosis to a gastroenterologist or hepatologist for further workup and long-term management
  • Goal is to prevent progression to cirrhosis; weight loss is the main means of achieving this ^r11r147
    • Weight loss of at least 5%, but preferably at least 10%, is needed to improve liver histology
  • No specific treatments exist for nonalcoholic steatohepatitis, so medications should be chosen based on efficacy in treating hyperglycemia and obesity, especially significant fibrosis ^r147
    • Pioglitazone or glucagon-like peptide-1 receptor agonists are preferred treatments for hyperglycemia in patients with type 2 diabetes and biopsy-proven nonalcoholic steatohepatitis or high risk for nonalcoholic fatty liver disease with clinically significant liver fibrosis on noninvasive tests ^r146
      • Pioglitazone reduces nonalcoholic fatty liver disease activity and resolves nonalcoholic steatohepatitis in about half of treated patients ^r148
      • Glucagon-like peptide-1 receptor agonists are also effective in treating steatohepatitis and may slow fibrosis progression; can be used as adjunctive therapy with lifestyle interventions for weight loss
    • Other glucose-lowering agents may be continued as needed for glycemic control; however, they have either failed to reduce steatohepatitis in studies (metformin) or have not been studied with regard to liver histologic end points (sulfonylureas, glitinides, dipeptidyl peptidase 4 inhibitors, or acarbose) ^r146
    • Bariatric surgery is effective for weight loss and liver fat reduction in patients with severe obesity ^r146r147
      • Use with caution for patients with compensated cirrhosis due to nonalcoholic fatty liver disease; not recommended for those with decompensated cirrhosis
    • Insulin therapy is preferred for treatment of hyperglycemia in adults with type 2 diabetes and decompensated cirrhosis ^r146
• Obstructive sleep apnea ^{c176c177c178c179}
  • Associated with obesity (particularly central obesity), male sex, and older age
  • Affects approximately 58% to 77% of patients with type 2 diabetes and 86% of those with both diabetes and obesity ^r27
  • 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 ^r149
  • 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
• Liver failure and cirrhosis ^c180c181
  • Treatment of diabetes in these patients is complex because many diabetes drugs can promote hypoglycemia and lactic acidosis ^r150
  • In most cases, insulin therapy, including insulin analogues, is the safest choice ^r146
  • Oral diabetes medications are contraindicated for patients with advanced liver diseases who have cirrhosis, ascites, or encephalopathy ^r151
  • Glucagon-like peptide-1 receptor agonists exenatide and liraglutide have been shown to be safe for patients with liver disease ^r150
  • Dipeptidyl-peptidase IV inhibitors appear to be safe for use by patients with liver cirrhosis ^r150
• Osteoporosis ^c182
  • Use thiazolidinediones and the sodium-glucose cotransporter-2 inhibitor canagliflozin with caution
• HIV ^c183
  • Fasting glucose levels are the preferred method of diagnosis ^r1
    • Do not use a hemoglobin A1C test to diagnose diabetes in patients with HIV because it underestimates glycemia in this population ^r152
  • Risk of developing diabetes is increased with treatment with some protease inhibitors and nucleoside reverse transcriptase inhibitors ^r11
• Psychosocial disorders ^r153
  • Depression ^c184d9
    • Highly prevalent in patients with type 2 diabetes; 20% to 25% of patients with diabetes are affected by depression^r154
    • 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 mental health specialist for assessment and treatment ^r97
  • Anxiety ^c185d10
    • Anxiety over aspects of the disease or diabetes care (eg, complications, injections, hypoglycemia) is common and can lead to maladaptive behavior (eg, avoidance, withdrawal, excessive repetitive habits) ^r97
    • Fears of hypoglycemia can lead to self-relaxing of glycemic goals and reducing intensity of measures to treat the disease
    • Refer patients to diabetes education for blood glucose awareness training or to 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 ^r154c186
    • Refer such patients to diabetes education or to mental health specialist if areas of diabetes care are adversely impacted

Special populations

• Older adults ^r155
  • 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;^r156 instead, modify treatment to avoid hypoglycemia^r155
  • 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 ^r155
    • 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
  • Lifestyle modifications are a cornerstone of treatment for diabetes in older adults as for other ages ^r157
    • Intensive lifestyle modification results in greater reductions in hemoglobin A1C level and weight but increased incidence of mild hypoglycemic episodes in older adults
  • Metformin is the first line agent for treatment of type 2 diabetes in older adults ^r158
  • Dipeptidyl-peptidase IV inhibitors are also a safe and easy-to-use option for older patients ^r159
  • Medications to improve cardiovascular and renal outcomes (sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists) are also beneficial for older adult patients; age alone should not be an obstacle to treatment ^r42
  • However, drug therapy may need to be adjusted for older adults, especially in the setting of comorbidities or frailty ^r42r155
    • Simplify drug regimens (eg, combination drug pills) when possible
    • Once-daily injection of basal insulin may be a reasonable option for some older adults
  • Older adults with type 2 diabetes are at increased risk for hypoglycemia owing to decreased insulin level and increased renal insufficiency ^r155r158
    • Require closer monitoring when treated with medications that can cause hypoglycemia; consider continuous glucose monitoring for those on multiple daily doses of insulin
• Pregnant patients
  • Manage patients with preexisting type 2 diabetes who are planning a pregnancy or who become pregnant in a multidisciplinary care setting, if available
  • Some medications commonly used for both diabetes and its complications are teratogenic and should be discontinued before conception or during pregnancy, including:
    • Statins
    • ACE inhibitors
    • Angiotensin receptor blockers
    • Most noninsulin glucose-lowering medications
  • Insulin is the preferred medication for managing glycemia during pregnancy ^r27r33
    • 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
  • Metformin is considered to be a relatively safe alternative to insulin during pregnancy ^r27
  • Glucose targets for pregnant patients with pregestational type 2 diabetes are more aggressive than for general population of patients with type 2 diabetes ^r27
    • Preprandial, bedtime, and overnight (ie, fasting) glucose levels: 60 to 95 mg/dL
    • 1-hour postprandial blood glucose level: 110 to 140 mg/dL
    • 2-hour postprandial blood glucose level: 100 to 120 mg/dL
    • Target hemoglobin A1C level of less than 6% or lower only if this can be achieved without significant hypoglycemia; target can be less than 7% if necessary to prevent hypoglycemia ^r27r33
  • Pregnant patients with type 2 diabetes are more likely to be overweight or have obesity ^r33
    • Suggested weight gain for a pregnant patient with overweight and diabetes is 15 to 25 pounds
    • Suggested weight gain for a pregnant patient with obesity and diabetes is 10 to 20 pounds
  • In pregnancy complicated by preexisting type 2 diabetes and hypertension, blood pressure targets and treatment may differ from those of prepregnancy care ^r33
    • Blood pressure threshold for initiation or titration of therapy of 140/90 mm Hg is recommended to reduce adverse pregnancy outcomes without compromising fetal growth ^r33
    • Blood pressure target of 110 to 135/85 mm Hg reduces risk for accelerated maternal hypertension and minimizes impairment of fetal growth; therapy should be relaxed if blood pressure falls below 90/60 mm Hg ^r6r33
    • Safe antihypertensive drugs to use in pregnancy include methyldopa, nifedipine, labetalol, diltiazem, clonidine, and prazosin ^r33
  • Because diabetes is associated with increased risk of preeclampsia, prescribe low-dose aspirin during second and third trimesters to reduce risk ^r33
    • Doses of 100 to 150 mg/day are recommended; however, a dose of 162 mg/day (ie, 2 81-mg tablets, which is the low-dose aspirin available in the United States) may be acceptable
    • Aspirin doses of less than 100 mg are not effective in reducing risk of preeclampsia ^r33
• Hospitalized patients
  • Scheduled insulin therapy is recommended for most hospitalized patients with hyperglycemia (with or without known type 2 diabetes) ^r160
    • Either a dipeptidyl-peptidase IV inhibitor with correction insulin or scheduled insulin therapy may be given to selected well-managed patients with mild hyperglycemia hospitalized for a noncritical illness ^r160
  • Inpatient glucose targets vary per setting and circumstance ^r31
    • Initiate insulin therapy for hospitalized patients with persistent hyperglycemia of 180 mg/dL or more (checked on 2 occasions)
    • Maintain glucose level between 140 and 180 mg/dL in most critically and noncritically ill patients
    • More stringent glucose targets between 110 and 140 mg/dL may be appropriate for select patients (eg, those who had previous cardiac surgery, stroke, or acute ischemic cardiac events), provided that target can be achieved without significant hypoglycemia
    • Target range of 100 to 180 mg/dL may be acceptable in noncritically ill patients
    • Glucose levels greater than 250 mg/dL may be acceptable in terminally ill patients with short life expectancy
  • ICU
    • 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
  • Perioperative care
    • Target glucose range for perioperative period is 100 to 180 mg/dL; attempts to achieve tighter perioperative glucose control lead to unacceptable rates of hypoglycemia^r161r160
    • Withhold metformin 24 hours before surgery, and withhold all other oral hypoglycemic drugs beginning on the morning of surgery ^r31
    • 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 ^r31
    • Give insulin in portions designated as basal, nutritional, and correctional
    • Dosing can be determined by preadmission basal insulin dose
    • Neutral protamine Hagedorn–based or basal bolus regimens are recommended for patients receiving enteral nutrition ^r160
    • 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 feeding
    • Continuous peripheral or central parenteral delivery: add 1 unit of regular insulin per 10 g of dextrose
    • Administer correctional doses, based on point-of-care blood glucose measurements, every 6 hours in all cases using regular insulin or an immediate-acting insulin
    • Continuous enteral or parenteral feeding results in a constant postprandial state; attempting to reduce blood glucose levels to below 140 mg/dL greatly increases risk of hypoglycemia
  • Avoid iatrogenic hypoglycemia (less than 70 mg/dL) ^r31
    • 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
      • New NPO status
    • Hemoglobin A1C level at admission can predict risk for in-hospital hypoglycemia for older patients; levels less than 7% are associated with highest rate of hypoglycemic episodes ^r162
    • Continuous glucose monitoring is recommended for inpatients at high risk for hypoglycemia ^r89r163
      • Use in combination with periodic point-of-care blood glucose testing to validate accuracy of continuous glucose monitoring

At-risk populations

• Consider screening of the following asymptomatic adults at any age: ^r1r27
  • Patients who are overweight (BMI of 25 kg/m² or more, or 23 kg/m² or more in Asian American individuals) who have 1 or more additional risk factors, such as:
    • First-degree relative with diabetes ^c232c233c234
    • High-risk race or ethnicity (eg, Black, Latino, American Indian, Pacific Islander, Asian American) ^{c235c236c237c238c239c240c241c242c243c244c245c246c247c248c249}
    • Physical inactivity ^c250c251c252
    • Hypertension (blood pressure 140/90 mm Hg or higher or currently on therapy for hypertension) ^c253c254c255
    • Dyslipidemia (HDL-C level less than 35 mg/dL and/or triglyceride level more than 250 mg/dL) ^c256c257c258
    • Polycystic ovary syndrome ^c259c260c261
    • Conditions associated with insulin resistance (eg, metabolic syndrome, nonalcoholic fatty liver disease, acanthosis nigricans) ^{c262c263c264c265c266c267c268c269c270c271c272c273}
    • Long-term use of glucocorticoids ^c274c275c276
    • Antipsychotic therapy for severe bipolar disorder or schizophrenia ^{c277c278c279c280c281c282}
    • Sleep disorders in conjunction with glucose intolerance (eg, obstructive sleep apnea, chronic sleep deprivation, night shift work schedule) ^{c283c284c285c286c287c288c289c290c291c292c293c294}
    • History of cardiovascular disease ^c295c296c297
  • Patients with hemoglobin A1C level of 5.7% or more, impaired glucose tolerance, or impaired fasting glucose level on previous testing ^{c298c299c300c301c302c303c304c305c306}
  • Patients with HIV
  • Patients with past diagnosis of gestational diabetes
• Screen the following asymptomatic patients beginning at age 35 years: ^c307c308c309
  • Patients who are overweight or have obesity with no other risk factors for diabetes ^r179
  • Patients with no risk factors for diabetes ^r1r27
• If results of initial screening are normal, repeat testing at least every 3 years ^r1
  • Consider more frequent testing depending on initial results and risk status; for example:
    • Test patients with prediabetes annually ^c310c311c312
    • Test patients with history of gestational diabetes at least every 3 years
    • Monitor glucose status regularly in patients at high risk of developing type 2 diabetes who are on statin therapy ^r10

Screening tests

• Screening tests are similar to diagnostic testing and include any of the following: ^r1
  • Fasting plasma glucose level ^c313
  • Oral glucose tolerance test ^c314
  • Hemoglobin A1C level ^c315