Metformin Remains Best First-line Therapy for Type 2 Diabetes

Becky McCall

April 18, 2016

Metformin should remain the first choice for the treatment of type 2 diabetes, even in the face of competition from a host of newer agents, concludes a new review.

Nisa M Maruthur, MD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, led the review, published today in the Annals of Internal Medicine.

"We conclude that metformin should remain a first-line therapy because its effect on HbA1c is similar to other medications. Metformin has a long-term safety profile, it's weight neutral or helps people lose weight, it has gastrointestinal side effects but they are avoidable or tolerable, and of course metformin looks better for cardiovascular mortality than sulfonylureas," she told Medscape Medical News in an interview.

Among the drugs evaluated along with metformin were the latest approvals for type 2 diabetes, including the newest class of sodium–glucose cotransporter 2 (SGLT2) inhibitors, the dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagonlike peptide-1 (GLP-1) receptor agonists. Other drugs reviewed were thiazolidinediones, sulfonylureas, and selected metformin-based combinations.

Asked to comment, Darren McGuire, MD, of the University of Texas Southwestern Medical Center, Dallas, remarked: "I do find it odd that the justification for metformin first hinges on its comparison with sulfonylureas, which have minimal data available suggesting efficacy and ongoing concern about adverse cardiovascular effects.

"That is, it is possible that sulfonylureas have adverse outcomes, which of course in these analyses will exaggerate what, if any, cardiovascular risk efficacy metformin has."

Review Includes Latest Data on Newer Agents

Amid the plethora of newly approved antidiabetic drugs and an abundance of new data in recent years, Dr Maruthur explained that this systematic review brings the comparative effectiveness and safety analysis up to date.

It includes new information since the last comprehensive review published in 2011 (Ann Intern Med. 2011;154:602-613), featuring the novel SGLT2 inhibitors as well as much more information on the relatively new DPP-4 inhibitors and GLP-1 receptor agonists.

The strength of this updated review lies in covering outcomes and comparisons not found elsewhere, including direct comparisons of monotherapies and metformin-based combination therapies for type 2 diabetes (with over 100 newly included articles), she added.

"This…fills many gaps left by prior work," she and her colleagues state.

"Most reviews have not evaluated head-to-head comparisons and usually have evaluated one medication class against placebo or multiple medication classes for a limited number of outcomes. In this review, we include more recent articles [and] focus squarely on comparative effectiveness with direct medication comparisons."

Dr Maruthur added: "For comparative effectiveness we really want to know what is going on with a range of outcomes important to clinicians and patients. We provided that."

In total, the review comprised 179 trials and 25 observational studies of head-to-head monotherapy or metformin-based combinations. The authors noted that most studies were short, with limited ability to assess rare safety and long-term clinical outcomes.

Across the 204 studies reviewed in total, HbA1c reduction was similar with most diabetes medications, but DPP-4 inhibitors reduced HbA1c less than metformin and sulfonylureas. The comparative effects of GLP-1 receptor agonists on HbA1c were inconsistent, possibly hinting at within-class differences.

With respect to weight change, thiazolidinediones, sulfonylureas, and insulin were associated with weight gain compared with medications that were weight neutral or led to weight reduction — notably, metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors.

Analysis of adverse effects showed that sulfonylureas increased hypoglycemia risk; metformin and GLP-1 receptor agonists increased gastrointestinal side effects; thiazolidinediones increased risk for congestive heart failure; and SGLT2 inhibitors increased risk for genital mycotic infections.

On the basis of less evidence, results for add-on therapies to metformin were similar to those for monotherapies.

And although evidence was also limited, the review found no increased risk for lactic acidosis with metformin, a rare but feared side effect. This conclusion was based on a recent review of observational work.

Since this paper was written, the FDA has announced that metformin can be used safely in patients with mild and, in some cases, moderate renal impairment after decades of warning against it.

Dr Maruthur and colleagues conclude that future research should prioritize the comparative effects of diabetes medications on long-term mortality, cardiovascular mortality and morbidity, microvascular outcomes, and rare, serious adverse events.

EMPA-REG Not Included as It Was Not a Comparative Study

Of note, the review did not include the large EMPA-REG OUTCOME study, the landmark cardiovascular outcomes trial of the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) in patients with type 2 diabetes at high risk of cardiovascular disease.

Results, reported in September 2015, showed a cardiovascular mortality benefit of empagliflozin over placebo (38% relative risk reduction), the first time that any glucose-lowering agent has positively affected mortality.

Studies involving empagliflozin were included in the review, but Dr Maruthur explained that they did not include the EMPA-REG OUTCOME trial because it wasn't suitable for their aim.

EMPA-REG "wasn't a direct comparison of empagliflozin and another drug. EMPA-REG OUTCOME study entrants could be on other diabetes medications or not before randomization. Other medications were then added in as required. You can't compare empagliflozin with metformin in this setting," she explained.

Dr McGuire observed: "The volume of outcomes data and patient-year observation of parallel randomized groups in [EMPA-REG]…eclipses the totality of data available on cardiovascular outcomes with metformin when combining all randomized comparative trials."

Also missing from the review are new data on pioglitazone, demonstrating cardiovascular benefits in the IRIS trial in patients with insulin resistance and a history of stroke or transient ischemic attack. Pioglitazone reduced the risk for recurrent stroke or myocardial infarction vs placebo.

And perhaps more understandably, findings from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) study were also not included.

Slated to show that the GLP-1 receptor agonist liraglutide (Victoza, Novo Nordisk) significantly reduces the risk of major adverse cardiovascular events compared with placebo, top-line data were released for this study in March, but the full results will not be available until the ADA meeting in June.

Will Guidelines Change?

Current recommendations from most diabetes associations worldwide place metformin firmly as the first-line treatment of choice for type 2 diabetes, barring any contraindications, thereby supporting the finding of this new review.

But given the plethora of new outcomes data, Dr McGuire queries whether metformin will one day soon even be placed after empagliflozin and other newer drugs based on these recent results.

"Except for important cost considerations, and the caveat that EMPA-REG OUTCOME enrollment was restricted to type 2 diabetes patients who had prevalent cardiovascular disease, one could argue that metformin might be positioned below empagliflozin, perhaps below liraglutide, and perhaps below pioglitazone based on the IRIS trial results," he suggested.

Dr Maruthur takes a more cautious approach. She said she did not feel that EMPA-REG OUTCOME provided evidence to suggest that empagliflozin should be placed above metformin in protocol.

"I don't think one trial will make you change guidelines and certainly not one where it is unclear whether you are looking at the effect of drug A or the detrimental effect of drug B."

With respect to liraglutide, said she had not seen the results of the LEADER study but that, "similar to empagliflozin, it was unlikely to be a direct comparison of agents."

Dr McGuire said he wishes the diabetes guideline writers good luck.

"For the first time, clinical-outcomes data will have to factor into the recommended algorithms for management of hyperglycemia."

Dr Maruthur reports a contract with the Agency for Healthcare Research and Quality during the conduct of the study. Disclosures for the coauthors are listed in the article. Dr McGuire reported receiving personal fees from Boehringer Ingelheim, Janssen, Sanofi, Genentech, Merck Sharp & Dohme, Daiichi Sankyo, Lilly, Novo Nordisk, GlaxoSmithKline, Takeda Pharmaceuticals North America, Bristol-Myers Squibb, AstraZeneca, Orexigen, Lexicon, Eisai, Regeneron, Merck, Pfizer, and Genfit.

Ann Intern Med. Published online April 18, 2016. Abstract

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