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Comparing Medications for Adults With Type 2 Diabetes

Slide: 25 of 35

Overview of Adverse Events and Side Effects

Mild to Moderate Hypoglycemia
Hypoglycemic episodes were three to seven times as frequent in people taking sulfonylureas as in those taking metformin,  thiazolidinediones, or DPP-4 inhibitors (moderate to high strength of evidence). Combination therapies that included a sulfonylurea plus metformin also had an excess hypoglycemia risk when compared to metformin plus a thiazolidinedione (moderate strength of evidence). No monotherapy or combination therapy convincingly demonstrated more occurrences of severe hypoglycemia than another.

Gastrointestinal side effects
Metformin was associated with higher risk of gastrointestinal side effects than were all other medications, regardless of whether the  metformin was used as monotherapy or as part of combination therapy (moderate to high strength of evidence).

Congestive heart failure
There was moderate strength evidence for a higher risk of CHF with thiazolidinedione monotherapy than with sulfonylurea monotherapy (OR 1.68, 95% CI 0.99 to 2.85). Low-grade evidence from the RECORD trial showed that the combination of thiazolidinediones and another agent (second or third generation sulfonylurea or metformin) was associated with a significant doubling in the risk of heart failure in comparison to the combination of sulfonylurea and metformin (61/2220 versus 29/2227, RR 2.1, 95 percent CI, 1.35 to 3.27). No long-term trials assessed the comparative effects of the DPP-4 inhibitors and GLP-1 receptor agonists on the risk of heart failure. No further conclusions could be drawn regarding CHF risk from other drug comparisons of interest, either because of an absence of evidence, conflicting results, or the low quality of the studies.

* In 2007, the FDA issued an alert and changed labeling to state that TZDs cause or exacerbate CHF in some patients. In 2010, the FDA placed additional prescribing restrictions on rosiglitazone use for type 2 diabetes in response to data that suggest an elevated risk of cardiovascular events including myocardial infarction and stroke.

Hip and nonhip Fractures
There was high strength of evidence showing that thiazolidinediones, either in combination with another medication or as monotherapy, were associated with a 1.5-fold higher risk of bone fractures than was metformin alone or in combination with sulfonylurea.

Other adverse events
Reports of four types of adverse events were found that were not addressed in the previous 2007 evidence report: macular edema, cholecystitis,  pancreatitis, and fractures. Except for fractures, the majority of the evidence was graded as low strength because the availability of only a few studies and events limited the assessment of consistency and precision of the results. There was also only a little evidence regarding liver injury and cancer, outcomes included in the 2007 evidence report. However, in agreement with other reviews, there was a moderate  strength of evidence for a lack of increased risk of lactic acidosis with metformin treatment, as compared to a sulfonylurea or a combination of metformin and sulfonylurea.