Retrospective #274: “Should Everyone Take Metformin?”

When I read “Everyone” should take Metformin, I assumed wrongly, I thought, that by “everyone” the title of the Medscape article meant as the initial choice of oral glucose-lowering medication for the treatment of Type 2 Diabetes Mellitus. That’s the way the new guidelines for prescribing statins are being interpreted; that everyone over 39 years of age and under 76 with a Total Cholesterol ≥200mg/dl should be on a statin for the very dubious, almost exclusive purpose of lowering LDL-C. To read about that, go to Retrospective #180, “The AHA/ACC Cholesterol Guidelines.”

No, this Medscape story, about a paper in JAMA Internal Medicine, was an “observational cohort study [that] sought to determine the effect of initial oral glucose-lowering class on subsequent need to additional anti-hyperglycemia therapy.” The participants, none of whom had previously been treated for diabetes, were started on 1) metformin, 2) a sulfonylurea, like glyburide, 3) a TZD like Avandia, or 4) a DPP4, like Januvia and Onglyza. “The primary outcome was time to treatment intensification, defined as initiation of a different class of oral glucose-lowering medication.”

“Secondary outcomes included time to composite cardiovascular event (coronary heart disease, congestive heart failure, unstable angina, ischemic stroke, acute myocardial infarction [heart attack], or a revascularization procedure [stent], congestive heart failure alone, an emergency department visit for hypoglycemia, and any other diabetes emergency department visit.” That’s one heck of a scary list of secondary outcomes. Something to think about…

“The Winner, and Still Champion: Metformin,” the Medscape sub-head declared. Well, there should be no surprise there. But if you are Prediabetic, or just diagnosed a Type 2 diabetic, and you weren’t started on Metformin, you might want to print this out – better yet, go to the Medscape and JAMA Internal Medicine stories above, print them out, and give them to your doctor and ask why you were not. I’d be interested to hear his or her answer.

The Medscape piece amplifies this finding: “Relative to Metformin uses, the risk of treatment intensification was 68% greater among SU users, 61% greater among TZD users, and 62% greater among DPP4 users.” That’s really significant.

As to the “secondary outcomes,” Medscape states this dramatic finding: “Also relative to Metformin, SU use was associated with an increased risk for composite cardiovascular events, congestive heart failure, and hypoglycemia.”

Then this Medscape analysis of comparative effectiveness took an interesting turn. It began with this question, posed by another study: “Can People with Type 2 Diabetes Live Longer Than Those Without? A Comparison of Mortality in People Initiated with Metformin or Sulphonylurea Monotherapy and Matched Non-diabetic Controls.” This British study, which appeared in Diabetes Obesity and Metabolism, essentially asked, “Does Metformin Reduce Mortality?” Hmmm… Maybe the title of the Medscape piece was intended to mean “everyone everyone.” I read on to find out.

In this study, “patients initiating Metformin therapy were compared with those initiating treatment with a SU, and both diabetic groups were compared with their matched nondiabetic controls.” Subsequent mortality was tracked for up to 5.5 years. The FINDINGS: “Crude death rates were substantially lower for Metformin users that SU users” and, “All subgroup comparisons favored Metformin over SU and were statistically significant.” But here’s the zinger.

“Perhaps the most striking finding was that survival time for controls [the non-diabetics who were not taking Metformin] was 15% shorter than for matched Metformin users. This finding was consistent across all subgroups, nearly all of which demonstrated statistical significance, and was particularly strong among patients with high comorbidity.”

“The protective effect of Metformin relative to SUs was not a surprise,” the Medscape piece says. The remarkable finding was an apparent protective effect of Metformin compared with nondiabetic individuals. Because of Metformin’s favorable results among people with diabetes, it has been postulated that the drug may also provide benefit to people without diabetes.” Sort of like statin therapy… What are they saying? What am I saying? Everyone should take metformin??!!!