Metformin Neglected as First-Line Therapy for Diabetes

October 27, 2014

The results of a new US study show that only 58% of individuals with type 2 diabetes were started on metformin as their first oral glucose-lowering medication, despite the fact that this drug is widely recommended as the initial therapy of choice in numerous diabetes guidelines.

The research is published October 27 in JAMA Internal Medicine, by Dr Seth A Berkowitz (Massachusetts General Hospital, Boston) and colleagues.

Importantly, the results also show that those patients beginning with metformin were less likely to require treatment intensification with other medications or insulin than those initiating with other therapies, explained senior author Dr Niteesh K Choudhry, from the division of pharmacoepidemiology at Harvard Medical School, Boston, MA.

"These findings have significant implications for quality of life and medication costs," he and his coauthors state.

And, said Dr Choudhry, "We also looked at whether, if metformin appears better [in terms of treatment intensification], might it be worse in some other regard," such as differences in rates of hypoglycemia or other adverse clinical events, "but we found no evidence of that."

Dr Choudhry acknowledges that prior to this work, whether published research supports the choice of metformin as initial therapy was a subject of debate — it was, in fact, discussed at the recent European Association for the Study of Diabetes 2014 Meeting in Vienna. Therefore, he and his colleagues "were really seeking to address a clinical question." The results, he told Medscape Medical News, "provide data to support what the existing treatment recommendations are."

"For those thinking of initiating therapy, in the absence of contraindications — which incidentally are fewer than we might perceive — metformin is probably the right choice. If I've got a patient starting on an oral hypoglycemic agent, I'll have to think hard why not to use metformin," he stated.

In an accompanying commentary, Drs Jodi B Segal and Nisa M Maruther (Johns Hopkins University School of Medicine, Baltimore, Maryland) agree with these conclusions. "This meticulously conducted study… adds modestly to what is already known on this topic. First-line therapy should be metformin in patients without contraindications."

Additional Data on Comparative Effectiveness of Agents

Dr Choudhry explained that there is a "paucity" of data about how antihyperglycemic agents compare in terms of clinical outcomes or treatment intensification (the addition of a further medication). And now, in the diabetes world, physicians "are confronted by a larger and larger number of products providing more and more therapeutic options, which adds some confusion to choice," he observed.

"The purpose of our study was to provide some additional data on comparative effectiveness. We wanted to add data to the debate."

Using a retrospective cohort design with 4 years of recent claims data from a large national insurer (Aetna), they looked at patients who had been newly prescribed an oral diabetes medication from one of four classes — metformin; sulfonylureas; thiazolidinediones; and dipeptidyl peptidase 4 (DPP-4) inhibitors — from July 2009 to end of June 2013 and who filled a second prescription for a medication in the same class within 90 days of the first.

"So we were comparing apples and apples," Dr Choudhry explained.

In their commentary, Drs Segal and Maruthur wonder why injectable glucagonlike peptide 1 (GLP-1) agonists were not included in the analysis, "despite their approval for use as monotherapy and availability since 2005." But Dr Choudhry told Medscape Medical News that although GLP-1 agonists are technically approved for monotherapy, "almost no one uses them as initial therapy, so, simply stated, there weren't enough people to study" taking this class of drug.

The main outcomes were the time to addition of a second oral agent or insulin, each component separately, hypoglycemia, other diabetes-related emergency-department visits, and cardiovascular events.

Although the study did not examine the specific prescribers involved, with this type of national insurer the "vast majority" of physicians would have been primary-care providers (general internists) seeing patients in routine care settings, said Dr Choudhry.

A total of 15 516 patients met the inclusion criteria, of whom 8964 (57.8%) started therapy with metformin. Sulfonylurea treatment was the first drug in 23% of cases, 6.1% began treatment with thiazolidinediones, and 13.1% with DPP-4 inhibitors.

Patients prescribed metformin were less likely to require treatment intensification compared with those who used the other medications: 24.5% who started on metformin required a second oral medication, compared with 37.1% of patients prescribed a sulfonylurea, 39.6% who began with a thiazolidinedione, and 36.2% given a DPP-4 inhibitor first.

In adjusted models, those taking sulfonylureas were 68% more likely to require treatment intensification relative to first therapy with metformin (hazard ratio [HR], 1.68); this was also the case for those on thiazolidinediones (HR, 1.61) and for DPP-4 inhibitors (HR, 1.62), "without greater clinical benefits (and often more short-term adverse events)," observe Drs Segal and Maruther in their commentary.

Sulfonylureas, in particular, were associated with more adverse cardiovascular events and hypoglycemia.

Is Treatment Intensification Bad or Just Necessary?

Drs Segal and Maruthur also wonder about "the choice of addition of medication as the only indicator of treatment intensification rather than a dosage increase."

"This consideration is particularly germane to use of metformin because the slow titration of metformin typically reduces gastrointestinal adverse effects…[and this] may delay the time until a second agent is added without indicating the superiority of metformin," they observe.

But Dr Choudhry said that dose intensification "wasn't really relevant in our study, since we studied only individuals who were on therapeutically effective (ie, essentially maximum) doses of the agents (as defined by the World Health Organization) to make the comparison between classes as fair as possible."

The editorialists add that, in any case, it is perhaps time to start considering "treatment intensification" in diabetes as "a necessary step for wellness and health maintenance," in the same way as it is viewed in hypertension management.

In the latter, "the use of several submaximal doses of medication is supported by evidence and well accepted by patients…as an unfortunate but necessary part of good…care," they point out.

But what to choose as second-line therapy after metformin remains a mystery, which the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), study should go some way toward helping to inform upon, they note. However, this study is not expected to report for some time.

This work was supported by an unrestricted grant from CVS Health to Brigham and Women's Hospital. Dr Berkowitz reported receiving funding from an Institutional National Research Service Award, the Ryoichi Sasakawa Fellowship Fund, and the general medicine division at Massachusetts General Hospital. The coauthors and Drs Segal and Maruthur report they have no financially relevant relationships.

JAMA Intern Med. Published online October 27, 2014. Abstract, Editorial

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