Trending Clinical Topic: Metformin

Ryan Syrek


November 22, 2021

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New data from the GRADE trial, a pair of disappointing studies, and troubling information from a retrospective analysis resulted in metformin becoming this week's top trending clinical topic. The GRADE trial ran for roughly 5 years at 36 US centers. It compared various medications as potential add-ons to metformin in the treatment of type 2 diabetes. Preliminary results were released over the summer at the American Diabetes Association meetings. More recently, some of the final results were presented at the European Association for the Study of Diabetes (EASD) meeting. The newly released data specifically focus on cardiovascular outcomes.

In the findings presented at the EASD meeting, the participants were at low risk for cardiovascular events. They had a mean age of 57 years and a diabetes duration of 4 years. Two thirds had hypertension and one third had a low-density lipoprotein (LDL) cholesterol level > 100 mg/dL. Among the four different medications compared, no difference was reported in terms of hospitalization, heart failure, cardiovascular death alone, or all-cause mortality; however, liraglutide was associated with numerically fewer events.

In the GRADE data released in June, liraglutide and insulin glargine outperformed glimepiride and sitagliptin as single add-on agents to metformin. The primary endpoint was change in A1c level and overall glycemic control. During the average 5-year follow-up, the rates of patients progressing to a confirmed A1c of 7% or higher were lowest, at 67%, among patients randomized to insulin glargine; 68% for those maintained on liraglutide; 72% for patients taking the sulfonylurea glimepiride; and 77% in those taking sitagliptin, reported John M. Lachin, ScD, a biostatistician at George Washington University in Rockville, Maryland.

In other metformin news, two recent phase 2 trials recently found that the medication does not improve survival when given alongside chemoradiotherapy to patients with locally advanced non–small cell lung cancer (NSCLC), and it may even make survival worse. In the first trial, which was an open-label phase 2 study, NRG-LU001, patients with unresectable stage 3 NSCLC who did not have diabetes were randomized to carboplatin and paclitaxel-based chemoradiation either alone or with metformin. Among the 167 patients eligible for analysis, 1-year progression-free survival was 60.4% in the control group and 51.3% in the metformin group (P = .24) after a median follow-up of 27.7 months. The 1-year overall survival rate was 80.2% in the control group and 80.8% in the metformin arm, and no significant differences were found in rates of locoregional recurrence or distant metastasis.

The second randomized controlled trial, OCOG-ALMERA, involved patients with locally advanced NSCLC stratified into stages 3A and 3B, again without diabetes. One group received standard radiation therapy plus platinum-based chemotherapy with or without consolidation; the other received the same chemoradiation regimen, but with concurrent metformin. The primary outcome was progression-free survival at 12 months, but the trial had to be stopped early because of slow accrual. The results revealed that treatment failure at 1 year was seen in 69.2% of metformin patients and 42.9% of those in the control arm.

In other disappointing news, the MAVMET study, the first randomized controlled trial of maraviroc (Selzentry) with or without metformin, failed to reduce liver fat in people living with HIV and nonalcoholic fatty liver disease compared with placebo — and in some cases, prolonged use actually increased liver fat. The results showed that the mean liver fat percentage rose by 2.2% in the maraviroc group, 1.3% in the metformin group, and 0.8% in the combination group. The control group saw an increase of 1.4%.

When it comes to the condition for which metformin has proven efficacy, type 2 diabetes, a retrospective analysis of administrative data found that nearly half of all adults stopped taking the medication within 1 year. The research showed that the fall-off in metformin adherence was most dramatic during the first 30 days, and in most cases, no concomitant substitution of another glucose-lowering drug occurred. Similar drop-offs have been seen with antihypertensive and lipid-lowering drugs, which have fewer side effects. Some experts believe this is because metformin does not make patients feel better, even if it is effective and crucial to long-term health. From studies exploring potential add-ons to troubling data, various news about metformin drove interest, leading it to become this week's top trending clinical topic.

Learn more about the pharmacologic treatment of type 2 diabetes.


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