A systematic review of metformin treatment in
persons at risk for diabetes mellitus

http://www.cardiologyreviewonline.com/issues/articles/2008-07_01.asp

by Shelley R. Salpeter, MD

From the Santa Clara Valley Medical Center, San Jose, and Stanford University School
of Medicine, Stanford, CA.

Diabetes mellitus is a significant risk factor for cardiovascular morbidity and mortality,
and its prevalence has reached epidemic proportions in the United States.1,2
Dyslipidemia, high blood pressure, a family history of diabetes, obesity, insulin
resistance, polycystic ovary syndrome, and physical inactivity are risk factors for
diabetes.3 The metabolic syndrome, which is characterized by obesity, hypertension,
insulin resistance, and dyslipidemia, carries significant risk.4 The 2 most important
methods of decreasing new-onset diabetes are lifestyle modifications, such as diet
and exercise, and treatment with metformin (Fortamet, Glucophage, Riomet), which
decreases insulin resistance and weight.5 A recent meta-analysis evaluated the
metabolic effects of metformin treatment in individuals at risk for diabetes.6

TIME-SAVER
A recent meta-analysis of 31 randomized controlled trials with 4500 participants
showed that metformin treatment significantly decreased weight, improved
dyslipidemia and insulin resistance, and reduced the incidence of new-onset diabetes
by 40%, with beneficial effects maintained over time. Further studies will show
whether the metabolic improvements achieved with metformin treatment will
ultimately result in a decrease in cardiovascular morbidity and mortality.
Subjects and methods
Electronic databases and selected journals were reviewed for randomized controlled
trials that compared metformin treatment with placebo or no treatment in individuals
at risk for diabetes; trials were included if they lasted 8 weeks or longer and provided
information on the development of new-onset diabetes or supplied metabolic
parameters. Net treatment effects were pooled for each variable measured to
determine weighted mean differences with 95% confidence intervals (CIs). We
obtained a summary odds ratio and absolute risk difference by pooling the proportion
of subjects with new-onset diabetes to subjects without diabetes from each trial.
Subgroup analyses evaluated the differences in results for subjects with and without
obesity (body mass index [BMI] >30 kg/m2) and for those with and without polycystic
ovary syndrome.

Results
Of the 2000 studies identified by the search, the inclusion criteria were met by 31
studies, with a total of 4570 participants followed for 8267 patient-years.6 The
average length of the trials was 1.8 years, with an average metformin dose of 1.6
g/day (range, 500-2550 mg/day).

Among subjects receiving metformin, BMI decreased by 5.3% (95% CI, 4.0%-6.7%)
compared with placebo and 5.9% from baseline. Statistically significant reductions in
BMI were observed in individuals with and without polycystic ovary syndrome, with
and without obesity, and in those taking a higher-than-average or
lower-than-average daily dose of metformin.

Low-density lipoprotein (LDL) cholesterol levels decreased by 5.6% (95% CI,
3.0%-8.3%) and high-density lipoprotein (HDL) cholesterol levels increased by 5.0%
(95% CI, 1.6%-8.3%) among those taking metformin. Furthermore, triglyceride levels
decreased by 5.3% (95% CI, 0.03%-10.5%), and the LDL/HDL ratio decreased by
8.5% (95% CI, 2.6%-14.0%).

Compared with no treatment or placebo, metformin treatment reduced
new-onset diabetes by 40%, with a pooled odds ratio of 0.6 (95% CI, 0.5-0.8).
Metformin was shown to decrease the absolute risk of diabetes by 6% (95% CI,
4%-8%) over an average period of 1.8 years, when all trials with and without
new cases of diabetes were pooled together.

Discussion
Based on data from 31 randomized controlled trials, HDL cholesterol levels were
significantly increased, and triglyceride levels, LDL cholesterol levels, BMI, fasting
glucose levels, and insulin resistance were significantly decreased among subjects at
risk for diabetes who received metformin treatment. Furthermore, the risk of
developing new-onset diabetes was decreased by 40% with metformin, with an
absolute risk reduction of 6% over the trial duration. This indicates that only 17
subjects would need to be treated for 1.8 years to prevent 1 case of diabetes
mellitus.

The trials in this meta-analysis assessed different populations of persons with risk
factors for diabetes, including dyslipidemia, high blood pressure, peripheral vascular
disease, polycystic ovary syndrome, obesity, abdominal obesity, glucose intolerance
or insulin resistance, a family history of diabetes, and metabolic syndrome. Subjects
with and without obesity as well as those with and without poly-cystic ovary
syndrome experienced similar improvements in metabolic parameters; these results
were observed in adults, adolescents, and children alike.

Other favorable cardiovascular benefits were shown with metformin treatment in the
trials we evaluated, including decreases in tissue-type plasminogen activator antigen,
urinary albumin excretion, the incidence of metabolic syndrome, left ventricular mass,
systolic and diastolic blood pressures, waist-to-hip ratio, waist circumference, and
visceral fat mass.6 Metformin has been extensively studied in patients with polycystic
ovary syndrome. Patients with this condition generally exhibit insulin resistance,
obesity, dyslipidemia, hyperandrogenism, infertility, and anovulation. Metformin has
been shown to stimulate ovulation, increase pregnancy rates, and markedly decrease
systolic and diastolic blood pressures among these patients.

Because most of the trials included in the meta-analysis recommended lifestyle
interventions, such as diet and exercise, in the treatment and control groups, the
metabolic effects shown in our analysis were a result of treatment plus lifestyle
modification, although the extent to which lifestyle modification was followed is not
known. Two trials specifically compared the effects of metformin treatment with
lifestyle modification on the development of new-onset diabetes.5,10 The pooled
results show that lifestyle modification was significantly more effective than treatment
with metformin. Compared with either metformin treatment alone or lifestyle
modification alone, the greatest decreases in weight occurred with the combination of
metformin treatment and intensive lifestyle modifications.12

It is not known whether metformin reduces diabetes strictly through its effect on
weight or whether other mechanisms are at work, such as a direct action on insulin
resistance. Subgroup analysis of this meta-analysis showed that metformin produced
equivalent weight loss in nonobese and obese patients. Obesity and insulin
resistance usually precede the development of diabetes, and weight loss through
lifestyle modifications decreases insulin resistance and new-onset diabetes, such that
a 1% decrease in weight results in a 5% reduction in insulin resistance and a 5% to
15% decrease in diabetes.5 In this meta-analysis, for each 1% decrease in BMI,
metformin decreased insulin resistance by 5% and new-onset diabetes by 8%,
indicating that the main mechanism of action of metformin is probably achieved
through weight loss.

Metformin has a direct effect on reducing fasting blood glucose levels, so it is possible
that the diagnosis of diabetes in the trials was affected by a direct pharmacologic
action of metformin on glucose. One study evaluated that effect by measuring
glucose tolerance tests 2 weeks after the discontinuation of the trial. Compared with
placebo, metformin still significantly decreased the risk of diabetes, even after the
direct pharmacologic effects had resolved.13

There is some evidence that, over time, the metabolic changes that occur in
individuals at risk for diabetes and taking metformin decrease cardiovascular risk.14
This effect would not be unexpected, as obesity, dyslipidemia, insulin resistance,
hyperglycemia, and diabetes increase the risk of cardiac events and death. Metformin
treatment among individuals at risk for diabetes might possibly increase life
expectancy, at a cost of $1800 per quality-adjusted life-year gained, according to a
cost-effectiveness analysis.15

Metformin has been shown to be safe since its introduction 50 years ago.16 The chief
side effects are mild nausea, abdominal discomfort, and diarrhea. Some patients
treated with metformin, as well as those treated with sulfonylureas and insulin, have
been reported to develop lactic acidosis, which is a rare metabolic disorder
associated with such serious metabolic conditions as renal failure and shock.17 A
meta-analysis assessing the association between the risk of lactic acidosis and
metformin showed no cases of lactic acidosis in almost 50,000 patient-years of
metformin use.17 Approximately 96% of the trials had allowed for the inclusion of at
least 1 of the standard contraindications to metformin. This indicates that there is no
evidence that metformin actually increases the risk of lactic acidosis under the
present conditions of use.

Another class of drugs used for the treatment of diabetes is thiazo-lidinediones
(rosiglitazone [Avan-dia] and pioglitazone [Actos]). Like metformin, these agents
decrease insulin resistance and can decrease the risk of new-onset diabetes. One
study showed a 60% decrease in the development of diabetes over 3 years among
individuals at risk for diabetes who took rosiglitazone.18 Compared with placebo,
however, treatment was associated with a 7-fold increase in congestive heart failure
and a 3% increase in weight. Treatment with rosiglita-zone in patients with diabetes
was shown to be associated with a nonsignificant trend toward increased mortality
from all cardiovascular causes and a significant 45% increase in myocardial infarction
in a recent meta-analysis.19

Conclusion
Significant improvements in weight, lipid profiles, fasting glucose levels, and insulin
resistance, as well as a 40% decrease in the progression to new-onset diabetes over
time, have been shown with metformin treatment among individuals at risk for
diabetes. Studies have shown that the most successful strategy to decrease weight
and the incidence of diabetes is to implement intensive lifestyle modifications in
persons at risk for diabetes, although long-term sustained effects are difficult to
achieve. The available evidence indicates that metformin now can be added to
lifestyle interventions as an approach to the prevention of diabetes. The results of
new long-term studies will show whether the metabolic improvements achieved with
metformin treatment will ultimately result in a decrease in cardiovascular morbidity
and mortality.
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