REACH for Metformin to Reduce Deaths in Patients With Diabetes and Atherothrombosis

Fran Lowry

July 01, 2010

July 1, 2010 (Orlando, Florida) — In patients with diabetes and documented atherothrombosis, the use of metformin was associated with a significant 24% reduction in all-cause mortality after two years of follow-up, according to a subgroup analysis from a large registry study presented here at the American Diabetes Association (ADA) 2010 Scientific Sessions.

Even patients thought to have contraindications to metformin, such as those with moderate renal failure, congestive heart failure, or advanced age up to 80 years, showed benefit, said Dr Ronan Roussel (Hôpital Bichat, Paris, France).

The results are from the Reduction of Atherothrombosis for Continued Health (REACH) registry, a worldwide registry designed to determine which patients are at high risk for cardiovascular disease from a population of more than 67 000 patients from 5473 sites in 44 countries.

This particular analysis focused on some 20 000 diabetic patients in the REACH registry who were at least 45 years of age and who had documented cerebrovascular disease, coronary disease, or historical or current intermittent claudication associated with an ankle brachial index (ABI) score of 0.9 or less, plus at least three atherothrombotic risk factors, including current smoking, hypercholesterolemia, diabetic nephropathy, hypertension, asymptomatic carotid stenosis >70%, and the presence of at least one carotid plaque.

Metformin Conferred Survival Benefit

Patients were divided into two groups; those who used metformin (n=7457) and those who did not (n=12 234). Patients who used metformin were younger, had greater waist circumference, greater body-mass index, and higher fasting blood glucose levels, fasting triglycerides, and systolic blood pressure than nonusers. More metformin users had prior arterial disease, compared with nonusers.

After adjustment for a number of variables, survival according to metformin use was significantly greater than that without metformin.

REACH: Survival With and Without Metformin at Two-Year Follow-up

Outcome No metformin use Metformin use p
Deaths per patients, n 929/12 156 341/7397  
2-y mortality rate (95% CI) 9.83 (8.40–11.23) 6.33 (5.24–7.41)  
Adjusted for sex and age HR (95% CI) 1 0.67 (0.59–0.75) <0.001
Adjusted for sex, age, propensity scorea and significant factorsb 1 0.76 (0.65–0.89) <0.001

a. The probability of receiving metformin, given an individual's characteristics

b. Region, ethnic origin, education, employment, hypercholesterolemia, carotid surgery, atrial fibrillation/flutter, congestive heart failure, aortic-valve stenosis, abdominal aortic aneurysm, antiplatelet agents, anticoagulants, lipid-lowering agents, other cardiovascular agents, body-mass index, and systolic blood pressure

Metformin Is Not Used in High-Risk Patients

"Metformin is a first-line drug for patients with type 2 diabetes. This is universally admitted by the medical community," Roussel told heartwire . "But it is not used very often in high-risk diabetic patients with comorbidities. Yet, this observation study shows that they do, in fact, benefit."

He added that the contraindications against metformin are very restrictive, perhaps too much so. "They are not very well based on evidence. People are afraid of lactic acidosis, which was seen previously with phenformin, but actually not so much with metformin. This is probably one of the main reasons why physicians don't use metformin very often. In our analysis, we found that only 40% of high-risk patients were taking metformin at baseline."

Dr Richard Bach (Washington University School of Medicine, St Louis, MO) told heartwire he was surprised by the 24% reduced mortality. "These are very interesting results from an observational study. I think it's fascinating. Certainly, metformin appears to be very favorable with an impact on mortality."

Weighing in with his opinion, Dr David Kendall, ADA chief scientific and medical officer, said that these results support the view that there can indeed be benefits with metformin in high-risk patients.

"My personal perspective is that obviously, metformin has been established as preferred or initial therapy in most patients with type 2 diabetes. This study expands the support of that position," he told heartwire.

He added that metformin's reputation for being potentially unsafe in patients with renal disease and heart failure should be investigated in clinical trials. "While risk can't be minimized as an issue, we really need long-term and careful observational and randomized trials that look at medications that are clearly effective, and where small risks, in this case the risk of lactic acidosis, cannot drive all of our clinical discussions, nor supplant long-term experience with some agents."

This study was sponsored by Sanofi-Aventis, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan). Roussel reported financial relationships with Sanofi-Aventis, Merck Sharp et Dohme-Chibret, Servier, Roche, Eli Lilly, Novo Nordisk, Medtronic, and Lifescan.

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