Treatment options for patients with type 1 and type 2 diabetes have significantly expanded in recent years with FDA approval of several new drug classes. These include exogenous insulin, several oral medication classes and two injectable medication classes for insulin management.1
Most of these medications act by enhancing endogenous insulin production or secretion or by improving the body’s efficiency in using circulating insulin. Before prescribing medications to control diabetes, clinicians should consider potential adverse events and drug interactions.
Sulfonylureas
Sulfonylureas, which stimulate insulin production from pancreatic ß cells, are among the oldest oral medications used to control blood sugar in people with type 2 diabetes and continue to be a widely used option.1
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However, research indicates that first generation sulfonylureas, which include acetohexamide, chlorpropamide, tolazamide and tolbutamide, can cause adverse events such as hypoglycemia, nausea, vomiting, heartburn, diarrhea, headache, significant weight gain, allergic reactions and excess mortality from cardiovascular events.2
Second-generation sulfonylureas — glyburide, glizipide and glimepiride — have a lower or absent adverse event incidence rate compared with early sulfonylureas. The most common side effect remains hypoglycemia: lower than normal levels of blood glucose with symptoms ranging from mild, such as shaking and sweating, to more severe symptoms including dizziness and fainting, and even life-threatening adverse events, such as coma or death.
Research indicates that patients can develop sulfonylurea-associated hypoglycemia at one-half of the maximum recommended dose. To avoid potential hypoglycemic episodes with sulfonylureas, clinicians should consider alternative or combination therapies with other drugs for patients who do not achieve adequate glucose control at this one-half maximum dose.
All sulfonylureas can cause weight gain. When mixed with alcohol, sulfonylureas can cause vomiting or flushing.3
In some cases, patients on prolonged treatment with sulfonylureas will no longer response to treatment. Annually, this occurs in about 5% to 10% of patients with type 2 diabetes that are taking these medications.1
Meglinitides
The meglinitide drug class includes the agents repaglinide (Prandin, Novo Nordisk) and nateglinide (Starlix, Norvartis). Like sulfonylureas, meglinitides are secretagogues used to treat type 2 diabetes, but can also induce hypoglycemia. Other side effects include upper respiratory tract infection, arthralgia, chest pain and cardiac ischemia.3,4
Biguanides
Biguanides are an oral class of diabetes medication among the most commonly prescribed. Currently, metformin is the only FDA-approved biguanide.
An insulin sensitizer, metformin inhibits the liver from releasing glucose and makes muscle tissue more sensitive to insulin, so that it removes more glucose from circulation, thus lowering blood glucose levels.
The most common adverse effects include diarrhea, upset stomach, flatulence, nausea and loss of appetite. About one-third of people taking metformin experience these gastrointestinal problems, but these adverse reactions can be ameliorated if the medication is taken with food.
Other mild side effects include headache and fatigue, but these diminish after steady use. Some patients taking metformin complain of metallic taste.
Metformin is not associated with hypoglycemia or weight gain, but when used with sulfonylurea or insulin, hypoglycemia can occur. Rarely metformin can lead to lactic acidosis, in which circulating lactic acid increases more rapidly than it can be removed.4
Thiazolidinediones
Thiazolidinediones are a class of insulin sensitizers that have been plagued by adverse event concerns. The first drug in this class, troglitzone, was removed from the market in 2000 due to rare cases of liver toxicity.
The other thiazolidinediones, rosiglitazone (Avandia, GlaxoSmithKline) and pioglitazone (Actos, Takeda), appear to lack this liver toxicity, but patients taking these medications are closely monitored for early warning signs of these and other adverse effects. 3,9
Aside from significant weight gain, both rosiglitazone and pioglitazone are known to increased risk for heart failure. Researchers have linked rosiglitazone to increased cardiovascular events including myocardial infarction. In September 2010, the European Medicines Agency (EMEA) removed rosiglitazone from the European market because of this risk. 10
In May 2011, the FDA announced plans to restrict access to rosiglitazone — by Nov. 2012, the medication will no longer be available on retail pharmacy shelves. Clinicians who still wish to prescribe patients the medication must enroll them in a special registry. 11
Similarly two European nations, France and Germany, banned pioglitazone in June 2011 after interim results from an epidemiologic study indicated an increased risk for bladder cancer among patients taking the medication for longer than one year.
The FDA approved adding bladder cancer warning risks to pioglitazone labels in August 2011. The drug’s manufacturer, Takeda, plans to continue the study through its scheduled completion date in late 2012. 12
Alpha-glucosidase inhibitors
The alpha-glucosidase inhibitors acarbose and miglitol are diabetes medications that inhibit starch breakdown in the intestine, slowing sugar degradation and carbohydrate absorbtion. The most adverse events with these drugs are diarrhea, excess gas, abdominal bloating and discomfort;1 however, these symptoms typically resolve with medication discontinuation.
DPP-4 inhibitors
The dipeptidyl peptidase-4 (DPP-4) inhibitors are the newest class of oral diabetes medications. Medications that belong to this class include sitagliptin (Januvia, Merck), saxagliptin (Onglyza, Bristol Myers Squibb) and vildagliptin (Galvus, Novartis).13-15
DPP-4 inhibitors work by inhibiting the degradation of glucagon-like peptide-1 (GLP-1), a natural glucose stabilizer.
The most common adverse event with sitagliptin and vildagliptin is an increased risk for upper respiratory tract infections. Other side effects include cold-like symptoms such as sore throat and headache. 13-15 Common adverse events with saxagliptin include diarrhea, metallic taste, abdominal pain, nausea and flatulence.14
DPP-4 inhibitor monotherapy does not cause weight gain or hypoglycemia. Research is ongoing to probe for purported cardiovascular benefits among patients taking these drugs. Two randomized controlled clinical trials, the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) and the Saxagliptin Assessment of Vascular Outcomes (SAVOR-TIMI 53), are currently underway to evaluate CV benefits. 16
Incretin mimetics
Incretin mimetics are injectable medications designed to mimic the action of the incretin hormones, including glucagon-like peptide-1 (GLP-1), and also slow the rate of digestion. These include exanatide (Byetta, Amylin Pharmaceuticals), liraglutide (Victoza, Novo Nordisk) and pramlintide (Symlin, Amylin Pharmaceuticals). All are FDA-approved for use with other oral diabetes medications.15
Nausea and diarrhea are the most common side effects of incretin mimetics. Unlike other diabetes medications, these drugs do not lead to weight gain; instead, some people taking them experience weight loss, anorexia and reduced appetite.17-19
Reported adverse events include acute pancreatitis with exenatide and liraglutide.18,20 Research is ongoing to further clarify these associations.
Data from clinical trials indicate that liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors in rats and mice. However, the risk for these types of tumors in humans, including medullary throid carcinoma (MTC), has neither been proven nor ruled out in clinical or nonclinical trials. 20
References
1. Luna B, Feinglos MN, Am Fam Physician. 2001;63:1747-1757.
2. Tzoulaki I et al. BMJ. 2009;339:b4731.
4. Slagle M. South Med J. 2002;95(1):50-55.
8. PubMed Health: Lactic acidosis. Accessed Aug. 8, 2011.
9. Scheen AJ. Diabetes Metab. 2001;27(3):305-13.
10. McGrane D, Fisher M, McKay GA. Br J Cardiol. 2011;18:24-27.
13. PubMed Health: Sitagliptin. Accessed online Aug. 8, 2011.
14. PubMed Health: Saxagliptin. Accessed online Aug. 8, 2011.
15. Kalra S. J Assoc Physicians India. 2011;59:237-245.
16. McDougall C, McKay G, Fisher M. Br J Cardiol. 2011;18(3):130-132.
19. Hinnen D. Journal of the American Board of Family Medicine. 2006; 19:612-620.
20. FDA. Drug Safety Communication: Victoza Injection: REMS – Risk of Thyroid C-cell Tumors, Acute Pancreatitis. Accessed online Aug. 8, 2011.
