Metformin More Effective if Initiated Soon After Diabetes Diagnosis

Nancy Fowler Larson

March 22, 2010

March 22, 2010 — Starting patients with metformin within 3 months of their diabetes diagnosis increases the drug's efficacy, according to a study published in the March issue of Diabetes Care.

"To our knowledge, no studies have examined the potential benefits of immediate vs. delayed metformin initiation used with a modern A1C [glycated hemoglobin] treatment threshold of 7%," write Jonathan B. Brown, PhD, MPP, Kaiser Permanente Center for Health Research, Portland, Oregon, and colleagues. "Furthermore, although metformin fails at a rate of about 4% per year in clinical trials, the failure rate in the real world of clinical practice has not been reported."

Nearly 24 million Americans have type 2 diabetes. In 2008, the researchers studied the electronic records of 1799 patients with type 2 diabetes who received metformin as their first antihyperglycemic medication. All were treated in clinical practice settings.

The goal of the study was to evaluate the failure rate of secondary metformin monotherapy in those who saw their A1C levels decrease to less than 7% in the previous 2 to 5 years. Secondary failure was defined as an A1C level of greater than 7.5% or the need to add or substitute a different antihyperglycemic agent.

Early Treatment, Starting Metformin When A1C Levels Are Low Yields Best Outcome

Forty percent of those whose first-line therapy was metformin started their course within 3 months of diagnosis; 25% waited 36 months or longer. Twenty seven percent began metformin with an A1C level of less than 7%; 23% received it only after their A1C level was greater than 9.0%. A lower rate of secondary failure occurred in those who began metformin soon after their diagnosis, as follows:

  • Among all patients, the failure rate was 42% with a mean rate of 17% (range, 15.8% - 18.2%) a year during the 2- to 5-year period.

  • Patients who started taking metformin within 3 months of diagnosis had a failure rate of 12.2% (range, 10.5% - 14.4%) per year, after adjustment for age and A1C level.

  • Patients who initiated metformin 4 to 11 months after diagnosis were 56% more likely to experience secondary failure (odds ratio, 1.56; 95% confidence interval [CI], 1.12 - 2.18).

  • Those whose metformin therapy began 3 or more years after diagnosis were even more likely to experience failure (odds ratio, 2.20; 95% CI, 1.68 - 2.87).

Results also showed that A1C levels at the time of metformin initiation are significant. Patients who started the medication with a level of less than 7% failed at an adjusted rate of 12.3% per year.

"Our study suggests that initiating metformin soon after diabetes diagnosis and while A1C is low may improve the durability of metformin; thereby delaying the need for therapeutic adjustments and reducing the glycemic burden associated with its failure," the study authors write.

The study authors noted several limitations to their observational analysis. The results may have been affected by the fact that A1C measurements were taken at irregular interludes and with varying frequency. Additionally, researchers could not determine why clinicians added or substituted a secondary drug before a patient's A1C levels increased to 7% or more.

Finally, the researchers speculated that factors involving the structure of Kaiser and its highly technical recordkeeping may make it difficult to generalize their findings to other clinical settings.

Findings Support ADA Guidelines but Treatment Should Be Individual

When asked for independent comment from Medscape Diabetes & Endocrinology, Richard Bergenstal, MD, president, medicine and science, American Diabetes Association (ADA), Alexandria, Virginia, called metformin an effective, inexpensive, and well-tolerated drug. He applauded the study findings, noting that they reinforce ADA promotion of early metformin treatment.

"This was the first study that said, 'Maybe we shouldn't wait until diabetes gets out of control to add the first medication.' Let's see if we can start it early and slow down this progression of diabetes and the need for more medication," Dr. Bergenstal told Medscape Diabetes & Endocrinology.

Study coauthor Gregory A. Nichols, PhD, pointed out that although the findings provide a stronger basis for early metformin, treatment decisions should be made on a case-by-case basis.

"It's still up to the doctors and the patients as to when is the best time [to initiate metformin]," Dr. Nichols told Medscape Diabetes & Endocrinology. "We think this data will help inform that decision and may encourage doctors to have patients start metformin earlier."

Future study is needed to determine whether controlling diabetes with early metformin therapy will lower the risk for microvascular and macrovascular complications, Dr. Nichols said.

Although Novo Nordisk supported the study, the company does not make a monotherapy metformin drug. Although Dr. Nichols prefers not to know the interests of drug companies funding his studies, he speculated that Novo Nordisk may have sought to further explore the market for its other products.

"They make drugs that would be used as second or third line agents in diabetes care," Dr. Nichols said. "Their interest in understanding metformin failure may be to better position themselves as what to do next."

Novo Nordisk did not respond to a request for comment.

Novo Nordisk Inc, Seattle, Washington, supported the study. Study author Christopher Conner, PharmD, PhD, is employed by Novo Nordisk. The other study authors have disclosed no other relevant financial relationships.

Diabetes Care. 2010;33:501-506.


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