American Diabetes Association

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

Class	Compound(s)	Cellular mechanism(s)	Primary physiological action(s)	Advantages	Disadvantages	Cost*
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
				• ↓ CVD events (UKPDS)	• Multiple contraindications: CKD, acidosis, hypoxia, dehydration, etc.
Sulfonylureas	2nd Generation	Closes K_ATP 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				• Low durability
Meglitinides (glinides)	• Repaglinide	Closes K_ATP 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 HbA_1c efficacy	Moderate
	• Miglitol			• ↓Postprandial glucose excursions	• Generally modest HbA_1c efficacy
				• ? ↓ 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				• ? Acute pancreatitis
	• Linagliptin				• ? ↑ Heart failure hospitalizations
	• Alogliptin				• ? ↑ Heart failure hospitalizations
Bile acid sequestrants	• Colesevelam	Binds bile acids in intestinal tract, increasing hepatic bile acid production	• ? ↓ Hepatic glucose production	• No hypoglycemia	• Generally modest HbA_1c 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 HbA_1c efficacy	High
			• Modulates hypothalamic regulation of metabolism	• No hypoglycemia	• 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			• ↓ Weight	• 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)	• No hypoglycemia	• ↑ Heart rate
	• Liraglutide		• ↓ Glucagon secretion (glucose-dependent)	• ↓ 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		• ↑ Satiety	• ↓ Some cardiovascular risk factors	• Training requirements
Amylin mimetics	• Pramlintide§	Activates amylin receptors	• ↓ Glucagon secretion	• ↓ Postprandial glucose excursions	• Generally modest HbA_1c efficacy	High
			• ↑ Satiety	• ↓ Weight	• Gastrointestinal side effects (nausea/ vomiting)
			• ↑ Satiety		• 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				• Weight gain
	• 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)		• Other	• Theoretically unlimited efficacy	• Patient reluctance

Class	Compound(s)	Cellular mechanism(s)	Primary physiological action(s)	Advantages	Disadvantages	Cost*
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
				• ↓ CVD events (UKPDS)	• Multiple contraindications: CKD, acidosis, hypoxia, dehydration, etc.
Sulfonylureas	2nd Generation	Closes K_ATP 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				• Low durability
Meglitinides (glinides)	• Repaglinide	Closes K_ATP 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 HbA_1c efficacy	Moderate
	• Miglitol			• ↓Postprandial glucose excursions	• Generally modest HbA_1c efficacy
				• ? ↓ 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				• ? Acute pancreatitis
	• Linagliptin				• ? ↑ Heart failure hospitalizations
	• Alogliptin				• ? ↑ Heart failure hospitalizations
Bile acid sequestrants	• Colesevelam	Binds bile acids in intestinal tract, increasing hepatic bile acid production	• ? ↓ Hepatic glucose production	• No hypoglycemia	• Generally modest HbA_1c 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 HbA_1c efficacy	High
			• Modulates hypothalamic regulation of metabolism	• No hypoglycemia	• 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			• ↓ Weight	• 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)	• No hypoglycemia	• ↑ Heart rate
	• Liraglutide		• ↓ Glucagon secretion (glucose-dependent)	• ↓ 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		• ↑ Satiety	• ↓ Some cardiovascular risk factors	• Training requirements
Amylin mimetics	• Pramlintide§	Activates amylin receptors	• ↓ Glucagon secretion	• ↓ Postprandial glucose excursions	• Generally modest HbA_1c efficacy	High
			• ↑ Satiety	• ↓ Weight	• Gastrointestinal side effects (nausea/ vomiting)
			• ↑ Satiety		• 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				• Weight gain
	• 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)		• Other	• Theoretically unlimited efficacy	• Patient reluctance

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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