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      News & Perspective Drugs & Diseases CME & Education Academy Video Decision Point
      Drugs & Diseases > Endocrinology

      Type 2 Diabetes Mellitus Medication

      Updated: Jan 24, 2023
      • Author: Romesh Khardori, MD, PhD, FACP; Chief Editor: George T Griffing, MD  more...
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      Medication

      Medication Summary

      Pharmacologic therapy of type 2 diabetes has changed dramatically in the last 10 years, with new drugs and drug classes becoming available. These drugs allow for the use of combination oral therapy, often with improvement in glycemic control that was previously beyond the reach of medical therapy.

      Agents used in diabetic therapy include the following:

      • Biguanides

      • Sulfonylureas

      • Meglitinide derivatives

      • Alpha-glucosidase inhibitors

      • Thiazolidinediones (TZDs)

      • Glucagonlike peptide–1 (GLP-1) agonists 

      • GLP-1 and glucose-dependent insulinotropic polypeptide agonists 

      • Dipeptidyl peptidase IV (DPP-4) Inhibitors

      • Selective sodium-glucose transporter-2 (SGLT-2) inhibitors

      • Insulins

      • Amylinomimetics

      • Bile acid sequestrants

      • Dopamine agonists

      Traditionally, diet modification has been the cornerstone of diabetes management. Weight loss is more likely to control glycemia in patients with recent onset of the disease than in patients who are significantly insulinopenic. Medications that induce weight loss, such as orlistat, may be effective in highly selected patients but are not generally indicated in the treatment of the average patient with type 2 diabetes mellitus.

      Patients who are symptomatic at initial presentation with diabetes may require transient treatment with insulin to reduce glucose toxicity (which may reduce beta-cell insulin secretion and worsen insulin resistance) or an insulin secretagogue to rapidly relieve symptoms such as polyuria and polydipsia.

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      Antidiabetics, Biguanides

      Class Summary

      These agents are considered the first choice for oral type 2 diabetes treatment. They reduce hyperglycemia by decreasing hepatic gluconeogenesis (primary effect) and increasing peripheral insulin sensitivity (secondary effect). They do not increase insulin levels or cause weight gain. Alone, they rarely cause hypoglycemia.

      Biguanides are absorbed from the intestines and are not bound to plasma proteins. They are not metabolized and are rapidly eliminated by the kidneys. Drug levels increase markedly in renal insufficiency. Lactic acidosis is a rare, but serious, complication that may occur with drug accumulation.

      Metformin (Glucophage, Fortamet, Glumetza, Riomet)

      Metformin is used as monotherapy or in combination with sulfonylureas, thiazolidinediones, or insulin. It is taken with food to minimize adverse GI effects. Metformin is available in immediate-release and extended-release formulations, as well as in combination with other antidiabetic drugs.

      Metformin is contraindicated in patients with impaired renal function, as indicated by a serum creatinine level of greater than 1.5 mg/dL in men or of more than 1.4 mg/dL in women, or an estimated GFR of less than 60 mL/min. It also should not be used within 48 hours of IV iodinated contrast medium.

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      Antidiabetics, Sulfonylureas

      Class Summary

      Sulfonylureas are time-honored insulin secretagogues (ie, oral hypoglycemic agents). They have been used as monotherapy and in combination with other oral hypoglycemic agents or with insulin, although glimepiride is the only sulfonylurea approved by the FDA for combination therapy. Sulfonylureas function by stimulating the release of insulin from pancreatic beta cells and can usually reduce HbA1c by 1-2% and blood glucose concentrations by about 20%.

      Glyburide (DiaBeta, Glynase)

      Glyburide is a second-generation sulfonylurea. It is more potent and exhibits fewer drug interactions than first-generation agents. It also has a longer half-life than most sulfonylureas., Glyburide has been used as an alternative to insulin for the treatment of gestational diabetes, although it is not FDA approved for this indication. Glyburide (known as glibenclamide in the United Kingdom) was one of the sulfonylureas used in the United Kingdom Prospective Diabetes Study (UKPDS). [63]

      Glipizide (Glucotrol, Glucotrol XL)

      Glipizide is also a second-generation sulfonylurea. It is more potent and exhibits fewer drug interactions than first-generation agents. It may cause more physiologic insulin release with less risk for hypoglycemia and weight gain than other sulfonylureas.

      Glimepiride (Amaryl)

      Stimulates insulin secretion from beta cells; may also decrease rate of hepatic glucose production and increase insulin receptor sensitivity.

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      Antidiabetics, Meglitinide Derivatives

      Class Summary

      Meglitinides are much more short-acting insulin secretagogues than sulfonylureas. Preprandial dosing potentially achieves more physiologic insulin release and less risk for hypoglycemia. Meglitinide monotherapy has efficacy similar to that of sulfonylureas.

      Repaglinide (Prandin)

      Repaglinide is probably most useful in patients at increased risk for hypoglycemia who still need an insulin secretagogue. It works by stimulating insulin release from pancreatic beta cells. Better control of postprandial glycemic excursions also may be achieved with repaglinide. It is FDA approved for monotherapy and for combination therapy with metformin or thiazolidinediones.

      Nateglinide (Starlix)

      Nateglinide mimics endogenous insulin patterns, restores early insulin secretion, and controls mealtime glucose surges. It works by stimulating insulin release from pancreatic beta cells. It is indicated as monotherapy for type 2 diabetes or as combination therapy with metformin or a thiazolidinedione. Nateglinide is available in 60-mg and 120-mg tablets.

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      Antidiabetics, Alpha-Glucosidase Inhibitors

      Class Summary

      Alpha-glucosidase inhibitors prolong the absorption of carbohydrates and thus help to prevent postprandial glucose surges. Their induction of flatulence greatly limits their use. Doses of these agents should be titrated slowly to reduce GI intolerance. Their effect on glycemic control is modest, affecting primarily postprandial glycemic excursions.

      Acarbose (Precose)

      Acarbose was the first alpha-glucosidase inhibitor approved by the FDA. It is absorbed to a small degree, so liver function abnormalities can occur rarely. It can be used as monotherapy or in combination with other treatment modalities. The modest effect of acarbose on glycemia and its high degree of GI adverse effects (flatulence) limit its use.

      Miglitol (Glyset)

      Miglitol is not absorbed, so liver function abnormalities do not occur. It is FDA approved for use as monotherapy or in combination with sulfonylureas. Its modest effect on glycemia and high degree of GI adverse effects (flatulence) limit its use.

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      Antidiabetics, Thiazolidinediones

      Class Summary

      Thiazolidinediones reduce insulin resistance in the periphery (ie, they sensitize muscle and fat to the actions of insulin) and perhaps to a small degree in the liver (ie, insulin sensitizers, antihyperglycemics). They activate peroxisome proliferator–activated receptor (PPAR) gamma, a nuclear transcription factor that is important in fat cell differentiation and fatty acid metabolism. The major action of thiazolidinediones is probably actually fat redistribution. These drugs may have beta-cell preservation properties.

      Thiazolidinediones have moderate glycemic efficacy, between that of alpha-glucosidase inhibitors and sulfonylureas.

      Pioglitazone (Actos)

      Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control. It improves target-cell response to insulin without increasing insulin secretion from the pancreas. It also increases insulin-dependent glucose use in skeletal muscle and adipose tissue. Pioglitazone lowers triglycerides more than rosiglitazone, probably because of its PPAR-alpha effect.

      Long duration of pioglitazone use and high cumulative doses have been linked with slightly increased risk for bladder cancer. The FDA currently recommends not prescribing pioglitazone for patients with active bladder cancer and using it with caution in patients with a history of bladder cancer.

      Rosiglitazone (Avandia)

      Rosiglitazone is an insulin sensitizer with a major effect on the stimulation of glucose uptake in skeletal muscle and adipose tissue. It lowers plasma insulin levels. It is indicated for type 2 diabetes associated with insulin resistance, as monotherapy and in conjunction with sulfonylureas and/or metformin and insulin. It may preserve beta-cell function and yields positive effects on vasculature and inflammation. It changes LDL and HDL particle size.

      Because of data suggesting an elevated risk of myocardial infarction in patients treated with rosiglitazone, this agent is currently available only via a restricted access program. Patients currently taking rosiglitazone and benefiting from the drug are permitted to continue using it if they choose to do so. Rosiglitazone is available to new patients only if they are unable to achieve glucose control on other medications and are not willing to take pioglitazone, the only other thiazolidinedione.

      As of November 18, 2011, rosiglitazone was no longer available in retail pharmacies. It can be purchased only through specially certified pharmacies participating in the Avandia-Rosiglitazone Medicines Access Program.

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      Antidiabetics, Glucagonlike Peptide-1 Agonists

      Class Summary

      Glucagonlike peptide–1 (GLP-1) agonists mimic the endogenous incretin GLP-1, stimulating glucose-dependent insulin release (as opposed to oral insulin secretagogues, which may cause non–glucose-dependent insulin release and hypoglycemia), reducing glucagon, and slowing gastric emptying.

      Semaglutide (Ozempic, Rybelsus)

      When blood glucose is high, semaglutide, a GLP-1 receptor agonist, lowers it by stimulating insulin secretion and reducing glucagon secretion. It may be administered as a once daily oral tablet or a weekly SC injection. The SC product is also indicated for cardiovascular risk reduction in adults with type 2 diabetes mellitus and heart disease.

      Exenatide injectable solution (Byetta)

      Exenatide is a GLP-1 agonist that improves glycemic control in patients with type 2 diabetes mellitus. Like endogenous incretins, it enhances glucose-dependent insulin secretion by pancreatic beta cells, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. The drug's 39–amino acid sequence partially overlaps that of the human incretin GLP-1.

      Exenatide is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who have not achieved glycemic control with metformin or a sulfonylurea. The solution is an immediate-release product administered by SC injection twice daily.

      Exenatide injectable suspension (Bydureon, Bydureon BCise)

      The injectable suspension is administered SC once weekly. The patient does not need to have undergone treatment with Byetta (short-acting exenatide injectable solution) prior to initiating therapy with the injectable suspension. Treatment with Byetta should be discontinued if it is already being used when Bydureon or Bydureon BCise (autoinjector) therapy is started.

      Liraglutide (Victoza, Saxenda)

      Liraglutide is a once-daily SC injectable GLP-1 receptor agonist that stimulates G-protein in pancreatic beta cells. It increases intracellular cyclic adenosine monophosphate (cAMP), leading to insulin release in the presence of elevated glucose concentrations. Liraglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. In addition, evidence from the LEADER clinical trial resulted in liraglutide’s approval for risk reduction of major cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease.

      It is also indicated for children aged 10 years or older with type 2 diabetes mellitus.

      The drug has not been studied in combination with prandial insulin.

      Liraglutide is not recommended as first-line pharmacologic therapy, because of potential serious adverse effects. Liraglutide is contraindicated in patients with a history or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, as dose- and duration-dependent thyroid C-cell tumors have occurred in animal studies of liraglutide.

      In addition, clinical studies suggest that liraglutide may cause pancreatitis, although conclusive evidence has not been established. Nevertheless, patients should be monitored for unexplained, persistent, severe abdominal pain, with or without vomiting, and liraglutide should be discontinued if pancreatitis is suspected.

      Note that the brand Saxenda is not indicated for the treatment of type 2 diabetes mellitus. Used as an adjunct to a reduced-calorie diet and increased physical activity, Saxenda is indicated for chronic weight management in adults with a BMI of 30 kg/m2 or greater (obesity) or adults with a BMI of 27-29.9 kg/m2 (overweight) and one or more weight-associated conditions (eg, hypertension, type 2 diabetes, dyslipidemia). Saxenda may also be prescribed for persons with overweight and a risk factor for type 2 diabetes. Do not use Saxenda in combination with another GLP-1 agonist or with insulin.

      Albiglutide (Tanzeum)

      Albiglutide is a once-weekly SC injectable GLP-1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It may be used with other antidiabetic agents, although a dose reduction may be needed for insulin secretagogues (eg, sulfonylureas) or insulin if coadministered. GLP-1 receptor agonists augment glucose-dependent insulin secretion.

      Dulaglutide (Trulicity)

      Dulaglutide is a glucagonlike peptide-1 (GLP-1) agonist that acts as an incretin mimetic. It increases insulin secretion in the presence of elevated blood glucose, delays gastric emptying to decrease postprandial glucose, and decreases glucagon secretion. It is administered as a once-weekly SC injection. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is also indicated for major adverse cardiovascular (CV) event reduction (with regard to CV death, nonfatal myocardial infarction, and nonfatal stroke) in adults with type 2 diabetes mellitus in whom established CV disease or multiple CV risk factors exist.

      Lixisenatide (Adlyxin)

      GLP-1 agonist indicated as adjunctive therapy to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is administered as a once daily SC injection.

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      Dual GIP/GLP-1 Agonists

      Class Summary

      Glucagon-like peptide-1 (GLP-1) receptors are expressed in pancreatic beta cells and the gastrointestinal tract. Signaling elicited by GLP-1 enhances glucose-stimulated insulin secretion, delays gastric transit, decreases plasma glucagon levels, and reduces body weight through activation of the brain’s anorexigenic pathways. Involved in glucose homeostasis, the peptide hormones glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 impact the pancreatic beta cells, promoting glucose-stimulated insulin secretion from these. Additionally, GIP responds to food intake by exerting insulinotropic effects.

      Tirzepatide (Mounjaro)

      Indicated, in adults with type 2 diabetes mellitus, for the improvement of glycemic control, serving as an adjunct to diet and exercise.

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      Antidiabetics, Dipeptidyl Peptidase IV Inhibitors

      Class Summary

      Incretin hormones are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. They increase insulin release and decrease glucagon levels in the circulation in a glucose-dependent manner. DPP-4 degrades numerous biologically active peptides, including the endogenous incretins GLP-1 and glucose-dependent insulinotropic peptide (GIP). DPP-4 inhibitors prolong the action of incretin hormones.

      Sitagliptin (Januvia)

      Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses. Sitagliptin can be used as a monotherapy or in combination with metformin or a thiazolidinedione. It is given once daily and is weight neutral.

      Saxagliptin (Onglyza)

      Saxagliptin inhibits DPP-4 and thereby increases concentrations of GLP-1 and GIP, which stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Saxagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

      Linagliptin (Tradjenta)

      Linagliptin is a DPP-4 inhibitor that increases and prolongs incretin hormone activity. It is indicated for adults with type 2 diabetes mellitus, along with diet and exercise, to lower blood glucose levels. It may be used as monotherapy or in combination with other common antidiabetic medications, including metformin, sulfonylurea, or pioglitazone; it has not been studied in combination with insulin.

      Alogliptin (Nesina)

      Selective dipeptidyl peptidase-4 (DPP-4) inhibitor; slows inactivation of incretin hormones (eg, GLP-1, GIP), thereby reducing fasting and postprandial glucose concentrations in a glucose-dependent manner

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      Antidiabetics, Amylinomimetics

      Class Summary

      These agents mimic endogenous amylin effects by delaying gastric emptying, decreasing postprandial glucagon release, and modulating appetite.

      Pramlintide (Symlin, SymlinPen 120, SymlinPen 60)

      This agent is a synthetic analogue of human amylin, a naturally occurring hormone made in pancreatic beta cells. It slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake because of centrally mediated appetite modulation.

      Pramlintide is indicated for the treatment of type 1 or type 2 diabetes in combination with insulin. It is administered before mealtime in patients who have not achieved desired glucose control despite optimal insulin therapy. It helps to achieve lower blood glucose levels after meals, less fluctuation of blood glucose levels during the day, and improvement of long-term control of glucose levels (ie, HbA1C levels), compared with insulin alone. Additionally, less insulin use and a reduction in body weight are observed.

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      Selective Sodium-Glucose Transporter-2 Inhibitors

      Class Summary

      The transporter known as sodium-glucose cotransporter 2 (SGLT2) handles reabsorption of most glucose from the renal glomerular filtrate in the renal proximal tubule. When SGLT2 is inhibited, renal reabsorption of filtered glucose is decreased, as is the renal threshold for glucose, with urinary glucose excretion consequently increased.

      Canagliflozin (Invokana)

      Indicated as an adjunct to diet and exercise, canagliflozin therapy is aimed at improving glycemic control in adults with type 2 diabetes. In addition, in adults with type 2 diabetes and diabetic nephropathy with albuminuria of more than 300 mg/day, canagliflozin is indicated to lower the chances of end-stage renal disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure.

      Dapagliflozin (Farxiga)

      Indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus. It is indicated as monotherapy, as initial therapy with metformin, or as an add-on to other oral glucose-lowering agents, including metformin, pioglitazone, glimepiride, sitagliptin, and insulin. It is also indicated to lower the risk of adults with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors being hospitalized for heart failure.

      Empagliflozin (Jardiance)

      Indicated as an adjunct to diet and exercise, empagliflozin therapy is aimed at improving glycemic control in adults with type 2 diabetes. It is also indicated for lowering the cardiovascular death risk in adults with type 2 diabetes and cardiovascular disease.

      Ertugliflozin (Steglatro)

      An SGLT2 inhibitor, ertugliflozin is indicated for improvement of glycemic control in adults with type 2 diabetes, serving as an adjunct to diet and exercise. It can also be found in the combination products ertugliflozin plus metformin and ertugliflozin plus sitagliptin.

      Bexagliflozin (Brenzavvy)

      Indicated, when used as an adjunct to diet and exercise, for the enhancement of glycemic control in adults with type 2 diabetes.

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      Bile Acid Sequestrants

      Class Summary

      Colesevelam is FDA approved as an adjunctive therapy to improve glycemic control in adults with type 2 diabetes mellitus.

      Colesevelam (WelChol)

      Colesevelam is a high-capacity bile acid sequestrant. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The precise mechanism by which colesevelam improves glycemic control is largely unknown.

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      Antidiabetics, Rapid-Acting Insulins

      Class Summary

      Rapid-acting insulins have a short duration of action and are appropriate for use before meals or when blood glucose levels exceed target levels and correction doses are needed. These agents are associated with less hypoglycemia than regular insulin.

      Insulin aspart (NovoLog, Fiasp)

      Insulin aspart has a short onset of action of 5-15 minutes and a short duration of action of 3-5 hours. The peak effect occurs within 30-90 minutes. Insulin aspart is FDA approved for use in insulin pumps.

      Fiasp also has a rapid onset of action, with its first measurable effect occurring within 16-20 minutes. The peak effect occurs within 91-133 minutes, and the usual duration of action is 5-7 hours.

      Insulin glulisine (Apidra)

      Insulin glulisine has a rapid onset of action of 5-15 minutes and a short duration of action of 3-5 hours. The peak effect occurs within 30-90 minutes. Insulin glulisine is FDA approved for use in insulin pumps.

      Insulin lispro (Humalog, Admelog, insulin lispro-aabc, Lyumjev)

      Insulin lispro has a rapid onset of action of 5-15 minutes and a short duration of action of 4 hours.

      Insulin inhaled (Afrezza)

      Orally inhaled rapid-acting insulin in powder form. When 8 units were administered, maximum serum insulin concentration was reached by 12-15 minutes and declined to baseline by about 180 minutes.

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      Antidiabetics, Short-Acting Insulins

      Class Summary

      Short-acting insulins are commonly used when a slower onset of action or a longer duration of action is desired.

      Regular insulin (Humulin R, Novolin R, Myxredlin)

      Regular insulin has a rapid onset of action of 0.5-1 hours and duration of action of 4-6 hours. The peak effects are seen within 2-4 hours. Preparations that contain a mixture of 70% neutral protamine Hagedorn (NPH) and 30% regular human insulin (ie, Novolin 70/30, Humulin 70/30) are also available.

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      Antidiabetics, Intermediate-Acting Insulins

      Class Summary

      Intermediate-acting insulins have a slow onset of action and a longer duration of action. These agents are commonly combined with faster-acting insulins to maximize the benefits of a single injection.

      Insulin NPH (Humulin N, Novolin N)

      Insulin neutral protamine Hagedorn (NPH) has an onset of action of 3-4 hours. The peak effect occurs within 8-14 hours, and its usual duration of action is 16-24 hours. The drug appears cloudy and must be gently mixed and checked for clumping; if clumping occurs, the insulin should be discarded.

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      Antidiabetics, Long-Acting Insulins

      Class Summary

      These insulins provide a longer duration of action, and, when combined with rapid- or short-acting insulins, they provide better glucose control.

      Insulin detemir (Levemir)

      Insulin detemir is indicated for once- or twice-daily dosing in patients with type 1 or 2 diabetes mellitus. The duration of action is up to 24 hours, the result of slow systemic absorption of detemir from the injection site.

      Insulin glargine (Lantus, Lantus SoloStar, Toujeo, Toujeo Max, Basaglar)

      Insulin glargine stimulates proper utilization of glucose by the cells and reduces blood sugar levels. It has no pronounced peaks of action, because a small amount of insulin is gradually released at a constant rate over 24 hours. The amount of insulin in Toujeo and Toujeo Max is three times greater (300 Units/mL) than in Lantus or Basaglar (100 Units/mL).

      Insulin degludec (Tresiba)

      Ultralong-acting basal insulin indicated to improve glycemic control in adults with diabetes mellitus who require basal insulin. It is highly protein bound, and following SC, the protein-binding provides a depot effect. The elimination half-life is 25 h and its duration of action is beyond 42 h.

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      Dopamine Agonists

      Class Summary

      Quick-release bromocriptine acts on circadian neuronal activities within the hypothalamus to reset the abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial states in patients with insulin resistance.

      Bromocriptine (Cycloset)

      This quick-release formulation is the only bromocriptine product indicated for type 2 diabetes mellitus. It is indicated as an adjunct to diet and exercise to improve glycemic control.

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