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What Are Your Waiting for? Start Metformin Early

Posted: Tuesday, January 04, 2011

For newly diagnosed Type 2 diabetes patients, waiting until lifestyle measures fail before starting metformin may jeopardize the long-term efficacy of the drug.

Metformin failed at an age- and hemoglobin A1c-adjusted rate of 12.2% per year for those who started the drug within three months of diagnosis compared with a failure rate of 17% per year overall among those who had an initial response to it.

Those who started metformin while their A1c remained below 7% also saw a lower adjusted failure rate of 12.3% per year. These findings reinforce the American Diabetes Association guidelines that recommend metformin with diet and exercise changes immediately after diagnosis.

Early initiation "while A1c is low might preserve beta cell function, prolong the effectiveness of metformin, reduce lifetime glycemic burden, and prevent diabetes complications," the researchers wrote.

The study of the health maintenance organization's members in parts of Oregon and Washington included 1,799 Type 2 diabetes patients for whom metformin successfully lowered A1c below 7% as their first antihyperglycemic drug.

Over two to five years of follow-up through Kaiser's medical records database, 42% of those patients saw their A1c rise above 7.5% or added or switched to another antihyperglycemic agent, which the researchers defined as secondary failure of metformin.

This real-world failure rate of 17% per year was substantially higher than the 4% typically seen in clinical trials, the researchers noted.

Compared with the 40% of patients who initiated metformin within three months after diagnosis, those who waited four to 11 months were 56% more likely to have the drug fail (95% confidence interval 12% to 218%), and the 25% who delayed 36 months or longer were 2.20-fold more likely to see secondary failure (95% CI 1.68 to 2.87).

Compared with the 27% who started on metformin before A1c got above 7%, metformin failure during follow-up was 53% more likely for those who waited until A1c was 7.0% to 7.9%, 74% more likely for those who started when their A1c was 8.0% to 8.9%, and 104% more likely for those who started after A1c was over 9.0% (all statistically significant).

These two factors appeared to have independent effects.

Other factors associated with metformin failure were younger age (57.7 versus 59.2 years, P=0.008) and longer duration of diabetes prior to therapy (26.5 versus 21.4 months, P<0.001).

The researchers noted that patients with a longer duration of diabetes prior to metformin initiation might have had their diabetes well-controlled for much of that time, "in which case their total time in control prior to metformin failure could have actually been greater than patients who initiated metformin immediately."

Nichols' group cautioned that their results were limited by the observational data, had questionable generalizability due to Kaiser's fairly unique record and notification system, and only applied to patients with successful initial metformin monotherapy.

Brown stated that about 20% of patients never respond to metformin, apparently for genetic reasons.

In the Kaiser database, another 23% of newly diagnosed patients didn't refill their first metformin prescription, did so only sporadically, or tried a second agent within the first six months.

"Clinicians wishing to optimize their patients' glycemic control should recognize that metformin may be less tolerable, less effective, and less durable than is commonly believed, and be prepared to respond to failure quickly," the investigators wrote.
Practice Pearl:

Note that the American Diabetes Association recommends initiation of metformin along with lifestyle changes at diagnosis of Type 2 diabetes.

Source:, Diabetes Care March 2010 vol. 33 no. 3 501-506; Brown JB, et al "Secondary failure of metformin monotherapy in clinical practice" Diabetes Care 2010.

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