Characteristics of Oral Antihyperglycemics

Generic Name	Comments
Insulin secretagogues: Long-acting (sulfonylureas)	Augment pancreatic beta-cell insulin secretion Can be used alone or in combination with insulin and other medications Their long duration of action may lead to serious hypoglycemia, especially in older patients Efficacy may wane after 5 years of use
Acetohexamide*	Not available in the United States
Chlorpropamide*	Chlorpropamide: May cause hyponatremia and flushing after alcohol ingestion
Tolazamide*	Not available in the United States
Tolbutamide*	—
	No evidence of increased effectiveness of doses > 10 mg/day
	No evidence of increased effectiveness of doses > 10 mg/day
	No evidence of increased effectiveness of doses > 10 mg/day
	No evidence of increased effectiveness of doses > 10 mg/day
	—
Insulin secretagogues: Short-acting (meglitinides)	Augment pancreatic beta-cell insulin secretion Can be used alone or in combination with other oral medications and insulin
	—
	—
Insulin sensitizers: Biguanides	Augment suppression of hepatic glucose production by insulin Can be used alone or in combination with other oral medications and insulin Major adverse effects: Lactic acidosis (rare) Contraindicated in at-risk patients, including those with renal insufficiency, metabolic acidosis, hypoxia, alcohol use disorder, or dehydration Do not cause hypoglycemia Other adverse effects: Gastrointestinal distress (diarrhea, nausea, pain), vitamin B12 malabsorption Potentiate weight loss Should be stopped temporarily before radiologic procedures requiring use of contrast agents
	—
	—
Insulin sensitizers: Thiazolidinediones	Augment suppression of hepatic glucose production by insulin and increase insulin sensitivity in muscle and adipose tissue Can be used alone or in combination with other oral medications and insulin Major adverse effects: Weight gain, fluid retention, anemia (mild) Hepatotoxicity rare, but liver monitoring required
	Pioglitazone: May increase risk of bladder cancer, heart failure, and fractures
	Rosiglitazone: May increase low-density lipoprotein cholesterol and may increase risk of heart failure, angina, myocardial infarction, stroke, and fractures
Alpha-glucosidase inhibitors	Intestinal enzyme inhibitors Used as monotherapy or combination therapy with other oral medications or insulin to decrease postprandial plasma glucose levels Must be taken with the first bite of meal Gastrointestinal adverse effects (flatulence, diarrhea, bloating) common but may decrease over time Start with small dose (25 mg/day) and gradually titrate over several weeks
	—
	—
Dipeptidyl peptidase-4 (DPP4) inhibitors	Inhibit the enzyme DPP-4, which is involved in the breakdown of GLP-1, a peptide that stimulates insulin secretion and inhibits glucagon secretion All DPP-4 inhibitors can be used in moderate to severe renal insufficiency. All except linagliptin require dose adjustment for estimated glomerular filtration rate Well-tolerated but cause only modest improvements in hemoglobin A1C A slight increase in risk of pancreatitis
	—
	—
	—
	—
Glucagon-like peptide-1 (GLP-1) receptor agonists‡	Mimic the effects of GLP-1, a peptide made in the small intestine that enhances glucose-dependent insulin secretion
	Low risk of hypoglycemia; may promote modest weight loss Increased risk of pancreatitis Thyroid C-cell tumors (medullary carcinoma) noted in rodents Weekly subcutaneous preparations may cause fewer gastrointestinal adverse effects. When given once or twice a day, lowest starting dose may minimize nausea Oral semaglutide may decrease cardiovascular death in patients with high risk of cardiovascular disease Semaglutide is associated with increased progression of diabetic retinopathy
Sodium-glucose co-transporter 2 (SGLT2) inhibitors	Inhibit SGLT-2 in the proximal tubule of the kidney, which blocks glucose reabsorption, thus causing glycosuria SGLT-2 inhibitors may cause Fournier gangrene, weight loss, orthostatic hypotension, yeast infections, and urinary tract infections Use cautiously in older adults and in patients with renal impairment Associated with euglycemic diabetic ketoacidosis. Ketogenic, or low-carbohydrate, diets should be avoided and medications should be stopped several days before procedures or during illness and inability to tolerate oral intake
	—
	Canagliflozin is associated with a higher rate of limb amputations Canagliflozin decreases mortality and heart failure hospitalizations in patients with cardiovascular risk. Decreases progression of chronic kidney disease
	Dapagliflozin decreases mortality and heart failure hospitalizations in patients with cardiovascular risk. Decreases progression of chronic kidney disease
	Empagliflozin decreases mortality and heart failure hospitalizations in patients with cardiovascular risk. Decreases progression of chronic kidney disease
	—
* First-generation sulfonylureas.
† 2nd-generation sulfonylureas.
‡ See table for information on injectable glucagon-like peptide-1 (GLP-1) receptor agonists.
¶ Also available in an injectable form.

Generic Name

Comments

Insulin secretagogues: Long-acting (sulfonylureas)

Augment pancreatic beta-cell insulin secretion

Can be used alone or in combination with insulin and other medications

Their long duration of action may lead to serious hypoglycemia, especially in older patients

Efficacy may wane after 5 years of use

Acetohexamide*

Not available in the United States

Chlorpropamide*

Chlorpropamide: May cause hyponatremia and flushing after alcohol ingestion

Tolazamide*

Not available in the United States

Tolbutamide*

—

No evidence of increased effectiveness of doses > 10 mg/day

—

Insulin secretagogues: Short-acting (meglitinides)

Augment pancreatic beta-cell insulin secretion

Can be used alone or in combination with other oral medications and insulin

—

Insulin sensitizers: Biguanides

Augment suppression of hepatic glucose production by insulin

Can be used alone or in combination with other oral medications and insulin

Major adverse effects: Lactic acidosis (rare)

Contraindicated in at-risk patients, including those with renal insufficiency, metabolic acidosis, hypoxia, alcohol use disorder, or dehydration

Do not cause hypoglycemia

Other adverse effects: Gastrointestinal distress (diarrhea, nausea, pain), vitamin B12 malabsorption

Potentiate weight loss

Should be stopped temporarily before radiologic procedures requiring use of contrast agents

—

Insulin sensitizers: Thiazolidinediones

Augment suppression of hepatic glucose production by insulin and increase insulin sensitivity in muscle and adipose tissue

Can be used alone or in combination with other oral medications and insulin

Major adverse effects: Weight gain, fluid retention, anemia (mild)

Hepatotoxicity rare, but liver monitoring required

Pioglitazone: May increase risk of bladder cancer, heart failure, and fractures

Rosiglitazone: May increase low-density lipoprotein cholesterol and may increase risk of heart failure, angina, myocardial infarction, stroke, and fractures

Alpha-glucosidase inhibitors

Intestinal enzyme inhibitors

Used as monotherapy or combination therapy with other oral medications or insulin to decrease postprandial plasma glucose levels

Must be taken with the first bite of meal

Gastrointestinal adverse effects (flatulence, diarrhea, bloating) common but may decrease over time

Start with small dose (25 mg/day) and gradually titrate over several weeks

—

Dipeptidyl peptidase-4 (DPP4) inhibitors

Inhibit the enzyme DPP-4, which is involved in the breakdown of GLP-1, a peptide that stimulates insulin secretion and inhibits glucagon secretion

All DPP-4 inhibitors can be used in moderate to severe renal insufficiency. All except linagliptin require dose adjustment for estimated glomerular filtration rate

Well-tolerated but cause only modest improvements in hemoglobin A1C

A slight increase in risk of pancreatitis

—

Glucagon-like peptide-1 (GLP-1) receptor agonists‡

Mimic the effects of GLP-1, a peptide made in the small intestine that enhances glucose-dependent insulin secretion

Low risk of hypoglycemia; may promote modest weight loss

Increased risk of pancreatitis

Thyroid C-cell tumors (medullary carcinoma) noted in rodents

Weekly subcutaneous preparations may cause fewer gastrointestinal adverse effects. When given once or twice a day, lowest starting dose may minimize nausea

Oral semaglutide may decrease cardiovascular death in patients with high risk of cardiovascular disease

Semaglutide is associated with increased progression of diabetic retinopathy

Sodium-glucose co-transporter 2 (SGLT2) inhibitors

Inhibit SGLT-2 in the proximal tubule of the kidney, which blocks glucose reabsorption, thus causing glycosuria

SGLT-2 inhibitors may cause Fournier gangrene, weight loss, orthostatic hypotension, yeast infections, and urinary tract infections

Use cautiously in older adults and in patients with renal impairment

Associated with euglycemic diabetic ketoacidosis. Ketogenic, or low-carbohydrate, diets should be avoided and medications should be stopped several days before procedures or during illness and inability to tolerate oral intake

—

Canagliflozin is associated with a higher rate of limb amputations

Canagliflozin decreases mortality and heart failure hospitalizations in patients with cardiovascular risk. Decreases progression of chronic kidney disease

Dapagliflozin decreases mortality and heart failure hospitalizations in patients with cardiovascular risk. Decreases progression of chronic kidney disease

Empagliflozin decreases mortality and heart failure hospitalizations in patients with cardiovascular risk. Decreases progression of chronic kidney disease

—

* First-generation sulfonylureas.

† 2nd-generation sulfonylureas.

‡ See table for information on injectable glucagon-like peptide-1 (GLP-1) receptor agonists.

¶ Also available in an injectable form.

In these topics

Medications for Diabetes Mellitus Treatment