Table 6.2-5. Antidiabetic agents

Biguanides

Drug and dosage

Metformin: Initially 500 or 850 mg PO once daily taken with largest meal. Dose increased by 500 mg/wk up to usual dose of 1000 mg bid or 850 mg tid (with meals). Max dose 2550 mg/d

Commentsa

Mechanism of action: ↓ liver production of glucose

Efficacyb: HbA1c ↓ 1%-2%

Contraindications: Renal failure with GFR <30 mL/min (or serum creatinine ≥132.6 micromol/L [1.5 mg/dL] in men or ≥123.8 micromol/L [1.4 mg/dL] in women according to manufacturer), severe hepatic dysfunction, decompensated or advanced HF, acidosis, hypoxia, shock, history of severe hypersensitivity to metformin

Frequent adverse effects: Diarrhea, nausea, vomiting, bloating, abdominal cramping, metallic taste

Rare adverse effects: Lactic acidosis

Risk of hypoglycemia: No if monotherapy

Effect on weight: Neutral or modest weight loss

Miscellaneous advantages: Extensive experience, low cost

Miscellaneous disadvantages: Can cause vitamin B12 deficiency. Manufacturer recommends temporarily discontinuing metformin in patients undergoing radiologic studies where intravascular iodinated contrast media are used

Other comments: GI adverse effects more frequent early in the course of treatment. Extended-release metformin may be better tolerated in patients with GI adverse effects. Elderly patients should not be titrated to max dose. Careful use in patients ≥80 years (normal renal function has to be established)

Sulfonylureas

Drug and dosage

Glipizide: 2.5-20 mg PO once daily. Doses >15 mg/d should be administered in 2 divided doses. Immediate-release tablets should be administered 30 min before meals (typically before breakfast if once daily); extended-release tablets should be given with breakfast. Titrate in 2.5-5 mg increments. Max recommended dose 20 mg/d

Glimepiride: 1-8 mg PO once daily. Administer once daily with breakfast or first main meal of the day. Titrate in 1-2 mg increments. Max recommended dose 8 mg/d

Glyburide: 1.25-20 mg PO once daily. Patients receiving >10 mg daily may have more satisfactory response with bid dosing. Administer with meals (typically before breakfast or first main meal of the day if once daily). Titrate in 1.25-2.5 mg increments. Max recommended dose 20 mg/d

Micronized glyburide (greater bioavailability): 0.75-12 mg PO once daily. Patients receiving >6 mg daily may have more satisfactory response with bid dosing. Administer with meals (typically before breakfast or first main meal of the day if once daily). Titrate in 0.75-1.5 mg increments. Max recommended dose 12 mg/d

Gliclazide: 80-320 mg/d in 2 divided doses, 30 min before meals. Modified-release tablets 30 mg once daily (with breakfast). Increase dose (by 30 mg every 2 weeks) up to max of 120 mg/d 

Commentsa

Mechanism of action: Closes KATP channels on beta-cell plasma membranes. ↑ insulin secretion

Efficacyb: HbA1c ↓ 1%-2%

Contraindications: History of severe hypersensitivity reactions

Frequent adverse effects: Lack of energy and strength

Rare adverse effects: Diarrhea, nausea, constipation, flatulence, dizziness, headaches

Risk of hypoglycemia: Present, particularly in the elderly, with strenuous exercise, or due to interactions with other drugs (eg, sulfonamides, alcohol)

Effect on weight: Modest gain

Miscellaneous advantages: Extensive experience, low cost

Miscellaneous disadvantages: Failure rate may exceed other drugs (this is attributed to exacerbation of islet dysfunction)

Other comments: Reduces postprandial glucose excursions. Usually start with lowest dose and increase every 1-2 weeks based on blood glucose. Patients with decreased caloric intake or fasting may need doses held to avoid hypoglycemia. Long-acting sulfonylureas (eg, glyburide) may be associated with higher risk of hypoglycemia than short-acting sulfonylureas (eg, glipizide, glimepiride)

Meglitinides (glinides)

Drug and dosage

Repaglinide: 0.5-4 mg PO 1-30 min before each meal 2, 3, or 4 times/d based on meal pattern. Titrate in 1-2 mg increments weekly. Max recommended dose 16 mg/d

Nateglinide: 60-120 mg PO 1-30 min before each meal 2, 3, or 4 times/d based on meal pattern

Commentsa

Mechanism of action: Closes KATP channels on beta-cell plasma membranes. ↑ insulin secretion

Efficacyb: HbA1c ↓ 1%-2%

Contraindications: History of severe hypersensitivity reactions

Frequent adverse effects: Headaches

Rare adverse effects: Diarrhea, arthralgias

Risk of hypoglycemia: Present (possibly smaller than with sulfonylureas)

Effect on weight: Modest gain

Miscellaneous advantages: Both can be used in patients allergic to sulfonylureas. Short duration of action allows dosing flexibility

Miscellaneous disadvantages: Tid dosing, expensive

Other comments: Reduces postprandial glucose excursions. Repaglinide is more effective at lowering HbA1c than nateglinide. Repaglinide is principally metabolized by liver with <10% excreted by kidneys (dose adjustments not typically required in patients with renal insufficiency). Nateglinide has active metabolites excreted by kidneys and should be used with caution in renal insufficiency. If patient misses a meal, glinides should not be administered to avoid hypoglycemia

Alpha-glucosidase inhibitors

Drug and dosage

Acarbose: Initially 25 mg PO tid immediately before main meals (some patients benefit from starting with 25 mg once daily with gradual titration to 25 mg tid to reduce GI adverse effects). Dose may be increased every 2-4 weeks. Max dose 50 mg tid (≤60 kg) or 100 mg tid (>60 kg)

Commentsa

Mechanism of action: Inhibits intestinal alpha-glucosidase and slows down the final enzymatic stage of intestinal digestion of polysaccharides, oligosaccharides, and some disaccharides (maltose and sucrose)

Efficacyb: HbA1c ↓ 0.5%-1% (mainly ↓ postprandial glucose levels)

Contraindications: History of severe hypersensitivity reactions, IBD, colonic ulceration, conditions that may deteriorate due to increased intestinal gas formation, predisposition to intestinal obstruction, partial intestinal obstruction, cirrhosis, renal impairment (serum creatinine >2 mg/dL)

Frequent adverse effects: Flatulence, diarrhea, abdominal pain

Rare adverse effects: Ileus, hepatotoxicity

Risk of hypoglycemia: No if monotherapy

Effect on weight: Neutral

Miscellaneous advantages: No systemic effects

Miscellaneous disadvantages: Frequent GI adverse effects; frequent dosing; expensive

Other comments: Reduces postprandial glucose excursions. In case of hypoglycemia (eg, concomitant use of sulfonylureas), glucose (dextrose) recommended for treatment. GI adverse effects may be decreased by restricting dietary sucrose (table sugar)

Thiazolidinediones (TZD)

Drug and dosage

Pioglitazone: 15-30 mg PO once daily, administered without regard to meals. Dose can be increased in 15 mg increments with careful monitoring of adverse effects (eg, weight gain, edema, symptoms of heart failure). Max dose 45 mg once daily

Rosiglitazone: 4 mg PO once daily or in divided doses bid, administered without regard to meals. Dose can be increased up to 8 mg daily, as a single daily dose or in divided doses bid. Max dose 8 mg/d

Commentsa

Mechanism of action: Activates the nuclear transcription factor PPAR-gamma, ↑ insulin sensitivity

Efficacyb: HbA1c ↓ 0.5%-1.5%

Contraindications: History of severe hypersensitivity reactions, HF, serious hepatic impairment, active bladder cancer, history of bladder cancer; uninvestigated macroscopic hematuria, pregnancy

Frequent adverse effects: Edema, headaches

Rare adverse effects: HF exacerbation, bone fractures, anemia, possibly ischemic heart disease (rosiglitazone), possibly bladder cancer (pioglitazone)

Risk of hypoglycemia: No if monotherapy

Effect on weight: Modest gain

Miscellaneous advantages: Effectiveness may be more durable than sulfonylureas and metformin. ↑ HDL-C, ↓ triglycerides

Miscellaneous disadvantages: Rosiglitazone may ↑ LDL-C and is expensive

Other comments: Limit max dose of pioglitazone to 15 mg/d—and consider dose reduction of rosiglitazone—when used in combination with strong CYP2C8 inhibitors (eg, gemfibrozil)

Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins)

Drug and dosage

Sitagliptin: 100 mg PO once daily. Administer with or without food. If eGFR 30-50 mL/min, dose 50 mg once daily; if eGFR is <30 mL/min, dose 25 mg once daily

Linagliptin: 5 mg PO once daily. Administer with or without food. No dosage adjustment necessary for renal impairment

Saxagliptin: 2.5-5 mg PO once daily. Administer with or without food. If eGFR is ≤50 mL/min, dose 2.5 mg once daily. If concomitant use of strong CYP3A4/5 inhibitors, dose 2.5 mg once daily

Alogliptin: 25 mg PO once daily. Administer with or without food. If eGFR is 30-60 mL/min, dose 12.5 mg once daily. If eGFR is <30 mL/min, dose 6.25 mg once daily

Commentsa

Mechanism of action: Inhibition of DPP-4 activity leads to ↑ endogenous incretins (GLP-1 and GIP) after meals, ↑ glucose-dependent insulin secretion

Efficacyb: HbA1c ↓ 0.5%-0.8%

Contraindications: History of severe hypersensitivity reactions

Frequent adverse effects: Generally well tolerated

Rare adverse effects: Headaches, nausea, possibly pancreatitis

Risk of hypoglycemia: No if monotherapy

Effect on weight: Neutral

Miscellaneous advantages: Can be used in patients with advance renal disease

Miscellaneous disadvantages: Modest glucose-lowering efficacy, expensive

Other comments: Limited long-term safety data. Saxagliptin may increase risk of HF

Glucagon-like peptide 1 (GLP-1) agonists

Drug and dosage

Exenatide: Immediate release: Initial dose 5 microg SC bid within 60 min prior to 2 main meals (≥6 h apart). After 1 month dose may be increased to 10 microg bid. Extended release: 2 mg once weekly without regard to meals or time of day. Rotate injection sites weekly

Liraglutide: Initial dose 0.6 mg SC once daily for 1 week (dose intended to reduce GI symptoms but ineffective for glycemic control), then increase to 1.2 mg once daily. Dose may be increased to 1.8 mg once daily. Administer without regard to meals or time of day

Albiglutide: 30 mg SC once weekly. Dose may be increased to 50 mg once weekly. Administer without regard to meals or time of day. Rotate injection sites weekly

Dulaglutide: 0.75 mg SC once weekly. Dose may be increased to 1.5 mg once weekly. Administer without regard to meals or time of day. Rotate injection sites weekly

Lixisenatide: Initial dose 10 microg once daily for 14 days; on day 15 increase to 20 microg once daily. Maintenance dose 20 microg once daily. If dose is missed, administer within 1 h of next meal

Semaglutide: Initial dose 0.25 mg once weekly for 4 weeks. Increase to 0.5 mg once weekly for ≥4 weeks. If further glycemic control necessary, increase to max 1 mg once weekly

Commentsa

Mechanism of action: Stimulation of GLP-1 receptors leads to ↑ glucose-dependent insulin secretion; ↓ glucagon secretion; slow gastric emptying; ↑ satiety

Efficacyb: HbA1c ↓ 0.5%-1.5%

Proven CV benefit: Only liraglutide; semaglutide may be considered as it was shown to reduce MACE but at expense of stroke reduction rather than CV death. No CV benefit demonstrated with exenatide or lixisenatide

Reduction of CKD progression: Liraglutide and semaglutide

Contraindications: History of severe hypersensitivity reactions, history of pancreatitis, severe GI disease (eg, gastroparesis), history or family history of medullary thyroid carcinoma or MEN syndrome type 2; caution with severe renal impairment (exenatide contraindicated if eGFR <30 mL/min)

Frequent adverse effects: Nausea, vomiting, diarrhea, injection site reactions (eg, pruritus, swelling), headaches, dizziness, nervousness

Rare adverse effects: Possibly pancreatitis, possibly pancreatic cancer

Risk of hypoglycemia: No if monotherapy

Effect on weight: Modest to significant weight loss

Miscellaneous advantages: Once-weekly preparations can reduce treatment burden

Miscellaneous disadvantages: Injectable medications, expensive

Other comments: GI adverse effects more frequent early in the course of treatment. Administer SC injections in upper arm, thigh, or abdomen. Some patients develop high titers of antibodies that may ↓ glycemic response. Limited long-term safety data

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (flozins)

Drug and dosage

Canagliflozin: 100 mg PO once daily before first meal of day. Dose may be increased to 300 mg once daily. If eGFR is 45-59 mL/min, dose 100 mg once daily. Has also inhibitory effect on SGLT-1

Dapagliflozin: 5 mg PO once daily. Administer in the morning with or without food. Dose may be increased to 10 mg once daily

Empagliflozin: 10 mg PO once daily, may be increased to 25 mg

Sotagliflozin: Currently an investigational drug, under regulatory review by EMA and FDA for treatment of both type 1 and 2 DM. Has also inhibitory effect on SGLT-1

Commentsa

Mechanism of action: Promote renal excretion of glucose

Efficacyb: HbA1c ↓ 0.5%-0.8%

Proven CV benefit: Empagliflozin, canagliflozin, and dapagliflozin; empagliflozin has modestly stronger benefit

Reduction of CKD progression: Canagliflozin, dapagliflozin, and empagliflozin

Contraindications: History of severe hypersensitivity reactions, severe renal impairment (canagliflozin, GFR <45 mL/min; dapagliflozin, GFR <30 mL/min), severe hepatic impairment, active bladder cancer

Frequent adverse effects: Vulvovaginal candidiasis, urinary frequency, polyuria

Rare adverse effects: Urinary tract infections, symptomatic hypotension (particularly in the elderly), hyperkalemia

Risk of hypoglycemia: No if monotherapy

Effect on weight: Modest weight loss

Miscellaneous advantages: Can decrease blood pressure. Empagliflozin has been shown to reduce mortality among patients with type 2 DM at high risk of CV events

Miscellaneous disadvantages: Uncertain long-term effect of chronic glycosuria, modest glucose-lowering efficacy, expensive, LDL-C levels may increase, careful use in conditions associated with risk of dehydration

Other comments: Correct volume depletion prior to administration. Limited long-term safety data. May reduce postprandial hyperglycemia by delaying intestinal glucose absorption

Warning: Recent FDA review applied to all SGLT-2 inhibitors pointed to risk of ketoacidosis and serious urinary tract infections (fewer than 100 cases reported over >1 year)

a Adapted from the American Diabetes Association and the European Association for the Study of Diabetes 2012 position statement.

b Predicted reduction of HbA1c levels with monotherapy (expressed in percentage points).

↑, increase; ↓, decrease; bid, 2 times a day; CKD, chronic kidney disease; CV, cardiovascular; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; EMA, European Medicines Agency; FDA, US Food and Drug Administration; GFR, glomerular filtration rate; GI, gastrointestinal; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HF, heart failure; IBD, inflammatory bowel disease; LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiovascular events; MEN, multiple endocrine neoplasia; PO, oral administration; PPAR-gamma, peroxisome proliferator-activated receptor gamma; SGLT-2, sodium-glucose cotransporter 2; tid, 3 times a day.