History

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

Physical examination

• Overweight or obese body habitus in approximately 80% of patients ^r5c19c20
• Signs of insulin resistance
  • Increased abdominal adiposity ^c21
  • Acanthosis nigricans (cutaneous velvety hyperpigmented patches most prominent in intertriginous areas) when insulin resistance is extreme ^c22c23
• Elevated blood pressure (common) ^r6c24
  • Patients found to have blood pressure of 140/90 mm Hg or higher should have blood pressure confirmed using 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 a 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 ^{c25c26c27c28c29c30}
  • Decreased lower extremity sensation, pedal pulses, and/or reflexes ^{c31c32c33c34c35c36}
  • Foot ulcers, deformities, or wounds on inspection ^c37c38c39c40
  • Heart rate variability on deep inspiration, position change, and/or Valsalva maneuver ^{c41c42c43c44c45c46}

Causes

• Multifactorial pathogenesis in which metabolic, behavioral, lifestyle, and environmental factors precipitate disease in genetically predisposed persons ^r7c47c48c49
  • Combination of insulin resistance, increased hepatic gluconeogenesis, and relative defects in insulin secretion promote metabolic dysfunction
  • Overweight or obese body habitus is a major factor contributing to insulin resistance, which is a precursor to development of glucose intolerance and diabetes
  • Hypercaloric diet and sedentary lifestyle also worsen insulin resistance
  • Hyperglycemia develops when progressive impairments in insulin secretion render pancreatic β-cells unable to maintain euglycemia
• Strong hereditary component contributes to manifestation of the disease, with complex polygenic inheritance pattern underlying most cases

Risk factors and/or associations

Primary diagnostic tools

• Elements of history and physical examination findings can suggest the disorder, but biochemical parameters are essential for the diagnosis ^c80
• Issues to consider in the selection of the diagnostic testing method ^r7
  • Fasting glucose level
    • Advantage: easy, inexpensive measurement
    • Disadvantage: relatively insensitive, levels fluctuate, and test requires patient to fast overnight
  • Oral glucose tolerance test
    • Advantage: most sensitive as a metabolic test
    • Disadvantage: inconvenient and time-consuming for the patient
  • Hemoglobin A1C level
    • Advantage: convenient, best measure of chronic glycemia, closely associated with complications, and less biologic variability compared with glucose-based tests
    • Disadvantage: results are confounded in certain situations of increased RBC turnover and hemoglobinopathies
• Laboratory confirmation of diabetes mellitus can be achieved with any of the following: ^r4
  • Fasting plasma glucose measurement of at least 126 mg/dL (7 mmol/L)
  • Random glucose measurement of at least 200 mg/dL (11.1 mmol/L) when symptoms of hyperglycemia (eg, polyuria, polydipsia, polyphagia) are present
  • 2-hour glucose measurement of at least 200 mg/dL (11.1 mmol/L) from an oral glucose tolerance test
  • Hemoglobin A1C measurement of at least 6.5%
• Confirmation of the diagnosis requires 2 of the above abnormal test results unless accompanied by a clear clinical diagnosis of hyperglycemia ^r4
• Condition of prediabetes is met with 1 or both of the following states, or with hemoglobin A1C testing: ^r4
  • Impaired fasting glucose level: fasting glucose value of 100 to 125 mg/dL (5.6-6.9 mmol/L)
  • Impaired glucose tolerance: 2-hour post–oral glucose tolerance test value of 140 to 199 mg/dL (7.8-11 mmol/L)
  • Hemoglobin A1C level: 5.7% to 6.4%
• Additional clinical or laboratory tests to assess comorbidities and complications at time of diagnosis
  • Measure blood pressure, comprehensive metabolic panel (includes electrolytes, renal and liver function), fasting lipid panel, and assessment of urinary albumin excretion ^r10
  • Refer for baseline dilated eye examination ^r11
  • Obtain resting ECG in patients with hypertension or suspected cardiovascular disease ^r12
  • Assess osteoporosis risk factors and obtain fracture history in older patients with diabetes and recommend measurement of bone mineral density if appropriate for the patient's age and sex ^r10
  • Refer patients with symptoms suggestive of obstructive sleep apnea (eg, excessive daytime sleepiness, snoring, witnessed apnea) for screening of sleep apnea ^r13
  • Consider measurement of early morning serum testosterone level in men with diabetes and signs and symptoms of hypogonadism (eg, decreased libido, erectile dysfunction) ^r10
  • In patients with elevated liver enzymes obtain liver ultrasound and evaluate for presence of nonalcoholic steatohepatitis and liver fibrosis. ^r10
  • Recommend dental assessment for for periodontal disease ^r14r15

Laboratory ^c81c82

• Fasting glucose measurement ^r4c83
  • Fasting requires no caloric intake for at least 8 hours; in absence of unequivocal hyperglycemia, repeated testing is required to confirm
  • Diagnostic thresholds are as follows:
    • Fasting glucose reference range: less than 100 mg/dL (less than 5.6 mmol/L)
    • Impaired fasting glucose level: 100 to 125 mg/dL (5.6-6.9 mmol/L)
    • Diabetes mellitus: 126 mg/dL (7 mmol/L) or higher
      • In absence of unequivocal hyperglycemia, another abnormal test result from either the same specimen or a separate specimen is required to confirm diagnosis
• Random glucose measurement ^r4c84
  • Diagnostic threshold is 200 mg/dL (11.1 mmol/L) or higher when signs or symptoms of hyperglycemia are present
  • In absence of unequivocal signs or symptoms of hyperglycemia, repeated testing is required to confirm
• Oral glucose tolerance test ^r4c85
  • Performed 2 hours after oral ingestion of 75 g of glucose dissolved in water
  • Ensure patient has had an adequate carbohydrate intake (at least 150 g/day) for 3 days prior to 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 ^r4c86
  • Diagnostic threshold
    • Diabetes mellitus: 6.5% or greater
      • In absence of unequivocal hyperglycemia, another abnormal test result from either the same specimen or a separate specimen is required to confirm diagnosis
    • Prediabetes: suggested by 5.7% to 6.4% (requires confirmatory fasting plasma glucose measurement or oral glucose tolerance test for definitive diagnosis)
  • Accuracy is reduced in certain conditions
    • Hemoglobinopathies (eg, sickle cell anemia, thalassemias, spherocytosis)
    • Iron deficiency
    • Hemolytic anemia
    • Chronic kidney disease
    • Severe hepatic disease
    • Severe renal disease
    • HIV treated with certain medications
    • Pregnancy and postpartum period
    • Erythropoietin therapy
    • Recent blood loss or transfusion
  • Less accurate in Black patients (hemoglobin A1C measurement is higher than in White patients despite similar glucose levels) ^r16
• Pancreatic autoantibodies test ^r4c87
  • Aids in classification when uncertainty exists about type 1 versus type 2 diabetes but not routinely indicated for most patients
  • Autoantibodies include those against insulin, glutamic acid decarboxylase 2, certain islet cell antigens, zinc transporter 8, and protein tyrosine phosphatase receptor type N
  • Results are negative in most patients with type 2 diabetes
• C-peptide level ^c88
  • Normal or elevated C-peptide level is usually indicative of type 2 diabetes, whereas a frankly low or completely absent C-peptide level is indicative of type 1 diabetes ^r17
  • Can be low in the setting of glucotoxicity; may be most helpful when delayed until several months after metabolic control has been established
• Additional laboratory tests recommended at diagnosis to screen for associated diseases and complications include: ^r10
  • Fasting lipid panel ^c89
  • Renal function tests for nephropathy ^c90
    • Estimated GFR ^c91
    • Urine albumin to creatinine ratio ^c92
  • Liver function tests ^c93

Most common

• Type 1 diabetes ^c94d1
  • Often presents overtly rather than through screening, with moderate to severe hyperglycemia and accompanying symptoms of polyuria, polydipsia, polyphagia, and unexplained weight loss
  • Typically (although not always) distinguished by younger age at onset (younger than 40 years), BMI within reference range, and history of ketoacidosis ^r18
  • Diagnosis is confirmed by positive pancreatic autoantibodies (against insulin, glutamic acid decarboxylase 2, certain islet cell antigens, zinc transporter 8, and protein tyrosine phosphatase receptor type N)
• Diabetes insipidus ^c95d2
  • Spectrum of diseases that display hypotonic polyuria and inability to concentrate urine owing to inadequate secretion of or impaired renal responsiveness to arginine vasopressin
  • Presenting symptoms of polyuria, polydipsia, and nocturia overlap with those of diabetes mellitus when the latter is associated with symptomatic hyperglycemia
  • Diagnosis of diabetes insipidus is suggested by 24-hour urine volume more than 3 L^r19 and low urinary osmolality; a definitive diagnosis requires a water deprivation test
  • Most easily differentiated from diabetes mellitus on the basis of laboratory testing (ie, plasma glucose level, oral glucose tolerance test, or hemoglobin A1C level)
• Monogenic diabetes/maturity-onset diabetes of youth ^r20r21c96
  • 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 the long term
    • Gestational diabetes in women without typical risk factors
    • BMI is within reference range at onset without ketosis or pancreatic antibodies
    • Unusual sensitivity to low-dose sulfonylureas or meglitinides
  • Can be formally differentiated from type 2 diabetes by genetic testing, most commonly with identification of mutations in HNF1A gene (HNF1 homeobox A) or GCK gene (glucokinase) ^r23
• Medication-induced diabetes ^r24c97
  • Drugs promoting hyperglycemia may also induce type 2 diabetes in a genetically susceptible person ^r25
  • Common triggers include glucocorticoids, thiazide diuretics, atypical antipsychotics, statins, and calcineurin inhibitors
  • Identified by temporal association of hyperglycemia that develops after the inciting drug is used
  • Resolution of hyperglycemia after discontinuation of the introduced medication confirms medication-induced diabetes; however, when it is not practical to discontinue the medication, hyperglycemia is treated with pharmacotherapy as needed
• Endocrinopathies
  • Some rare neuroendocrine tumors secrete or cause the secretion of hormones that antagonize insulin action or reduce insulin secretion, leading to hyperglycemia ^c98
  • Cushing syndrome, acromegaly, glucagonoma, and pheochromocytomas are associated with glucose intolerance, and a subset of people with such conditions develop overt type 2 diabetes during the course of the disease ^{c99c100c101c102}

Admission criteria ^r43

DKA ^r44d3

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

Hyperglycemic hyperosmolar state ^r45

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

Hypoglycemia with neuroglycopenia ^r43

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

Uncontrolled diabetes ^r43

• Hyperglycemia with volume depletion
• Persistent hyperglycemia associated with metabolic deterioration
• Hemoglobin A1C level that is 100% or more above upper reference limit
• Recurrent fasting plasma glucose level greater than 300 mg/dL, refractory to outpatient treatment
• Frequent episodes of hypoglycemia with blood glucose level less than 50 mg/dL, refractory to outpatient treatment
• Metabolic instability as evidenced by frequent swings between fasting hyperglycemia and hypoglycemia
• Recurrent DKA not precipitated by infection or injury
• Severe psychosocial issues that cause uncontrolled metabolic function that cannot be managed in the 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 uncertain diagnosis, teaching and supervising insulin therapy, treatment of labile glycemia (eg, recurrent hypoglycemia, persistent hyperglycemia, ketoacidosis), or when the complexity of care exceeds the capacity of the primary care setting ^r7
• Nephrologist for persistent proteinuria, decreased GFR, labile blood pressure, or hyperkalemia
• Cardiologist for associated cardiovascular disease management
• Podiatrist for orthotic footwear and prevention or treatment of diabetic foot ulcers
• Dentist for periodontal examination
• Mental health specialist for depression, self-harm, blatant disregard for self-care, severe anxiety, diabetes-related distress, or cognitive impairment

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
      • Revised FDA labeling permits use in patients with renal impairment, based on safety and mortality data as used in patients with chronic kidney disease, congestive heart failure, and chronic liver disease
      • Before starting, estimated GFR should be greater than 45 mL/minute/1.73 m²; patient may remain on metformin until estimated GFR falls to 30 mL/minute/1.73 m², when it must be stopped
    • Low risk for hypoglycemia with long-lasting antihyperglycemic effect
    • May benefit cardiovascular health ^r79
    • Metformin reduces weight to a greater extent than all other oral agents except the sodium-glucose cotransporter-2 inhibitors ^r47
    • May cause gastrointestinal adverse effects (eg, cramping, diarrhea) and vitamin B₁₂ deficiency; monitor vitamin B₁₂ levels
    • Metformin immediate-release ^c103
      • 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 ^c104
    • 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 ^r80
    • May cause weight gain, and patients may experience decreased efficacy after several years of treatment
    • Glimepiride ^c105
      • 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; Geriatric 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 ^c106
      • 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; Geriatric 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; Geriatric 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 ^c107
      • 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 ^c108
    • 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 in patients with concurrent heart failure ^r78
    • May cause upper respiratory tract infections, pancreatitis, or immune-related dermatologic effects (eg, angioedema, urticaria)
    • Comparison with other oral agents ^r47
      • Favored over sulfonylureas for long-term all-cause mortality, long-term cardiovascular mortality, and cardiovascular morbidity
      • Favored over pioglitazone for short-term cardiovascular morbidity
      • Favored over sulfonylureas or thiazolidinediones for weight control
      • Inferior to metformin and sulfonylureas for hemoglobin A1C reduction
    • Dose adjustment is needed for patients with chronic kidney disease (except linagliptin)
    • Alogliptin ^c109
      • Alogliptin Oral tablet; Adults: 25 mg PO once daily.
    • Linagliptin ^c110
      • Linagliptin Oral tablet; Adults: 5 mg PO once daily.
    • Saxagliptin ^c111
      • 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 ^c112
      • Sitagliptin Phosphate Oral tablet; Adults: 100 mg PO once daily.
  • Sodium-glucose cotransporter-2 inhibitors ^c113
    • 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 ^r47
    • Low risk of hypoglycemia
    • Class-wide clinical benefits in addition to improved glycemic control include reduced risk of hospitalization due to heart failure (in patients with and without existing cardiovascular disease), reduced risk of major cardiovascular events in patients with atherosclerotic cardiovascular disease or chronic kidney disease, and improved renal outcomes in patients with kidney disease ^r58r59r81
    • May cause dehydration, hypotension, minimal increases in LDL-C level, weight loss, urinary tract infections, fungal genital tract infections, bone loss, and fractures
    • Canagliflozin ^c114
      • 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 ^c115
      • Dapagliflozin Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose to 10 mg PO once daily if needed.
    • Empagliflozin ^c116
      • Empagliflozin Oral tablet; Adults: 10 mg PO once daily, initially. May increase dose to 25 mg PO once daily if needed.
    • Ertugliflozin ^c117
      • Ertugliflozin Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose to 15 mg PO once daily if needed.
  • Meglitinides ^c118
    • Increase insulin secretion
    • Moderate risk of causing hypoglycemia
    • No clear evidence to support a cardiovascular benefit ^r82
    • May cause weight gain
    • May cause dizziness, diarrhea, and upper respiratory infections
    • Nateglinide ^c119
      • 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 ^c120
      • 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 ^c121
    • 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 ^r83r84
    • Contraindicated in New York Heart Association class 3 and 4 heart failure
    • May cause weight gain, fluid retention, peripheral edema, bone loss, and fractures
    • Useful in patients with nonalcoholic steatohepatitis
    • Safe in patients with renal insufficiency and renal failure
    • Whether pioglitazone increases risk of bladder cancer is controversial ^r85
    • Pioglitazone ^c122
      • 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 ^c123
      • 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 ^c124
    • Slow carbohydrate digestion and absorption from the intestines
    • Low risk of hypoglycemia
    • Treatment has been associated with decreased composite of cardiovascular outcomes in pre-diabetic patients ^r86r87
    • May cause gastrointestinal adverse effects (eg, flatulence, diarrhea) and is typically considered weight-neutral
    • Acarbose ^c125
      • 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 ^c126
      • 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 ^r88c127
    • Decrease hepatic glucose production and increase incretin levels
    • Low risk of hypoglycemia
    • Lower LDL-C level
    • May cause constipation
    • Colesevelam hydrochloride ^c128
      • Colesevelam Hydrochloride Oral tablet; Adults: 1.875 g PO twice daily or 3.75 g PO once daily.
  • Central acting dopamine-2 agonist ^c129
    • Decreases post-prandial glucose due to suppression of hepatic glucose production ^r89
    • Low risk of hypoglycemia
    • May improve cardiovascular health
    • May cause nausea, orthostatic hypotension, fatigue, or rhinitis
    • Contraindicated in patients taking antipsychotic medications
    • Bromocriptine mesylate ^c130
      • Bromocriptine Mesylate Oral tablet [Diabetic Therapy]; Adults: 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 ^c131
    • Increase glucose-dependent insulin secretion, decrease glucagon secretion, slow gastric emptying, and increase satiety
    • Low risk of hypoglycemia
    • Reduce risk of major cardiovascular events in patients with atherosclerotic cardiovascular disease ^r58r59
    • Frequently cause gastrointestinal adverse effects (eg, nausea, vomiting, diarrhea) and weight loss
    • Use with caution in patients with a history of pancreatitis; discontinue if pancreatitis develops
    • Contraindicated in patients with personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia type 2 (except twice-daily exenatide)
    • Dulaglutide ^c132
      • Dulaglutide Solution for injection; Adults: 0.75 mg subcutaneously once weekly, 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 ^c133
      • 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 ^c134
      • Liraglutide Solution for injection; Adults: 0.6 mg subcutaneously once daily for 1 week, then 1.2 mg subcutaneously once daily, initially. May increase dose after at least 1 week to 1.8 mg subcutaneously once daily if additional glycemic control is needed.
    • Lixisenatide ^c135
      • Lixisenatide Solution for injection; Adults: 10 mcg subcutaneously once daily for 14 days, then 20 mcg subcutaneously once daily.
    • Semaglutide ^c136
      • 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. Max: 2 mg/week.
  • Amylin mimetic/analogue ^c137
    • Decreases glucagon secretion, slows gastric emptying, and increases satiety
    • Low risk of hypoglycemia
    • Neutral cardiovascular effects ^r90
    • May cause gastrointestinal adverse effects (eg, nausea, vomiting) and weight loss
    • Pramlintide ^c138
      • 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.
  • Dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 agonists ^r53
    • 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 ^r53
    • Low risk of hypoglycemia
    • SURPASS-CVOT study is underway to evaluate long-term cardiovascular outcomes ^r91
    • May cause gastrointestinal effects (nausea, vomiting, diarrhea) and is 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.

  • Other injectables for type 2 diabetes mellitus.

    GLP-1, glucagon-like peptide 1; MACE, major adverse cardiovascular events; MEN-2, multiple endocrine neoplasia type 2. * Studied in patients with preexisting atherosclerotic cardiovascular disease.

    Adapted from Wallia A et al: Insulin therapy for type 2 diabetes. JAMA. 311:2315-25, 2014.

    Drug 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; renal function should be checked 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; renal function should be checked 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 ^c139
  • 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 ^r92
  • Selection of basal insulin ^r93
    • Both isophane insulin suspension and basal insulin analogues are capable of lowering hemoglobin A1C level to a similar extent, but the insulin analogues have the advantages of less frequent and severe hypoglycemia and reduced weight gain, and they provide basal coverage for up to 24 hours or longer with a single injection
    • Basal analogue duration of action (longer to shorter): degludec, longest; glargine, long; detemir, shortest
  • 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) ^r68
    • Step 1: start basal insulin analogue (eg, glargine, detemir, degludec) ^c140c141c142
      • If hemoglobin A1C level is less than 8%, start with 0.1 to 0.2 units/kg/day (or 10 units/day)
      • If hemoglobin A1C level is more than 8%, start with 0.2 to 0.3 units/kg/day
    • Step 2: titrate insulin approximately every 2 to 3 days until glycemic targets are reached (usually fasting blood glucose level is less than 110 mg/dL)
      • If fixed regimen is used, increase by 2 units per day
      • If adjustable regimen is used, titration is based on fasting blood glucose level
        • If fasting blood glucose level is more than 180 mg/dL, add 4 units
        • If fasting blood glucose level is between 140 and 180 mg/dL, add 2 units
        • If fasting blood glucose level is between 110 and 139 mg/dL, add 1 unit
    • Step 3: monitor for hypoglycemia
      • If blood glucose level is less than 70 mg/dL, reduce basal insulin by 10% to 20%
      • If blood glucose level is less than 40 mg/dL, reduce basal insulin by 20% to 40%
    • Insulin 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) ^{c143c144c145c146}
    • Various stepwise approaches may be used to start prandial insulin
      • Weight-based, given at each meal ^r33
        • Calculate total daily dose of insulin: 0.3 to 0.5 units/kg/day
        • Half of the total units are given as basal insulin and half are given as prandial insulin, divided equally among the 3 meals
        • If 2-hour postprandial glucose or preprandial glucose level is greater than 180 mg/dL, increase the prandial dose for the next meal by 10%
        • If hypoglycemia occurs between meals after prandial insulin, the next prandial insulin dose is reduced; if nighttime hypoglycemia occurs, reduce basal insulin or reduce prandial insulin taken before dinner
      • 1 prandial dose added, given before largest meal of day ^r68
        • 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 ^r94
          • Daily long-acting basal insulin and a prandial rapid-acting insulin with the largest meal is preferred approach rather than using premixed insulins ^r68
        • Add prandial doses to the second and third meals at 8- to 12-week intervals if hemoglobin A1C targets are not met
      • Titration of prandial insulin
        • On an ongoing basis, prandial doses can be fixed or can be adjusted for meal size using carbohydrate counting
          • Fixed prandial doses have the advantage of being simple and easier to adhere to; an individualized algorithm can be created to provide guidance on how to adjust doses based on preprandial blood glucose levels ^r95
          • 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 ^r29
        • If hypoglycemia occurs, determine and address the cause
          • If there is no obvious explanation for hypoglycemia, reduce the corresponding dose by 2 to 4 units ^r1
    • Insulin aspart
      • Insulin Aspart (Recombinant) Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily with 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 with 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 with 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 ^r68c147c148
    • 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 unit/mL
        • Insulin Regular (Recombinant) Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily with 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) ^r96
        • 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 ^r97
      • 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 ^r93
      • Insulin glargine U-300
        • Glargine formulation with smaller injection volume, prolonged insulin activity, and similar efficacy to glargine U-100
        • Available in a prefilled pen calibrated for the higher concentration, so no dose conversion calculations are required
        • Lower rates of nocturnal hypoglycemia compared directly versus insulin glargine U-100 and insulin detemir ^r98
      • Insulin degludec U-200
        • Degludec formulation with smaller injection volume and similar efficacy to U-100 basal analogues
        • Available in a prefilled pen also calibrated for the higher concentration
        • Similar ability to lower hemoglobin A1C level as glargine with lower rates of hypoglycemia ^r99

  • 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 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 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 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 ^r93
  • Insulin degludec; liraglutide (Xultophy, IDegLira)
    • Formulation contains 100 units/mL of insulin degludec and 3.6 mg/mL of liraglutide, so that each dosing unit increment contains 1 unit of insulin degludec with 0.036 mg of liraglutide up to a maximum dose of 50 units of insulin degludec with 1.8 mg of liraglutide
    • Dosage for persons naïve 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) ^c149
    • Formulation contains 100 units/mL of insulin glargine and 33 mcg/mL of lixisenatide, so that each dosing unit increment contains 1 unit of insulin glargine with 0.33 mcg of lixisenatide up to a maximum daily dose of 60 units of insulin glargine with 20 mcg of lixisenatide
    • Very potent hemoglobin A1C effect: During treatment in clinical trials, hemoglobin A1C level is lowered an average of 0.5% more versus use of insulin glargine alone ^r100
    • Dosage for persons naïve 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 inadequately controlled on 30 to 60 units 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 cotransporter-2; UKPDS, United Kingdom Prospective Diabetes Study.

  Adapted from Wallia A et al: Insulin therapy for type 2 diabetes. JAMA. 311:2315-25, 2014.

  Drug 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; renal function should be checked 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		Renal function should be checked 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 cholesterol
  α-glucosidase inhibitors	0.5%	Neutral		Neutral			Nonsystemic absorption
  Dopamine-2 agonists	0.5%	Neutral		Neutral

Nondrug and supportive care

Therapeutic lifestyle modifications ^r33r48c150

• Medical nutrition therapy ^r48r101c151
  • Counseling and education sessions for development of an individualized eating plan according to the metabolic needs of the individual patient, preferably provided by a registered dietitian ^r102
  • Incorporates weight loss goals, caloric needs, and distribution of macronutrients ^r102
  • Addresses lifestyle, preferences, eating patterns, culture, and comorbidities of the individual patient
  • Guidance is available with regard to management of diabetes during fasting for Ramadan and during intercurrent illness ^r103r104
  • Capable of reducing hemoglobin A1C level by 1% to 2% ^r102
  • Various eating patterns, including paleolithic, low-carbohydrate, high-protein, vegetarian, or nut-enriched diets, the DASH diet (Dietary Approaches to Stop Hypertension), and the Mediterranean diet,^r105 have beneficial effects on weight loss, glycemic control, and cardiovascular risk ^r48r75
    • In general, diets should emphasize nonstarchy vegetables, minimize added sugars and refined grains, and avoid highly processed foods ^r106
  • General recommendations consist of emphasizing nutrient-dense foods in appropriate portion sizes; consumption of fruits, vegetables, and low-fat dairy products; limiting added sugars; and substituting healthy fats for saturated and trans fats ^r107
  • Part of medical nutrition involves instruction in how to use carbohydrate, fat, and protein counting for patients who have advanced to flexible insulin therapy
  • Macronutrient consideration ^r48
    • Ideal distribution of calories among carbohydrates, fats, and proteins for patients with type 2 diabetes to optimize glycemic control is unknown
    • Individualize macronutrient distribution based on the dietary reference intake recommendations for healthy eating, metabolic goals, and total caloric needs ^r102
    • 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 ^r102
      • Certain sources of carbohydrates are preferred over others for patients with type 2 diabetes
        • Whole grains, vegetables, fruits, legumes, and dairy products are foods that are higher in fiber and lower in glycemic load; these sources are preferable over others, especially those containing sugars
      • Reduce consumption of sugar-sweetened and nonnutritive sweetened beverages and encourage water as an alternative
    • Fats
      • Recommended total fat intake is equal to 20% to 35% of total calories (same as in general population) ^r48
      • Emphasize consumption of healthy fats (eg, long-chain ω-3 fatty acids, eicosapentaenoic acid, docosahexaenoic acid, α-linolenic acid) from food sources, such as fish, nuts, and avocados
      • Limit consumption of saturated fats (such as those from full-fat dairy, red meat, and tropical oils) and trans fats
    • Proteins
      • Emphasize sources of protein that are low in saturated fat, such as fish, egg whites, and beans; avoid processed meats
      • Ideal amount of protein intake
        • Usual protein intake: 15% to 20% of total energy ^r48
        • For patients without diabetic nephropathy, the evidence is inconclusive regarding the ideal amount of protein intake for optimizing glycemic control or improving cardiovascular risk; therefore, protein intake should approximate the recommended daily allowance for the general population (0.8 g/kg body weight) ^r108
        • For people with diabetic nephropathy (either micro- or macroalbuminuria), dietary protein restriction is not recommended because it does not alter glycemic measures, cardiovascular risk measures, or the course of GFR decline
          • For patients with non–dialysis-dependent diabetic kidney disease, the recommended daily dietary protein intake is the same as that of the general population (0.8 g/kg body weight)
          • For patients receiving dialysis, consider higher levels of dietary protein intake
  • Micronutrients ^r107
    • Routine supplementation is not recommended because there is no clear evidence of benefit in patients with diabetes who do not have underlying deficiencies
    • A healthy diet can usually provide sufficient micronutrients
  • Alcohol ^r48
    • Alcohol should be consumed in moderation, if at all (1 or fewer drinks per day for women, 2 or fewer drinks per day for men)
    • Ingestion of alcohol increases the risk of delayed hypoglycemia, especially for patients who use insulin or insulin secretagogues
  • Sodium ^r48
    • Recommended total sodium is 2300 mg/day or less (same as in general population)
    • Further sodium reduction (less than 2000 mg/day or less) is recommended for concurrent hypertension ^r109
• Physical activity ^c152
  • Increased physical activity and exercise improves glycemic control, lipids, blood pressure, and insulin sensitivity, and lowers risk of cardiovascular disease and mortality ^r75
  • Prescribe exercise program with individualized goals ^r110
    • 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 ^r111
    • Participation in high-intensity interval training^r112 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 ^r110r113
  • 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 the demands of brisk walking, unless symptoms of cardiovascular disease or microvascular complications are present ^r110
  • 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 ^r110
    • American College of Sports Medicine exercise preparticipation health screening guidelines focus on assessing: ^r114
      • Patient's current level of physical activity
      • Presence of signs or symptoms and/or known cardiovascular, metabolic, or renal disease
      • Desired exercise intensity
• Weight management ^c153
  • Primary approach to weight management is through lifestyle modification, which includes dietary change focused on caloric restriction, increased energy expenditure through physical activity, and behavioral modification (monitoring of food, exercise, and weight)
  • Weight loss goals ^r115
    • For overweight patients (BMI 25-29.9 kg/m²)^r116, weight loss goal is to achieve BMI within reference range (18.5-24.9 kg/m²)^r116
    • For obese patients (BMI 30 kg/m² or higher),^r116 initial weight loss goal is 5% to 10% of body weight
  • Intensive lifestyle interventions, targeting weight reduction through caloric restriction and increased physical activity, are effective for modest weight loss (3%-5%) ^r115
    • Clinically meaningful health benefits include improved physical fitness and HDL-C levels, reductions in hemoglobin A1C level, and lower requirements for medication for glucose, blood pressure, and lipid control ^r75r115
    • Weight loss achieved through lifestyle modification improves cardiovascular risk factors, although available data do not demonstrate that this translates into reduction in cardiovascular events ^r117
  • Pharmacotherapy can be considered when lifestyle interventions do not achieve desired goals ^r73d4
    • Options include orlistat, lorcaserin, liraglutide, naltrexone/bupropion, phentermine/topiramate, and semaglutide ^r75
  • Minimally invasive approaches such as implanted gastric balloons are rarely utilized in patients with diabetes ^r73
    • An oral hydrogel that mimics the space-occupying effect of implantable gastric balloons has been approved for long-term use in patients with BMI >25 kg/m2 and demonstrated improved weight loss outcomes in the a subgroup of patients with prediabetes or diabetes
  • Bariatric surgery may be considered for patients whose BMI remains more than 30 kg/m² despite lifestyle and/or pharmacologic treatment ^r118
    • Achieves greater improvement in glycemic control and reduction of cardiovascular risk factors in patients with obesity and type 2 diabetes compared with lifestyle and pharmacologial interventions ^r75

Diabetes self-management education and support ^r48c154

• Ongoing processes of facilitating the knowledge, skill, and ability necessary for the patient to participate in diabetes self-care
• Focus is on helping patients make informed self-management decisions
• Core educational topics include: ^r119
  • Diabetes disease process and treatment options
  • Incorporating nutritional changes and physical activity into lifestyle
  • Monitoring blood glucose, then interpreting and using the results for day-to-day management decisions
  • Using medications safely for greatest effectiveness

Blood glucose monitoring

• Self-monitoring of blood glucose ^r72c155
  • Point of care testing technology in which a small volume of capillary blood is placed on a test strip and inserted into a glucometer, providing a real-time digital display of blood glucose level
  • Rationale for blood glucose monitoring, regardless of insulin use, is to encourage patients to play a more active role in their diabetes management and to maximize the efficacy and safety of glucose-lowering therapies
    • Glucose data are used by the patient to make immediate decisions regarding coordination of insulin dosing with food intake and physical activity
      • Instruct patients to record and store blood glucose data so that it may be reviewed by clinicians to assist in drug therapy titration
    • Glucose data are trended and analyzed by the health care professional to tailor the treatment plan
      • If the decline in bedtime to morning glucose level is more than 55 mg/dL (3.1 mmol/L), this suggests an excessive basal insulin dose ^r72
      • Overnight rise in glucose levels may indicate a need to increase basal insulin dose
  • Recommended regimen for blood glucose testing depends on medication regimen ^r72
    • 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 the knowledge, skills, and willingness to incorporate glucose monitoring and any therapeutic adjustments into their diabetes care plan
      • If using an insulin secretagogue (eg, sulfonylurea, meglitinide), test fasting blood glucose level once daily and periodically at other times to confirm effectiveness of therapy and detect possible hypoglycemia
      • If using medications with low risk of hypoglycemia, test at least weekly; initial daily testing at meals and bedtime may be helpful for patient understanding of the effects of medical nutrition therapy and lifestyle modifications on glucose levels
      • If using lifestyle therapy only, daily testing is not recommended; initial daily testing at meals and bedtime may be helpful for patient understanding of the effects of medical nutrition therapy and lifestyle modifications on glucose levels
    • More frequent monitoring is required for frequent hypoglycemia, recurrent episodes of severe or nocturnal hypoglycemia, or persistently elevated hemoglobin A1C level
• Continuous glucose monitoring ^r33r120c156
  • Testing technology uses a catheter with a glucose oxidase sensor, which is placed subcutaneously to measure and record interstitial glucose levels
  • Downloadable metrics from devices (eg, time in range, glycemic variability, patterns of hypoglycemia and hyperglycemia) are used to make adjustments to the insulin regimen
  • Personal-use continuous devices, which are owned and used over the long-term by patients, display glucose data in real time so that the patient can make immediate or retrospective adjustments to diabetes management
  • Professional-use devices are used on a short-term basis (eg, 72 hours) to assess glycemic patterns for therapeutic decision-making by a health care professional
    • Short-term, intermittent, real-time continuous glucose monitoring is appropriate for persons who use basal insulin alone and have hemoglobin A1C levels above 7% ^r121
  • 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 ^r122
    • Offer to all patients who use multiple daily insulin injections who are capable of using the devices, particularly those with a higher risk of hypoglycemia or hypoglycemia unawareness ^r123
      • Can also be offered to patients on basal insulin who are capable of using devices safely
    • A 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 ^r124r125
      • Based on this, it is recommended that continuous glucose monitoring can be used to improve glycemic levels in patients with type 2 diabetes who are treated with basal-bolus insulin therapy ^r126
  • Contraindication: physical or cognitive impairment precluding ability to effectively use the technology

Smoking cessation ^r48c157

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

Immunizations ^r10r33

• Hepatitis B vaccine is recommended for all adults with type 2 diabetes who are aged 19 to 59 years; consider for patients aged 60 years or older, depending on risk assessment and projected immune response ^c158c159
• Pneumococcal vaccination with PPSV23 is recommended for adults with type 2 diabetes aged up to 64 years; give additional PPSV23 vaccine to patients aged 65 years or older regardless of prior vaccination history ^c160c161
• Annual influenza vaccine is recommended for all patients with diabetes ^c162
• Administer other vaccines, including COVID-19, in accordance with age-specific CDC recommendations ^r127

Comorbidities

• Hypertension ^d5
  • Hypertension affects most patients with type 2 diabetes and greatly increases the risk of micro- and macrovascular complications
  • There is strong evidence supporting treatment of patients with diabetes and blood pressure of 140/90 mm Hg or higher with a goal to lower blood pressure to less than 140/90 mm Hg ^r136
  • Overall, available evidence suggests that blood pressure targets lower than 140/90 mm Hg yield cardiovascular benefits for some populations but increase adverse events (elevations in serum creatinine level and electrolyte disturbances) in other populations ^r136
    • More intensive treatment, with lower blood pressure targets, also provides lower risk of stroke^r37 and reduction in albuminuria ^r136
    • Patients with higher baseline cardiovascular risk and higher baseline blood pressure appear to derive greater benefits; patient characteristics that impart higher risk for adverse events of aggressive blood pressure lowering have not been identified ^r137
  • Optimal blood pressure targets in patients with hypertension and type 2 diabetes are uncertain; suggested targets vary by professional society ^r75r137c170
  • American Diabetes Association generally recommends blood pressure goals less than 140/90 mm Hg for patients with diabetes, but lower targets (less than 130/80 mm Hg) may be appropriate for certain people (eg, younger patients, patients with albuminuria, those with known atherosclerotic cardiovascular disease or 10-year atherosclerotic cardiovascular disease risk of 15% or higher ^r6
  • American College of Cardiology/American Heart Association recommend a uniform target blood pressure less than 130/80 mm Hg ^r36
  • The Association of British Clinical Diabetologists and the Renal Association UK recommends blood pressure target of 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) and 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), ^r109
  • 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 ^r138
    • The Association of British Clinical Diabetologists and the Renal Association UK recommends blood pressure targets of no lower than 150/90 mm Hg are recommended in patients who are aged 75 years or older ^r109
  • 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 obese
      • DASH (Dietary Approaches to Stop Hypertension) 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 140/90 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, or dihydropyridine calcium channel blocker
      • For patients with diabetes, albuminuria, and hypertension, start either an ACE inhibitor or an angiotensin receptor blocker, but not both; titrate to maximum tolerated dose ^r109
      • Multidrug therapy (ie, thiazide diuretic and ACE inhibitor/angiotensin receptor blocker at maximal doses) is often required to achieve blood pressure targets
        • If blood pressure is 160/100 mm Hg or more, start pharmacotherapy with 2 agents in addition to lifestyle therapy
• Dyslipidemia ^c171d6
  • Patients with type 2 diabetes have a specific type of dyslipidemia that promotes atherosclerosis and contributes to an elevated risk of atherosclerotic cardiovascular disease ^r139
    • 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 ^r83r139
  • There is a lack of consensus among medical societies regarding the use of numeric lipid goals
    • American Heart Association does not specify a numeric LDL-C goal ^r140
    • American Association of Clinical Endocrinologists recommends an LDL-C goal less than 100 mg/dL for patients with diabetes and no atherosclerotic cardiovascular disease or major risk factors, less than 70 mg/dL for patients with diabetes and at least other 1 major risk factor, and less than 55 mg/dL for patients with diabetes with established atherosclerotic cardiovascular disease ^r28r42
  • Lifestyle modifications for dyslipidemia are recommended for all patients with diabetes, regardless of whether pharmacotherapy is used, including: ^r139
    • Medical nutrition therapy (low saturated fat, low trans fat, low cholesterol, increased omega-3 fatty acids, increased fiber)
    • Weight loss if necessary
    • Increased physical activity
    • Smoking cessation
  • Intensify lifestyle modifications and optimize glycemic control for patients with triglyceride levels 150 mg/dL or greater and/or HDL-C levels lower than 40 mg/dL (for men) or lower than 50 mg/dL (women) ^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
    • Joint guidelines of American College of Cardiology and American Heart Association recommend the following: ^r140
      • Moderate-intensity statin therapy is indicated for adults aged 40 to 75 years with diabetes mellitus, regardless of estimated 10-year risk of atherosclerotic cardiovascular disease
      • It is reasonable to assess the 10-year risk of a first atherosclerotic cardiovascular event in adults aged 40 to 75 years with diabetes mellitus and an LDL-C level of 70 to 189 mg/dL
      • High-intensity statin therapy with the aim to reduce LDL-C levels by 50% or more is reasonable for adults with diabetes mellitus who have multiple risk factors for atherosclerotic cardiovascular disease
      • Addition of ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more may be reasonable for adults with diabetes mellitus and 10-year risk of 20% or higher for atherosclerotic cardiovascular events
      • It is reasonable to consider initiation of statin therapy in adults older than 75 years with diabetes mellitus based on individual risks and benefits; it is reasonable for those who are already on statin therapy to continue beyond age 75 years
      • Initiation of statin therapy may be reasonable in adults aged 20 to 39 years with type 1 diabetes mellitus for 20 years or longer, albuminuria (30 mcg or more of albumin per milligram of creatinine), estimated GFR less than 60 mL/minute/1.73 m², retinopathy, neuropathy, or ankle-brachial index less than 0.9
• Chronic kidney disease ^r141c172
  • Drug therapy is challenging owing to the potential for various adverse effects, such as lactic acidosis and hypoglycemia ^r142
  • Contraindications and dose adjustments exist in all medication classes and should be reviewed for patients with chronic kidney disease stages 2 to 5
  • Metformin
    • Initiation of therapy is appropriate if estimated GFR is more than 45 mL/minute/1.73 m²
    • Patient may remain on metformin until estimated GFR falls below 30 mL/minute/1.73 m², in which case continuation of metformin is contraindicated
  • Dipeptidyl-peptidase IV inhibitor
    • Can be used in all stages of renal impairment
    • Most require dosage adjustment, except linagliptin
  • Sulfonylureas
    • Undesirable to use this class in general, particularly glipizide, owing to the risk of hypoglycemia
    • Most sulfonylureas are contraindicated in patients with stage 4 chronic kidney disease
  • Meglitinides
    • May be used in stage 3 to 5 chronic kidney disease but requires careful dose adjustments
  • Glucagon-like peptide 1 receptor agonists
    • Dulagutide, 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 less than 15 mL/minute/1.73 m²
  • Sodium-glucose cotransporter-2 inhibitors ^r141
    • Recommended, in addition to the angiotension receptor blocker or ACE inhibitor, for patients with urinary albumin-creatinine ration greater than 30 mg/mmol ^r30
    • At stage 3 or greater, these drugs require dose adjustment or are contraindicated
    • Empagliflozin and canagliflozin are contraindicated if estimated GFR persistently falls below 45 mL/minute/1.73 m²
    • Dapagliflozin is not recommended if estimated GFR persistently falls below 60 mL/minute/1.73 m² and is contraindicated if estimated GFR is below 30 mL/minute/1.73m²
  • Thiazolidinediones
    • Only pioglitazone is advisable owing to safety concerns with other agents in this class ^r141
    • Do not use pioglitazone in 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 ^c173d7
  • Use American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease risk calculator to assess 10-year atherosclerotic cardiovascular disease risk and to guide therapy
  • Promote lifestyle modifications to reduce cardiovascular risk, including: ^r40r75
    • 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 (either a sodium-glucose cotransporter-2 inhibitor or glucagon-like peptide 1 receptor agonist) ^r58
    • Strongest evidence for cardiovascular benefit has been demonstrated with liraglutide, dulaglutide, semaglutide, empagliflozin, dapagliflozin, and canagliflozin ^r27r58
    • 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 such as hypertension and dyslipidemia
  • Antiplatelet therapy with low-dose aspirin is recommended for secondary prevention in patient with a history of cardiovascular disease and may be considered for primary prevention in patients at increased risk of cardiovascular events ^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 ^r75
    • 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 in high-risk patients with diabetes ^r75
  • An ACE inhibitor or angiotensin receptor blocker is recommended in patients with known cardiovascular disease ^r6
  • Obtain resting ECG in patients with hypertension or suspected cardiovascular disease ^r12
  • Routine screening for coronary artery disease is not recommended in asymptomatic patients
  • Exercise ECG may be considered for cardiovascular risk assessment in patients with cardiac symptoms or an abnormal resting ECG ^r6
  • Coronary artery calcium measurement may be considered for patients aged 40 years or older ^r6
• Congestive heart failure ^c174
  • Sodium-glucose cotransporter-2 inhibitors are recommended for patients with clinical heart failure ^r27r143
    • Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin have been shown to reduce the risk of heart failure hospitalizations in patients with type 2 diabetes mellitus and established cardiovascular disease ^r144
  • Thiazolidinedione class is contraindicated in class III and class IV heart failure
  • Some studies (not all) have reported an association between dipeptidyl-peptidase IV inhibitors and worsening heart failure; use with caution, if at all ^r27r145
• Obesity ^r73c175d4
  • Obesity (BMI of 30 kg/m² or more) is associated with insulin resistance ^r146
  • Abdominal adiposity (waist circumference greater than 102 cm in men and greater than 88 cm in women) in overweight patients (BMI of 25-30 kg/m²) is also associated with insulin resistance ^r33
  • 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%) ^r115
    • Greater amounts of weight loss will further reduce hemoglobin A1C level (0.6%-1%), reduce blood pressure (approximately 3 mm Hg), improve LDL-C and HDL-C levels, and reduce the need for medications to control blood pressure, blood glucose level, and lipid levels ^r115
  • First line therapy is lifestyle modification to achieve weight loss of 5% or more ^r73
    • Consists of reduced-calorie diet in conjunction with physical activity and behavioral therapy
    • Individual counseling sessions occur frequently (16 or more in 6 months) with goal of producing a 500 to 750 kcal/day energy deficit
    • Prescribe long-term (1 year or longer) comprehensive weight maintenance programs for patients who achieve short-term weight loss goals
    • Use of very-low-calorie diets (800 kcal/day or less) and total meal replacements are reserved for patients in whom careful medical monitoring is possible
  • Second line therapy is pharmacotherapy, which is indicated for a person who has diabetes and a BMI of 27 kg/m² or more ^r115
    • Agents include phentermine, orlistat, lorcaserin, phentermine–topiramate extended-release, naltrexone-bupropion, liraglutide, and semaglutide
    • Reassess medications for comorbid conditions and minimize those that cause weight gain, including atypical antipsychotics, antidepressants, glucocorticoids, anticonvulsants, antihistamines, and anticholinergics ^r73
  • Select a regimen for diabetes management to include drugs that have favorable effects on body weight where possible ^r73
    • Diabetes medication classes associated with weight gain include sulfonylureas, meglitinides, thiazolidinediones, and insulin
    • Diabetes medication classes that promote modest weight loss are biguanides, glucagon-like peptide 1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and amylin mimetics
    • Diabetes medication classes that are weight neutral include dipeptidyl-peptidase IV inhibitors
  • Bariatric surgery is a recommended option to treat type 2 diabetes in patients with: ^r73
    • BMI of 40 kg/m² or more (37.5 kg/m² or more in Asian Americans)
    • BMI of 35 to 39.9 kg/m² (32.5-37.4 kg/m² in Asian Americans) if unable to achieve durable weight loss and improvement in comorbidities (including hyperglycemia) with nonsurgical methods
  • Bariatric surgery may be also considered in patients with a BMI of 30 to 34.9 kg/m² (27.5-32.4 kg/m² in Asian Americans) if unable to achieve durable weight loss and improvement in comorbidities (including hyperglycemia) with nonsurgical methods ^r73
• Obstructive sleep apnea ^{c176c177c178c179}
  • Associated with obesity (particularly central obesity), male sex, and older age; affects approximately two-thirds of men who have diabetes and are older than 65 years ^r33
  • 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 ^r147
  • Treat with weight loss, CPAP, adjustable airway pressure devices, oral appliances, and/or surgery
  • Treatment of sleep apnea improves quality of life and positively affects blood pressure
• Nonalcoholic fatty liver disease ^r10c180d8
  • Excess of fat in the liver (steatosis) that is not a result of excessive alcohol consumption or other secondary causes
  • Type 2 diabetes is a risk factor for development of the disease
  • Among the available medications to treat type 2 diabetes, pioglitazone improves nonalcoholic fatty liver disease activity and resolves nonalcoholic steatohepatitis in about half of treated patients ^r148
• Liver failure and cirrhosis ^c181c182
  • Treatment of diabetes in these patients is complex because many diabetes drugs can promote hypoglycemia and lactic acidosis ^r149
  • In most cases, insulin therapy, including the insulin analogues, is the safest choice
  • Oral diabetes medications are contraindicated in patients with advanced liver diseases who have cirrhosis, ascites, or encephalopathy ^r150
  • Glucagon-like peptide 1 receptor agonists exenatide and liraglutide have been shown to be safe in patients with liver disease ^r149
  • Dipeptidyl-peptidase IV inhibitors appear to be safe for use in patients with liver cirrhosis ^r149
• Osteoporosis ^r10c183
  • Use thiazolidinediones and the sodium-glucose cotransporter-2 inhibitor canagliflozin with caution
• HIV ^c184
  • Fasting glucose levels are the preferred method of diagnosis ^r4
    • Do not use a hemoglobin A1C test to diagnose diabetes in patients with HIV because it underestimates glycemia in this population ^r151
  • Risk of developing diabetes is increased with treatment with some protease inhibitors and nucleoside reverse transcriptase inhibitors ^r10
• Psychosocial disorders ^r152
  • Depression ^c185d9
    • Highly prevalent in patients with type 2 diabetes; 20% to 25% of patients with diabetes are affected by depression^r153
    • Associated with increased risk of myocardial infarction and mortality
    • Depression- and diabetes-related distress are associated with poor self-care, nonadherence, and poor glycemic control
    • Refer to a mental health specialist for assessment and treatment ^r48
  • Anxiety ^c186d10
    • Anxiety over aspects of the disease or diabetes care (eg, complications, injections, hypoglycemia) is common and can lead to maladaptive behavior, such as avoidance, withdrawal, or excessive repetitive habits ^r48
    • Fears of hypoglycemia can lead to self-relaxing of glycemic goals and reducing the intensity of measures to treat the disease
    • Refer patients to diabetes education for blood glucose awareness training or to a mental health specialist for more severe forms of anxiety
  • Diabetes-related distress is the experience of people who become overly burdened by the ongoing behavioral demands of managing the disease ^r153c187
    • Refer such patients to diabetes education or to a mental health specialist if areas of diabetes care are adversely impacted

Special populations

• Older adults ^r154
  • 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;^r155 instead, modify treatment to avoid hypoglycemia^r156r154
  • 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 ^r154
    • In healthy older adults (few comorbidities, fully functional)
      • Hemoglobin A1C level: 7% to less than 7.5%
      • Fasting blood glucose level: 90 to 150 mg/dL
      • Bedtime blood glucose level: 100 to 180 mg/dL
    • In somewhat unhealthy older adults (multiple comorbidities, some functional or cognitive impairment)
      • Hemoglobin A1C level: 7.5% to less than 8%
      • Fasting blood glucose level: 100 to 150 mg/dL
      • Bedtime blood glucose level: 150 to 180 mg/dL
    • In very unhealthy older adults (eg, in long-term care, with end-stage chronic illness, significant physical impairment, moderate to severe dementia)
      • Hemoglobin A1C level: 8% to less than 8.5%
      • Fasting blood glucose level: 100 to 180 mg/dL
      • Bedtime blood glucose level: 110 to 250 mg/dL
  • Older adults with type 2 diabetes are at increased risk for hypoglycemia owing to decreased insulin and increased renal insufficiency, requiring closer monitoring when treated with medications that can cause hypoglycemia ^r154r156
  • Metformin is the first line agent for treatment of type 2 diabetes for older adults ^r156
  • Drug therapy may need to be adjusted for older adults, especially in the setting of comorbidities ^r154
    • Metformin is contraindicated in renal failure and heart failure
    • Use thiazolidinediones with caution in congestive heart failure
    • Saxagliptin may increase the risk of hospitalization for heart failure
    • Simplify drug regimens (eg, combination drug pills) where possible for elderly patients with cognitive impairments
    • Once-daily injection of basal insulin may be a reasonable option for some older adults
• Pregnant patients
  • Glucose targets for pregnant patients with pregestational type 2 diabetes are more aggressive than for the general population of patients with type 2 diabetes
    • American Association of Clinical Endocrinologists: ^r33
      • Hemoglobin A1C less than 6% during pregnancy
      • Preprandial, bedtime, and overnight glucose levels: 60 to 99 mg/dL
      • Peak postprandial blood glucose level: 100 to 129 mg/dL
    • American Diabetes Association ^r157
      • Hemoglobin A1C level: 6% or lower
      • Fasting blood glucose of less than 95 mg/dL
      • 1-hour postprandial blood glucose less than 140 mg/dL or 2-hour postprandial blood glucose less than 120 mg/dL
  • Insulin is the preferred medication for managing glycemia during pregnancy ^r157
    • Long-term safety profile is superior compared with noninsulin agents
    • Insulin can easily be titrated to match changing insulin demand in pregnancy
      • First trimester insulin requirements are typically lower, whereas second and third trimester requirements are typically higher owing to increasing insulin resistance
  • Oral agents considered to be relatively safe alternatives to insulin during pregnancy include metformin and glyburide ^r33
  • Pregnant patients with type 2 diabetes are more likely to be overweight or obese ^r157
    • Suggested weight gain for an overweight pregnant patient with diabetes is 6.8 to 11.3 kg
    • Suggested weight gain for an obese pregnant patient with diabetes is 4.5 to 9 kg
  • In pregnancy complicated by both diabetes and hypertension, blood pressure targets and treatment may differ compared with those of prepregnancy care ^r157
    • Target blood pressure of 135/85 mm Hg or lower is recommended
  • Diabetes is associated with an increased risk of preeclampsia; prescribe low-dose aspirin during second and third trimester to reduce risk ^r157
• Hospitalized patients
  • Inpatient glucose targets vary per setting and circumstance
    • Glucose target between 140 and 180 mg/dL is recommended for most critically and noncritically ill patients ^r35
    • Glucose target between 110 and 140 mg/dL may be appropriate for select patients (eg, those with previous cardiac surgery, stroke, or acute ischemic cardiac events) provided that the target can be achieved without significant hypoglycemia ^r35
  • ICU ^r35
    • 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 ^r35
  • Perioperative care
    • Target glucose range for perioperative period is 80 to 180 mg/dL; attempts to achieve tighter perioperative glucose control lead to unacceptable rates of hypoglycemia^r158r35
    • Withhold metformin 24 hours before surgery, and withhold all other oral hypoglycemic drugs beginning on the morning of surgery ^r35
    • 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 ^r35
    • Give insulin in portions designated as basal, nutritional, and correctional
    • Dosing can be determined by preadmission basal insulin dose; if no insulin was used, a dose of 10 units glargine every 24 hours may be used
    • Tube feedings: use 1 unit of insulin for 10 to 15 g of carbohydrate
    • Enteral bolus feeding: give 1 unit of regular or immediate-acting insulin per 10 to 15 g of carbohydrate before the feeding
    • Continuous peripheral or central parenteral delivery: add 1 unit of regular insulin per 10 g of dextrose
    • 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
  • Avoid iatrogenic hypoglycemia (less than 70 mg/dL) ^r35
    • Inpatient hypoglycemia is associated with higher complication rates and greater mortality
    • Triggers include emesis, reduced oral intake, reduction in glucocorticoid doses, misalignment between administration of rapid-acting insulin and meals, interruption of change in enteral/parenteral feedings, or new NPO status

At-risk populations

• Screen asymptomatic persons who are not overweight or obese beginning at age 45 years, with testing repeated at a minimum of 3-year intervals ^{r33c233c234c235}
  • Consider more frequent testing depending on initial results and risk status
    • Annually test persons with prediabetes ^c236c237c238
    • Consider screening patients with 2 or more risk factors annually
• Screen asymptomatic persons who are overweight or obese beginning at at age 35 years ^r172
• Consider screening in adults at any age who are overweight (BMI of 25 kg/m² or more, or 23 kg/m² or more in Asian Americans) and have additional risk factors, such as: ^r4
  • Physical inactivity ^c239c240c241
  • First-degree relative with diabetes ^c242c243c244
  • High-risk race or ethnicity (eg, African American, Latino, Native American, Pacific Islander, Asian American) ^{c245c246c247c248c249c250c251c252c253c254c255c256c257c258c259}
  • Hypertension (blood pressure 140/90 mm Hg or higher or currently on therapy for hypertension) ^c260c261c262
  • Dyslipidemia (HDL-C level less than 35 mg/dL and/or triglyceride level more than 250 mg/dL) ^c263c264c265
  • Polycystic ovary syndrome ^c266c267c268
  • Hemoglobin A1C level of 5.7% or more, impaired glucose tolerance, or impaired fasting glucose level on previous testing ^{c269c270c271c272c273c274c275c276c277}
  • Conditions associated with insulin resistance (eg, metabolic syndrome, nonalcoholic fatty liver disease, acanthosis nigricans) ^{c278c279c280c281c282c283c284c285c286c287c288c289}
  • History of cardiovascular disease ^c290c291c292
• Antipsychotic therapy for severe bipolar disease or schizophrenia ^{r33c293c294c295c296c297c298}
• Chronic use of glucocorticoids ^{r33c299c300c301}
• Sleep disorders in conjunction with glucose intolerance (eg, obstructive sleep apnea, chronic sleep deprivation, night shift work schedule) ^{r33c302c303c304c305c306c307c308c309c310c311c312c313}

Screening tests

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