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Metformin for Protection Against Alzheimer's,
Cancer and Heart Disease?

Written by Kathleen Doheny
[Lien / www.endocrineweb.com]

With commentary by Nir Barzilai, MD, director of the Institute for Aging Research, Albert Einstein College of Medicine, and Brian Kennedy, PhD, president and CEO of the Buck Institute for Research on Aging.

. Metformin may influence fundamental aging factors that underlie many age-related conditions, including cancer, heart disease and Alzheimer's, says Nir Barzilai, MD, director of the Institute for Aging Research at Albert Einstein College of Medicine, the Bronx.

"Metformin is generic, and it's cheap," Dr. Barzilai says. And accumulating data suggests that ''it interferes with the biology of aging."

Aging, he says, is a primary risk factor for not only diabetes but also most of our big killers, such as Alzheimer's, heart disease and cancer. In animal and human studies, metformin has shown promise in slowing the aging process and halting diseases.

To study the potential of metformin further, Dr. Barzilai plans to launch a large-scale study, Targeting Aging with METformin (TAME), to look at the effects of metformin compared to placebo. His team has already completed the MILES study, Metformin in Longevity, and are analyzing the results.

In that study, they gave some participants metformin, at 1,700 milligrams a day, and others placebo. The aim was to see if the metformin could restore the gene expression profile of an older person with blood sugar problems known as impaired glucose tolerance (but not yet diabetic), to that of a younger person.

Dr. Barzilai knows he has critics of his approach. He brushed them off, saying the people who don't see the value of the research ''don't understand the biology of aging and that it can be changed."

He doesn't see the research as testing an anti-aging drug. "Aging is not a disease and we don't want it to be a disease," he says. However, age is a risk factor for many disabling conditions, he says. "We want to increase the period without disease," he says. He calls that extending the ''health span."

Research has found that metformin reduces harmful oxidative stress and inflammation, among other benefits, he says.

Metformin as Health Booster? Perspective

"I think there is enough data in preclinical trials and in recent human ones to suggest it [metformin] is really targeting aging," says Brian Kennedy, PhD, president and CEO of the Buck Institute for Research on Aging, Novato, CA. He is familiar with the clinical trial protocol of Dr. Barzilai's.

While he supports the idea of testing metformin to ward off age-related diseases, ''I don’t think metformin is likely to be the most effective ant-aging drug," he says. Other drugs look more promising, he says. However, an important goal of the study is to set precedent, he says, to show that an older person's gene profile can be reset.

Researchers have been looking at the potential of metformin for about 15 years, Dr. Kennedy says, and research includes positive results in both animal and human studies. In one often-quoted study, diabetic patients taking metformin lived longer than those not on it, including those without diabetes. Researchers looked at more than 78,000 people with diabetes on metformin, more than 12,000 with diabetes on drugs known as sulfonylureas and more than 90,000 people who did not have diabetes.

The researchers found that those with type 2 diabetes on metformin lived longer than those in the non-diabetic comparison group and those on the other drug. The researchers wrote that the finding implies metformin may confer benefit in those without diabetes.

The finding may be partially explained by those with diabetes seeing their doctor more, and having conditions caught earlier, Dr. Kennedy says. Even so, he says, "I still think it's an important study."

Study Timeline

Dr. Barzilai estimates the new study will start in a year or two. The study will last five or six years. If results bear out, approval of the drug for aging could be secured soon after that, he says.

Asked if metformin is being used off-label now to prevent the age-related diseases, he says: "I hope not. Because we haven't done the study. We need it to succeed the way we want it to succeed'' before recommending it, he says.

Can people with type 2 diabetes live longer than those without?
A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls
[Lien onlinelibrary.wiley.com]

Aims
Clinical and observational studies have shown an increased risk of cardiovascular events and death associated with sulphonylureas versus metformin. However, it has never been determined whether this was due to the beneficial effects of metformin or detrimental effects of sulphonylureas. The objective of this study was therefore to compare all-cause mortality in diabetic patients treated first-line with either sulphonylurea or metformin monotherapy with that in matched individuals without diabetes.

Methods
We used retrospective observational data from the UK Clinical Practice Research Datalink (CPRD) from 2000. Subjects with type 2 diabetes who progressed to first-line treatment with metformin or sulphonylurea monotherapy were selected and matched to people without diabetes. Progression to all-cause mortality was compared using parametric survival models that included a range of relevant co-variables.

Results
We identified 78?241 subjects treated with metformin, 12?222 treated with sulphonylurea, and 90?463 matched subjects without diabetes. This resulted in a total, censored follow-up period of 503?384?years. There were 7498 deaths in total, representing unadjusted mortality rates of 14.4 and 15.2, and 50.9 and 28.7 deaths per 1000 person-years for metformin monotherapy and their matched controls, and sulphonylurea monotherapy and their matched controls, respectively. With reference to observed survival in diabetic patients initiated with metformin monotherapy [survival time ratio (STR)?=?1.0], adjusted median survival time was 15% lower (STR?=?0.85, 95% CI 0.81–0.90) in matched individuals without diabetes and 38% lower (0.62, 0.58–0.66) in diabetic patients treated with sulphonylurea monotherapy.

Conclusions
Patients with type 2 diabetes initiated with metformin monotherapy had longer survival than did matched, non-diabetic controls. Those treated with sulphonylurea had markedly reduced survival compared with both matched controls and those receiving metformin monotherapy. This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in non-diabetes. Sulphonylurea remains a concern.
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