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Comparing Medications for Adults With Type 2 Diabetes

Slide: 32 of 35

Long-Term Clinical Outcomes: Overview

Despite the inclusion of two additional large RCTs and 39 other studies since the 2007 systematic review, overall, low or insufficient strength of evidence was found to support conclusions about the comparative effectiveness of diabetes medications, either in monotherapy or combination therapy, on all-cause mortality, or macrovascular and microvascular long-term diabetes complications. Compared with the 2007 review, each drug-drug comparison has additional supportive data, specifically for metformin versus a thiazolidinedione, metformin versus a second-generation sulfonylurea, and comparisons with meglitinides. Metformin was associated with slightly lower all-cause mortality and cardiovascular disease mortality than were second-generation sulfonylureas. However, the evidence was limited by inconsistency between the trials and observational studies and the overall low precision of the results, due to the rarity of events. There were only a few studies with the newer DPP-4 inhibitors and GLP-1 receptor agonists, but overall the evidence on these newer agents was insufficient to allow for any meaningful conclusions. Few studies included insulin added to other medications or compared other two-drug combination therapies. Few studies addressed microvascular outcomes of nephropathy, retinopathy, or neuropathy.

Based on two short-duration RCTs, there was a moderate strength of evidence that pioglitazone was better than metformin at reducing the urinary albumin-to-creatinine ratio (15% and 19% decrease in two trials), likely indicating less nephropathy. Only three comparisons were included for the outcome of neuropathy, and these studies were limited by their small sample sizes and poorly defined outcomes. No studies were identified for the outcome of retinopathy. Overall, the data was unable to definitively support one drug or combination of drugs over another for mortality, macrovascular, and microvascular complications of diabetes.

In September 2010, the FDA placed restrictions on the use of rosiglitazone, through a Risk Evaluation and Mitigation Strategy, which in part, will require clinicians to attest to and document that the drug’s benefits outweigh the cardiovascular risks.

Unfortunately, no studies reporting the outcome of retinopathy met the inclusion criteria. In the 2007 review, six studies reported this outcome, which were all excluded from this updated review because participants were either taking additional background medications or because there was no comparison of interest (e.g., gliclazide versus glibenclamide). In  the 2007 review, three studies reported on the outcome of retinopathy. The most notable study was the U.K. PDS, which reported no difference in progression to retinopathy between a sulfonylurea and metformin at 12 years of followup. Unfortunately, no additional studies examining this clinically important outcome were found. Also, few studies reported on the outcomes of nephropathy or neuropathy. Pioglitazone had greater reductions in the albumin-to-creatinine ratio as compared with metformin, with unclear implications for long-term effects on diabetic nephropathy or chronic kidney disease progression. Conclusions could not be drawn about neuropathy because of small sample sizes and inconsistent definitions of the outcome. Because few studies have considered neuropathy and its profound implications for patient quality of life, this will be an important area for future research.