Treatment of Pre-Diabetes
March 22, 2012 — Long-term treatment with metformin is safe for preventing or delaying the development of type 2 diabetes, according to an article published in the April issue of Diabetes Care.
New data from the open-label Diabetes Prevention Program Outcomes Study (DPPOS) demonstrate that metformin is linked to "modest but durable weight loss" of 2% body weight over the course of 10 years, and appears to be safe and well tolerated.
The findings support the conclusions of the original 3-year DPP double-blind
study showing that use of metformin (850 mg twice daily) encouraged
stable weight loss. In both the metformin and placebo groups, weight loss was a
strong predictor of diabetes prevention.
According to the Diabetes Prevention Program Research Group, the pattern of
metformin-associated weight loss appears to differ from that observed
with caloric restriction, in that adipose tissue is affected more than lean
tissue mass. Metformin may also mimic the effects of exercise.
As previously reported by Medscape Medical News, metformin therapy may represent a more cost-effective alternative to lifestyle changes for preventing diabetes.
"We now know how to prevent type 2 diabetes and have the data to show that
doing so is not only safe, it is cost-effective," said Vivian
Fonseca, MD, president, medicine and science, American Diabetes Association, in
a news release. "We should be taking much greater steps on a broad
scale to reduce this serious health epidemic in our country.... I would
encourage every American to estimate their own risk using simple
tools (for example see diabetes.org/risktest)
and then, if at risk, take simple measures to prevent the disease."
Metformin Linked to Modest but Durable Weight Loss Over the Course of 10 Years
In the DPP, overweight and obese participants with impaired glucose
tolerance were randomly assigned to lifestyle intervention,
metformin, or placebo. Results reported in 2002 indicated that metformin
therapy resulted in a 31% reduction in the development of diabetes
during an average 2.8 years of follow-up.
During the study, participants randomly assigned to receive metformin
experienced a decrease in body weight and waist circumference
relative to placebo (mean, 2.06% ± 5.65% vs 0.02% ± 5.52%, and 2.13 cm ± 7.06
cm vs 0.79 cm ± 6.54 cm, respectively; P < .001 for
both).
Throughout the unblinded follow-up study that covered 10 years from the
start, weight loss remained significantly greater in the metformin
group relative to placebo (2.0% vs 0.2%; P < .001), and
was directly associated with the degree of therapeutic compliance (
P < .001).
Participants highly adherent to metformin therapy achieved a weight loss of
3.5% (3.1 kg, 6.8 pounds), whereas those in the low-adherence group
experienced an initial weight loss followed by weight changes similar to
placebo until 5 years, at which point weight increased.
The authors note that waist circumference increased after 2 years, with the
exception of highly adherent participants for whom the increase
occurred after the 5-year point. Because body weight did not increase, the
authors deduced that central adiposity was increased by a
redistribution of body fat.
"[M]etformin-induced weight loss is almost exclusively confined to
reductions in adipose mass with little change in lean tissue," the
authors write, emphasizing that the pattern is different than that observed with
caloric restriction, which tends to induce loss of lean, as well as
adipose, tissue.
The authors also note that metformin also has several effects on energy
metabolism that parallel physical exercise, such as phosphorylation
of AMP-activated protein kinase, which is an important regulator of
mitochondrial biogenesis, hepatic and muscle fatty acid oxidation,
glucose transport, insulin secretion, and lipogenesis.
"Collectively, the clinical data suggesting 'durable weight loss' combined
with the proposed cellular effects on energy metabolism continue to
support metformin as a viable strategy for widespread translational efforts in
prevention," comments William T. Cefalu, MD, from the Pennington
Biomedical Research Center at Louisiana State University in Baton Rouge, in an
accompanying editorial.
Long-Term Use of Metformin Is Generally Safe and Well-Tolerated
During the DPP through year 4, metformin-treated participants reported study
drug–related gastrointestinal symptoms more frequently than those
receiving placebo (9.5% vs 1.1%; P < .001). Reports declined over time, and rates were similar between groups during years 6 through 9 ( P > .10).
Nonserious hypoglycemia and anemia were uncommon, and occurred at similar
rates in metformin and placebo participants during nearly 18,000
patient-years of follow-up (n = 7 vs 8 and 50 vs 38, respectively). Serious
adverse events were rare: there were only 3 reports of anemia
(metformin, 2; placebo, 1), and no reports of lactic acidosis or hypoglycemia.
During the DPP, average hemoglobin and hematocrit declined slightly during
the first year among metformin-treated participants, but remained
stable thereafter (13.6 mg/dL vs 13.8 mg/dL and 40.6% vs 41.1%;
P < .001 for both).
Although the proportion of participants with low hemoglobin was similar
between groups (11.2% vs 7.6%; P = .17), low hematocrit was
more common among metformin-treated participants (12.6% vs 8.4%;
P = .035).
The authors note that 12% of DPP participants chose not to continue into the
follow-up study, potentially because of adverse events that may have
influenced the safety and tolerability profile observed.
The study was funded by the National Institute of Diabetes and Digestive
and Kidney Diseases of the National Institutes of Health.
Bristol-Myers Squibb and Parke-Davis provided additional funding and material
support during the DPP. Lipha (Merck-Sante) provided medication,
and LifeScan Inc donated materials, during the DPP and DPPOS. One coauthor
reports receiving grants from Novo Nordisk, the Swedish Heart-Lung
Foundation, the Swedish Diabetes Association, and the Swedish Research Council.
The other authors and Dr. Cefalu have disclosed no relevant
financial relationships.
Diabetes Care. 2012;35:663-665, 731-737.
New data from the open-label Diabetes Prevention Program Outcomes Study (DPPOS) demonstrate that metformin is linked to "modest but durable weight loss" of 2% body weight over the course of 10 years, and appears to be safe and well tolerated.
The findings support the conclusions of the original 3-year DPP double-blind
study showing that use of metformin (850 mg twice daily) encouraged
stable weight loss. In both the metformin and placebo groups, weight loss was a
strong predictor of diabetes prevention.
According to the Diabetes Prevention Program Research Group, the pattern of
metformin-associated weight loss appears to differ from that observed
with caloric restriction, in that adipose tissue is affected more than lean
tissue mass. Metformin may also mimic the effects of exercise.
As previously reported by Medscape Medical News, metformin therapy may represent a more cost-effective alternative to lifestyle changes for preventing diabetes.
"We now know how to prevent type 2 diabetes and have the data to show that
doing so is not only safe, it is cost-effective," said Vivian
Fonseca, MD, president, medicine and science, American Diabetes Association, in
a news release. "We should be taking much greater steps on a broad
scale to reduce this serious health epidemic in our country.... I would
encourage every American to estimate their own risk using simple
tools (for example see diabetes.org/risktest)
and then, if at risk, take simple measures to prevent the disease."
Metformin Linked to Modest but Durable Weight Loss Over the Course of 10 Years
In the DPP, overweight and obese participants with impaired glucose
tolerance were randomly assigned to lifestyle intervention,
metformin, or placebo. Results reported in 2002 indicated that metformin
therapy resulted in a 31% reduction in the development of diabetes
during an average 2.8 years of follow-up.
During the study, participants randomly assigned to receive metformin
experienced a decrease in body weight and waist circumference
relative to placebo (mean, 2.06% ± 5.65% vs 0.02% ± 5.52%, and 2.13 cm ± 7.06
cm vs 0.79 cm ± 6.54 cm, respectively; P < .001 for
both).
Throughout the unblinded follow-up study that covered 10 years from the
start, weight loss remained significantly greater in the metformin
group relative to placebo (2.0% vs 0.2%; P < .001), and
was directly associated with the degree of therapeutic compliance (
P < .001).
Participants highly adherent to metformin therapy achieved a weight loss of
3.5% (3.1 kg, 6.8 pounds), whereas those in the low-adherence group
experienced an initial weight loss followed by weight changes similar to
placebo until 5 years, at which point weight increased.
The authors note that waist circumference increased after 2 years, with the
exception of highly adherent participants for whom the increase
occurred after the 5-year point. Because body weight did not increase, the
authors deduced that central adiposity was increased by a
redistribution of body fat.
"[M]etformin-induced weight loss is almost exclusively confined to
reductions in adipose mass with little change in lean tissue," the
authors write, emphasizing that the pattern is different than that observed with
caloric restriction, which tends to induce loss of lean, as well as
adipose, tissue.
The authors also note that metformin also has several effects on energy
metabolism that parallel physical exercise, such as phosphorylation
of AMP-activated protein kinase, which is an important regulator of
mitochondrial biogenesis, hepatic and muscle fatty acid oxidation,
glucose transport, insulin secretion, and lipogenesis.
"Collectively, the clinical data suggesting 'durable weight loss' combined
with the proposed cellular effects on energy metabolism continue to
support metformin as a viable strategy for widespread translational efforts in
prevention," comments William T. Cefalu, MD, from the Pennington
Biomedical Research Center at Louisiana State University in Baton Rouge, in an
accompanying editorial.
Long-Term Use of Metformin Is Generally Safe and Well-Tolerated
During the DPP through year 4, metformin-treated participants reported study
drug–related gastrointestinal symptoms more frequently than those
receiving placebo (9.5% vs 1.1%; P < .001). Reports declined over time, and rates were similar between groups during years 6 through 9 ( P > .10).
Nonserious hypoglycemia and anemia were uncommon, and occurred at similar
rates in metformin and placebo participants during nearly 18,000
patient-years of follow-up (n = 7 vs 8 and 50 vs 38, respectively). Serious
adverse events were rare: there were only 3 reports of anemia
(metformin, 2; placebo, 1), and no reports of lactic acidosis or hypoglycemia.
During the DPP, average hemoglobin and hematocrit declined slightly during
the first year among metformin-treated participants, but remained
stable thereafter (13.6 mg/dL vs 13.8 mg/dL and 40.6% vs 41.1%;
P < .001 for both).
Although the proportion of participants with low hemoglobin was similar
between groups (11.2% vs 7.6%; P = .17), low hematocrit was
more common among metformin-treated participants (12.6% vs 8.4%;
P = .035).
The authors note that 12% of DPP participants chose not to continue into the
follow-up study, potentially because of adverse events that may have
influenced the safety and tolerability profile observed.
The study was funded by the National Institute of Diabetes and Digestive
and Kidney Diseases of the National Institutes of Health.
Bristol-Myers Squibb and Parke-Davis provided additional funding and material
support during the DPP. Lipha (Merck-Sante) provided medication,
and LifeScan Inc donated materials, during the DPP and DPPOS. One coauthor
reports receiving grants from Novo Nordisk, the Swedish Heart-Lung
Foundation, the Swedish Diabetes Association, and the Swedish Research Council.
The other authors and Dr. Cefalu have disclosed no relevant
financial relationships.
Diabetes Care. 2012;35:663-665, 731-737.