Table 8.1

Properties of available glucose-lowering agents in the U.S. that may guide individualized treatment choices in patients with type 2 diabetes (21)

ClassCompound(s)Cellular mechanism(s)Primary physiological action(s)AdvantagesDisadvantagesCost*
Biguanides• MetforminActivates AMP-kinase (? other)• ↓ Hepatic glucose production• Extensive experience • Rare hypoglycemia • ↓ CVD events (UKPDS) • Relatively higher A1C efficacy• Gastrointestinal side effects (diarrhea, abdominal cramping, nausea) • Vitamin B12 deficiency • Contraindications: eGFR <30 mL/min/1.73 m2, acidosis, hypoxia, dehydration, etc. • Lactic acidosis risk (rare)Low
Sulfonylureas2nd generation • Glyburide • Glipizide • GlimepirideCloses Katp channels on β-cell plasma membranes• ↑ Insulin secretion• Extensive experience • ↓ Microvascular risk (UKPDS) • Relatively higher A1C efficacy• Hypoglycemia • ↑ WeightLow
Meglitinides (glinides)• Repaglinide • NateglinideCloses Katp channels on β-cell plasma membranes• ↑ Insulin secretion• ↓ Postprandial glucose excursions • Dosing flexibility• Hypoglycemia • ↑ Weight • Frequent dosing scheduleModerate
TZDs• Pioglitazone • Rosiglitazone§Activates the nuclear transcription factor PPAR-γ• ↑ Insulin sensitivity• Rare hypoglycemia • Relatively higher A1C efficacy • Durability • ↓ Triglycerides (pioglitazone) • ? ↓ CVD events (PROactive, pioglitazone) • ↓ Risk of stroke and MI in patients without diabetes and with insulin resistance and history of recent stroke or TIA (IRIS study [42], pioglitazone)• ↑ Weight • Edema/heart failure • Bone fractures • ↑ LDL-C (rosiglitazone)Low
α-Glucosidase inhibitors• Acarbose • MiglitolInhibits intestinal α-glucosidase• Slows intestinal carbohydrate digestion/absorption• Rare hypoglycemia • ↓ Postprandial glucose excursions • ? ↓ CVD events in prediabetes (STOP-NIDDM) • Nonsystemic• Generally modest A1C efficacy • Gastrointestinal side effects (flatulence, diarrhea) • Frequent dosing scheduleLow to moderate
DPP-4 inhibitors• Sitagliptin • Saxagliptin • Linagliptin • AlogliptinInhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentrations• ↑ Insulin secretion (glucose dependent) • ↓ Glucagon secretion (glucose dependent)• Rare hypoglycemia • Well tolerated• Angioedema/urticaria and other immune-mediated dermatological effects • ? Acute pancreatitis • ↑ Heart failure hospitalizations (saxagliptin; ? alogliptin)High
Bile acid sequestrants• ColesevelamBinds bile acids in intestinal tract, increasing hepatic bile acid production• ? ↓ Hepatic glucose production • ? ↑ Incretin levels• Rare hypoglycemia • ↓ LDL-C• Modest A1C efficacy • Constipation • ↑ Triglycerides • May ↓ absorption of other medicationsHigh
Dopamine-2 agonists• Bromocriptine (quick release)§Activates dopaminergic receptors• Modulates hypothalamic regulation of metabolism • ↑ Insulin sensitivity• Rare hypoglycemia • ? ↓ CVD events (Cycloset Safety Trial)• Modest A1C efficacy • Dizziness/syncope • Nausea • Fatigue • RhinitisHigh
SGLT2 inhibitors• Canagliflozin • Dapagliflozin • EmpagliflozinInhibits SGLT2 in the proximal nephron• Blocks glucose reabsorption by the kidney, increasing glucosuria• Rare hypoglycemia • ↓ Weight • ↓ Blood pressure • Associated with lower CVD event rate and mortality in patients with CVD (empagliflozin EMPA-REG OUTCOME)• Genitourinary infections • Polyuria • Volume depletion/hypotension/dizziness • ↑ LDL-C • ↑ Creatinine (transient) • DKA, urinary tract infections leading to urosepsis, pyelonephritisHigh
GLP-1 receptor agonists• Exenatide • Exenatide extended release • Liraglutide • Albiglutide • Lixisenatide • DulaglutideActivates GLP-1 receptors• ↑ Insulin secretion (glucose dependent) • ↓ Glucagon secretion (glucose dependent) • Slows gastric emptying • ↑ Satiety• Rare hypoglycemia • ↓ Weight • ↓ Postprandial glucose excursions • ↓ Some cardiovascular risk factors • Associated with lower CVD event rate and mortality in patients with CVD (liraglutide LEADER) (30)• Gastrointestinal side effects (nausea/vomiting/diarrhea) • ↑ Heart rate • ? Acute pancreatitis • C-cell hyperplasia/medullary thyroid tumors in animals • Injectable • Training requirementsHigh
Amylin mimetics• Pramlintide§Activates amylin receptors• ↓ Glucagon secretion • Slows gastric emptying • ↑ Satiety• ↓ Postprandial glucose excursions • ↓ Weight• Modest A1C efficacy • Gastrointestinal side effects (nausea/vomiting) • Hypoglycemia unless insulin dose is simultaneously reduced • Injectable • Frequent dosing schedule • Training requirementsHigh
Insulins• Rapid-acting analogs  - Lispro  - Aspart  - Glulisine  - Inhaled insulin • Short-acting  - Human Regular • Intermediate-acting  - Human NPH • Basal insulin analogs  - Glargine  - Detemir  - Degludec • Premixed insulin products  - NPH/Regular 70/30  −70/30 aspart mix  −75/25 lispro mix  −50/50 lispro mixActivates insulin receptors• ↑ Glucose disposal • ↓ Hepatic glucose production • Suppresses ketogenesis• Nearly universal response • Theoretically unlimited efficacy • ↓ Microvascular risk (UKPDS)• Hypoglycemia • Weight gain • Training requirements • Patient and provider reluctance • Injectable (except inhaled insulin) • Pulmonary toxicity (inhaled insulin)High#
  • CVD, cardiovascular disease; EMPA-REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (29); GIP, glucose-dependent insulinotropic peptide; HDL-C, HDL cholesterol; IRIS, Insulin Resistance Intervention After Stroke Trial; LDL-C, LDL cholesterol; PPAR-γ, peroxisome proliferator–activated receptor γ; PROactive, Prospective Pioglitazone Clinical Trial in Macrovascular Events (43); STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (44); TIA, transient ischemic attack; TZD, thiazolidinedione; UKPDS, UK Prospective Diabetes Study (45,46). Cycloset trial of quick-release bromocriptine (47).

  • * Cost is based on lowest-priced member of the class (21).

  • lnitial concerns regarding bladder cancer risk are decreasing after subsequent study.

  • § Not licensed in Europe for type 2 diabetes.

  • # Cost is highly dependent on type/brand (analogs > human insulins) and dosage. Adapted with permission from Inzucchi et al. (21).