Should metformin be used to prevent diabetes in
high-risk patients?

http://www.cardiologyreviewonline.com/issues/articles/2008-07_03.asp

Byron Hoogwerf, MD, is a Cleveland Clinic Staff Physician, Department of
Endocrinology and the Preventive Cardiology Clinic, Cleveland Clinic, Cleveland, OH.

Lifestyle1,2 and pharmacologic efforts1,3,4 to reduce the risk of new-onset diabetes
mellitus have been the subject of multiple investigations. Retrospective and
prospective studies have suggested benefits with use of glucose-lowering
agents,1,4,5 angiotensin-converting enzyme inhibitors, and angiotensin receptor
blockers.3 The article by Salpeter and colleagues is a meta-analysis of the metformin
studies.6 As outlined by the authors' use of metformin is an appealing option
because it is safe, produces few side effects, and is a cost-effective way to target
some of the defects known to contribute to the metabolic defects associated with
diabetes.

The Diabetes Prevention Program, tested durability of effect, but only for a 2-week
period. The trial showed that metformin reduced the incidence of diabetes by 31% as
compared with placebo. The reduction after only a 2-week washout was 25%.  
Furthermore, data from the United Kingdom Prospective Diabetes Study (UKPDS)
demonstrated quite clearly that metformin use does not slow the progressive loss of
beta cell function, which is one of the major defects in diabetes.  Based on these
considerations, the authors' conclusions about the magnitude of the effect of
metformin should be interpreted cautiously.

The authors have noted that metformin has a number of favorable effects on risk
factors associated with coronary artery disease (CAD). Use of this drug in the UKPDS
trial was associated with a 39% reduction in the risk for myocardial infarction in
obese patients compared with conventional treatment. The UKPDS was clearly an
"impact" trial, but it was carried out at a time when statin therapy was not in use,
blood pressure goals were higher than currently recommended, and many of the
strategies for risk reduction were not in place; thus, the inference that the favorable
effects of metformin on obesity, insulin resistance, and lipids would likely reduce CAD
risk may be correct. Nevertheless, in the absence of clinical outcomes data, cautious
interpretation is advisable.

The authors contrast their study with recent thiazolidinedione (TZD) studies, which
have shown a reduction in diabetes risk and suggest a "durable" effect.4,5 However,
the authors point out that this class of agents may have unacceptable adverse side
effects, including an increased risk for CAD and heart failure. Durability of effect on
glucose control also has been supported by data from A Diabetes Outcomes
Progression Trial (ADOPT), in which glycemic control was maintained for longer
periods of time with rosiglitazone than with metformin.10 The effects of TZDs on
exacerbating heart failure are well known, but were very low in the Diabetes
Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study; the
patients in this trial were similar to those studied in the authors' meta-analysis.4

The meta-analysis by Nissen and Wolski11 found that rosiglitazone was associated
with a significantly increased risk of myocardial infarction and death from
cardiovascular causes; however, this study has been criticized for the use of a
random effects model in subjects from studies that were clearly heterogeneous (eg, a
nondiabetic cohort in DREAM4 and a diabetic cohort in ADOPT10).

The recent Action to Control Cardiovascular Risk in Diabetes trial,12 which assessed a
population at high risk for CAD and carefully characterized each patient and had
well-adjudicated end points, does not confirm that the small increase in all-cause
mortality was attributable to any adverse effect of TZDs. In fact, the study showed a
reduction in atherosclerotic disease events of about 10% (P = NS). In light of the
recent clinical trial data, the somewhat negative picture of TZDs painted by the
authors needs more cautious interpretation. I think there may be a role for the use of
metformin in patients at risk of developing diabetes, but widespread use of this drug
has not yet become the clinical norm.

References
1.        Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of
type 2 diabetes with lifestyle intervention or metformin. N Engl J Med.
2002;346(6):393-403.
2.        Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes
mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N
Engl J Med. 2001; 344(18):1343-1350.
3.        Andraws R, Brown DL. Effect of inhibition of the renin-angiotensin system on
development of type 2 diabetes mellitus (meta-analysis of randomized trials). Am J
Cardiol. 2007;99(7):10061012.
4.        Gerstein HC, Yusuf S, Bosch J, et al. Effect of rosiglitazone on the frequency of
diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a
randomised controlled trial. Lancet. 2006;368(9541):1096-1105.
5.        Knowler WC, Hamman RF, Edelstein SL, et al. Prevention of type 2 diabetes
with troglitazone in the Diabetes Prevention Program. Diabetes. 2005;
54(4):1150-1156.
6.        Salpeter SR, Buckley NS, Kahn JA, et al. Meta-analysis: metformin treatment in
persons at risk for diabetes mellitus. Am J Med. 2008;121(2):149-157.
7.        Diabetes Prevention Program Research Group. Effects of withdrawal from
metformin on the development of diabetes in the diabetes prevention program.
Diabetes Care. 2003;26(4): 977-980.
8.        UK Prospective Diabetes Study (UKPDS) Group. UK prospective diabetes study
16. Overview of 6 years' therapy of type 2 diabetes: a progressive disease. Diabetes.
1995; 44(11):1249-1258.
9.        UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive
blood-glucose control with metformin on complications in overweight patients with
type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854-865.
10.        Viberti G, Kahn SE, Greene DA, et al. A diabetes outcome progression trial
(ADOPT): an international multicenter study of the comparative efficacy of
rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes.
Diabetes Care. 2002; 25(10):1737-1743.
11.        Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction
and death from cardiovascular causes. N Engl J Med. 2007; 356(24):2457-2471.
12.        Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC,
Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes.
N Engl J Med. 2008;358(24):2545-2559.
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