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Patient Requesting Drug Treatment for Insulin Resistance

A healthy 31-year-old patient requests a prescription for rosiglitazone because he had insulin resistance. He had seen a movie shown by an endocrinologist that said anyone with insulin resistance should be on medication. He then had an insulin resistance test done and requested the medication. Should this patient be given a prescription for rosiglitazone?

Yes
No

When glycemic benefit is coupled with treatment of insulin resistance, both metformin and the thiazolidinediones are highly effective and reasonable agents and their use should be encouraged; but, at present, there is no convincing evidence that such an approach is appropriate for the person described.

Discussion:
Insulin resistance is a common condition affecting some 47 million persons in the United States.[1] The condition is easily diagnosable by assessing a patient for the characteristics of the metabolic syndrome: waist circumference > 102 cm (40 in) in men and > 88 cm (35 in) in women; serum triglyceride > 150 mg/dL; HDL-C < 40 mg/dL in men and < 50 mg/dL in women; blood pressure > 130/85 mm Hg; serum glucose > 110 mg/dL. Anyone with 3 or more of these findings (and probably anyone with 2 or more) has the syndrome, and hence has insulin resistance. Although body weight measurement is not required, if the waist circumference is measured, one should certainly also assess the degree of overweight, with body mass index > 30 kg/m2 indicative of obesity. If this set of clinical measurements outlines the "insulin resistance test" performed for the patient described, one would presume that the physician had already assessed these factors in routine management.

Although it is a complex topic, one should note that there is no good clinical test for insulin sensitivity, with measurement of fasting insulin and glucose being most widely used but actually only being sensitive to the more extreme degrees of insulin resistance, and hence likely to miss the majority of persons who have this abnormality. Low HDL cholesterol and high blood pressure appear to convey most of the increased cardiac risk of the syndrome,[2] and therefore would be the most logical therapeutic targets. Indeed, there is excellent evidence that fibrate treatment[3] is particularly beneficial for persons with low HDL and insulin resistance, and certainly our approaches to antihypertensive treatment now emphasize achievement of very low BP targets using a variety of therapeutic modalities.

Metabolic syndrome is also the precursor state for many -- although not all -- cases of type 2 diabetes, and as such one might consider the use of diabetes treatment before the development of actual diabetes. A number of studies have analyzed such an approach.

The Diabetes Prevention Program[4] compared a placebo group of 1082 persons with impaired glucose tolerance with 1073 persons who were treated with metformin 850 mg twice daily and with 1079 persons who participated in a program of moderate exercise (at least 150 min/week) and weight loss of at least 7% of body weight using one-on-one intensive lifestyle modification instruction. At 4 years, 29%, 22%, and 14% of the 3 groups had developed diabetes. In a study of women who had had gestational diabetes that compared placebo with troglitazone 400 mg daily, 53% vs 19% developed diabetes over the subsequent 5 years.[5] The STOP-NIDDM Trial showed similar effects for the alpha-glucosidase inhibitor acarbose.[6] Thus, lifestyle modification is certainly indicated for the person described. Such an approach has an excellent chance of preventing diabetes, as well as offering benefit in modifying cardiovascular risk factors. No pharmacologic approach is more effective and none would be as safe! Metformin causes gastrointestinal side effects in approximately one quarter of persons who use it, although most are able to tolerate this. Acarbose also causes gastrointestinal side effects, which unfortunately appear to be socially unacceptable to most patients in the United States, although not in other countries, and the drug is quite popular for diabetes treatment in Germany and Spain. Troglitazone is, of course, no longer available because of the rare but major side effect of hepatotoxicity. The available thiazolidinediones, rosiglitazone and pioglitazone, cause fluid retention, particularly in persons with an underlying tendency. These drugs also cause weight gain, averaging 5-10 pounds but considerably greater in perhaps one quarter of patients. When glycemic benefit is coupled with treatment of insulin resistance, both metformin and the thiazolidinediones are highly effective and reasonable agents and their use should be encouraged; but, at present, there is no convincing evidence that such an approach is appropriate for the person described.

References
1. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287:356-359. Abstract
2. Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210-1214. Abstract
3. Robins SJ, Rubins HB, Faas FH, et al. Insulin resistance and cardiovascular events with low HDL cholesterol. The Veterans Affairs HDL Intervention Trial (VA-HIT). Diabetes Care. 2003;26:1513-1517. Abstract
4. Knowler WC, Barrett-Connor E, Fowler SE, et al. Diabetes prevention program research group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. Abstract
5. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes. 2002;51:2796-2803. Abstract
6. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trail Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072-2077. Abstract

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