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Table 1

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

ClassCompound(s)Cellular mechanism(s)Primary physiological action(s)AdvantagesDisadvantagesCost*
Biguanides • Metformin Activates AMP-kinase  (? other) • ↓ Hepatic glucose production • Extensive experience • Gastrointestinal side effects (diarrhea, abdominal cramping) Low 
• No hypoglycemia • Lactic acidosis risk (rare) 
• ↓ CVD events (UKPDS) • Vitamin B12 deficiency 
• Multiple contraindications: CKD, acidosis, hypoxia, dehydration, etc. 
Sulfonylureas 2nd Generation Closes KATP channels on  β-cell plasma membranes • ↑ Insulin secretion • Extensive experience • Hypoglycemia Low 
• Glyburide/glibenclamide • ↓ Microvascular risk (UKPDS) • ↑ Weight 
• Glipizide • ? Blunts myocardial ischemic preconditioning 
• Gliclazide • Low durability 
• Glimepiride 
Meglitinides (glinides) • Repaglinide Closes KATP channels on  β-cell plasma membranes • ↑ Insulin secretion • ↓Postprandial glucose excursions • Hypoglycemia Moderate 
• Nateglinide • Dosing flexibility • ↑ Weight 
• ? Blunts myocardial ischemic preconditioning 
• Frequent dosing schedule 
TZDs • Pioglitazone Activates the nuclear  transcription factor PPAR-γ • ↑ Insulin sensitivity • No hypoglycemia • ↑ Weight Low 
• Rosiglitazone§ • Durability • Edema/heart failure 
• ↑ HDL-C • Bone fractures 
• ↓ Triglycerides (pioglitazone) • ↑ LDL-C (rosiglitazone) 
• ? ↓ CVD events  (PROactive,  pioglitazone) • ? ↑ MI (meta-analyses, rosiglitazone) 
α-Glucosidase inhibitors • Acarbose Inhibits intestinal  α-glucosidase • Slows intestinal carbohydrate digestion/absorption • No hypoglycemia • Generally modest HbA1c efficacy Moderate 
• Miglitol • ↓Postprandial glucose excursions 
• ? ↓ CVD events (STOP-NIDDM) • Gastrointestinal side effects (flatulence, diarrhea) 
• Nonsystemic • Frequent dosing schedule 
DPP-4 inhibitors • Sitagliptin Inhibits DPP-4 activity,  increasing postprandial  active incretin (GLP-1, GIP) concentrations • ↑ Insulin secretion (glucose-dependent) • No hypoglycemia • Angioedema/urticaria and other immune-mediated dermatological effects High 
• Vildagliptin • ↓ Glucagon secretion (glucose-dependent) • Well tolerated • ? Acute pancreatitis 
• Saxagliptin 
• Linagliptin • ? ↑ Heart failure hospitalizations 
• Alogliptin 
Bile acid sequestrants • Colesevelam Binds bile acids in  intestinal tract, increasing  hepatic bile acid  production • ? ↓ Hepatic glucose production • No hypoglycemia • Generally modest HbA1c efficacy High 
• ? ↑ Incretin levels • ↓ LDL-C • Constipation 
• ↑ Triglycerides 
• May ↓ absorption of other medications 
Dopamine-2 agonists • Bromocriptine (quick release)§ Activates dopaminergic  receptors • Modulates hypothalamic  regulation of metabolism • No hypoglycemia • Generally modest HbA1c efficacy High 
• Dizziness/syncope 
• ↑ Insulin sensitivity • ? ↓ CVD events (Cycloset Safety Trial) • Nausea 
• Fatigue 
• Rhinitis 
SGLT2 inhibitors • Canagliflozin Inhibits SGLT2 in the proximal nephron • Blocks glucose reabsorption  by the kidney, increasing  glucosuria • No hypoglycemia • Genitourinary infections High 
• Dapagliflozin • ↓ Weight • Polyuria 
• Empagliflozin • Volume depletion/hypotension/dizziness 
• ↓ Blood pressure • ↑ LDL-C 
• Effective at all stages of T2DM • ↑ Creatinine (transient) 
GLP-1 receptor agonists • Exenatide Activates GLP-1 receptors • ↑ Insulin secretion (glucose-dependent) • No hypoglycemia • Gastrointestinal side effects (nausea/ vomiting/diarrhea) High 
• Exenatide extended release • ↓ Glucagon secretion (glucose-dependent) • ↑ Heart rate 
• Liraglutide • ↓ Weight • ? Acute pancreatitis 
• Albiglutide • Slows gastric emptying • ↓ Postprandial glucose excursions • C-cell hyperplasia/medullary thyroid  tumors in animals 
• Lixisenatide • ↑ Satiety • ↓ Some cardiovascular risk factors • Injectable 
• Dulaglutide • Training requirements 
Amylin mimetics • Pramlintide§ Activates amylin receptors • ↓ Glucagon secretion • ↓ Postprandial glucose excursions • Generally modest HbA1c efficacy High 
• ↑ Satiety • ↓ Weight • Gastrointestinal side effects (nausea/ vomiting) 
• Hypoglycemia unless insulin dose is simultaneously reduced 
• Slows gastric emptying • Injectable 
• Frequent dosing schedule 
• Training requirements 
Insulins • Rapid-acting analogs Activates insulin receptors • ↑ Glucose disposal • Nearly universal response • Hypoglycemia Variable# 
 - Lispro 
 - Aspart 
 - Glulisine 
• Short-acting 
 - Human Regular 
• Intermediate-acting • Weight gain 
 - Human NPH 
• Basal insulin analogs • ↓ Hepatic glucose production • ↓ Microvascular risk (UKPDS) • ? Mitogenic effects 
 - Glargine • Injectable 
 - Detemir • Training requirements 
 - Degludec • Other • Theoretically unlimited efficacy • Patient reluctance 
• Premixed (several types) 
ClassCompound(s)Cellular mechanism(s)Primary physiological action(s)AdvantagesDisadvantagesCost*
Biguanides • Metformin Activates AMP-kinase  (? other) • ↓ Hepatic glucose production • Extensive experience • Gastrointestinal side effects (diarrhea, abdominal cramping) Low 
• No hypoglycemia • Lactic acidosis risk (rare) 
• ↓ CVD events (UKPDS) • Vitamin B12 deficiency 
• Multiple contraindications: CKD, acidosis, hypoxia, dehydration, etc. 
Sulfonylureas 2nd Generation Closes KATP channels on  β-cell plasma membranes • ↑ Insulin secretion • Extensive experience • Hypoglycemia Low 
• Glyburide/glibenclamide • ↓ Microvascular risk (UKPDS) • ↑ Weight 
• Glipizide • ? Blunts myocardial ischemic preconditioning 
• Gliclazide • Low durability 
• Glimepiride 
Meglitinides (glinides) • Repaglinide Closes KATP channels on  β-cell plasma membranes • ↑ Insulin secretion • ↓Postprandial glucose excursions • Hypoglycemia Moderate 
• Nateglinide • Dosing flexibility • ↑ Weight 
• ? Blunts myocardial ischemic preconditioning 
• Frequent dosing schedule 
TZDs • Pioglitazone Activates the nuclear  transcription factor PPAR-γ • ↑ Insulin sensitivity • No hypoglycemia • ↑ Weight Low 
• Rosiglitazone§ • Durability • Edema/heart failure 
• ↑ HDL-C • Bone fractures 
• ↓ Triglycerides (pioglitazone) • ↑ LDL-C (rosiglitazone) 
• ? ↓ CVD events  (PROactive,  pioglitazone) • ? ↑ MI (meta-analyses, rosiglitazone) 
α-Glucosidase inhibitors • Acarbose Inhibits intestinal  α-glucosidase • Slows intestinal carbohydrate digestion/absorption • No hypoglycemia • Generally modest HbA1c efficacy Moderate 
• Miglitol • ↓Postprandial glucose excursions 
• ? ↓ CVD events (STOP-NIDDM) • Gastrointestinal side effects (flatulence, diarrhea) 
• Nonsystemic • Frequent dosing schedule 
DPP-4 inhibitors • Sitagliptin Inhibits DPP-4 activity,  increasing postprandial  active incretin (GLP-1, GIP) concentrations • ↑ Insulin secretion (glucose-dependent) • No hypoglycemia • Angioedema/urticaria and other immune-mediated dermatological effects High 
• Vildagliptin • ↓ Glucagon secretion (glucose-dependent) • Well tolerated • ? Acute pancreatitis 
• Saxagliptin 
• Linagliptin • ? ↑ Heart failure hospitalizations 
• Alogliptin 
Bile acid sequestrants • Colesevelam Binds bile acids in  intestinal tract, increasing  hepatic bile acid  production • ? ↓ Hepatic glucose production • No hypoglycemia • Generally modest HbA1c efficacy High 
• ? ↑ Incretin levels • ↓ LDL-C • Constipation 
• ↑ Triglycerides 
• May ↓ absorption of other medications 
Dopamine-2 agonists • Bromocriptine (quick release)§ Activates dopaminergic  receptors • Modulates hypothalamic  regulation of metabolism • No hypoglycemia • Generally modest HbA1c efficacy High 
• Dizziness/syncope 
• ↑ Insulin sensitivity • ? ↓ CVD events (Cycloset Safety Trial) • Nausea 
• Fatigue 
• Rhinitis 
SGLT2 inhibitors • Canagliflozin Inhibits SGLT2 in the proximal nephron • Blocks glucose reabsorption  by the kidney, increasing  glucosuria • No hypoglycemia • Genitourinary infections High 
• Dapagliflozin • ↓ Weight • Polyuria 
• Empagliflozin • Volume depletion/hypotension/dizziness 
• ↓ Blood pressure • ↑ LDL-C 
• Effective at all stages of T2DM • ↑ Creatinine (transient) 
GLP-1 receptor agonists • Exenatide Activates GLP-1 receptors • ↑ Insulin secretion (glucose-dependent) • No hypoglycemia • Gastrointestinal side effects (nausea/ vomiting/diarrhea) High 
• Exenatide extended release • ↓ Glucagon secretion (glucose-dependent) • ↑ Heart rate 
• Liraglutide • ↓ Weight • ? Acute pancreatitis 
• Albiglutide • Slows gastric emptying • ↓ Postprandial glucose excursions • C-cell hyperplasia/medullary thyroid  tumors in animals 
• Lixisenatide • ↑ Satiety • ↓ Some cardiovascular risk factors • Injectable 
• Dulaglutide • Training requirements 
Amylin mimetics • Pramlintide§ Activates amylin receptors • ↓ Glucagon secretion • ↓ Postprandial glucose excursions • Generally modest HbA1c efficacy High 
• ↑ Satiety • ↓ Weight • Gastrointestinal side effects (nausea/ vomiting) 
• Hypoglycemia unless insulin dose is simultaneously reduced 
• Slows gastric emptying • Injectable 
• Frequent dosing schedule 
• Training requirements 
Insulins • Rapid-acting analogs Activates insulin receptors • ↑ Glucose disposal • Nearly universal response • Hypoglycemia Variable# 
 - Lispro 
 - Aspart 
 - Glulisine 
• Short-acting 
 - Human Regular 
• Intermediate-acting • Weight gain 
 - Human NPH 
• Basal insulin analogs • ↓ Hepatic glucose production • ↓ Microvascular risk (UKPDS) • ? Mitogenic effects 
 - Glargine • Injectable 
 - Detemir • Training requirements 
 - Degludec • Other • Theoretically unlimited efficacy • Patient reluctance 
• Premixed (several types) 

CVD, cardiovascular disease; GIP, glucose-dependent insulinotropic peptide; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; MI, myocardial infarction; PPAR-γ, peroxisome proliferator–activated receptor γ; PROactive, Prospective Pioglitazone Clinical Trial in Macrovascular Events (26); STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (60); T2DM, type 2 diabetes mellitus; UKPDS, UK Prospective Diabetes Study (4,61). Cycloset trial of quick-release bromocriptine (62).

*

Cost is based on lowest-priced member of the class (see Supplementary Data).

Not licensed in the U.S.

Initial 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.

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