REVIEW Weight gain associated with antidiabetic medications Diabetes has emerged as the major epidemic of modern times, with obesity, particularly central obesity, being a major risk factor for Type 2 diabetes and its attendant cardiovascular disease. Furthermore, weight reduction has been shown to prevent Type 2 diabetes in people with prediabetes and to improve glycemic control and reduce cardiovascular disease risk in the diabetic population. Weight gain is a major problem that faces physicians striving to achieve adequate glycemic, blood pressure and lipid control for their diabetic patients. The use of antidiabetic agents, particularly insulin, insulin secretagogs and thiazolidinediones, has long been associated with weight gain, not only complicating the management of diabetes but also sending mixed messages to patients who are being asked to lose weight. This article presents the effects of antidiabetic medications on bodyweight, explaining the potential mechanisms of weight gain and also discusses the available therapeutic options that could achieve better glycemic control without adverse effects on bodyweight or, even better, cause weight loss. 1 KEYWORDS: antidiabetic medications n insulin n sulfonylurea n thiazolidinedione Alfrede Provilus , n weight gain Marie Abdallah2 & Samy I McFarlane†1 Obesity in diabetic populations had high frequencies of hypertension (88%) 1Division of Endocrinology, Medical Most people with Type 2 diabetes are either and hyperlipidemia (81%), as well as micro- Director of Clinical Research, College of Medicine, State University of New York overweight or obese, with up to 90% of peo- albuminuria (29%) [5]. Interestingly, control of – Downstate Medical Center, ple with diabetes being overweight at diagno- blood pressure, a major risk factor for CVD in 450 Clarkson Avenue, Box 50, Brooklyn, New York, 11203, USA sis [1]. These patients continue to gain weight this population, to a goal of 130/80 mmHg was 2Staten Island University Hospital, over time, with the exception of the postdiag- only achieved in 11% of patients [5]. Data for Staten Island, NY, USA †Author for correspondence: nosis period where patients are educated and various ethnic minorities demonstrated a high Tel.: +1 718 270 3711 encouraged to lose weight for better control of prevalence of obesity and poor control of CVD Fax: +1 718 270 6358 [email protected] their illness [1]. While risk factors for diabetes risk factors in patients with diabetes [6,7]. In include increased age, hypertension, sedentary studies conducted in 2001 and 2004, less than lifestyle, family history of diabetes and ethnic 5% of diabetic patients achieved blood pressure, minorities (BOX 1) [2], obesity is one of the most glycemic and lipid control simultaneously [6,7]. important risk factors for insulin resistance, Type 2 diabetes patients generally gain Type 2 diabetes and cardiovascular disease weight throughout the course of the disease. (CVD) [3]. Central obesity clusters with other This weight gain is associated with worsening cardiovascular risk factors in people with dia- glycemic control and further increases CVD betes and is a major component of the meta- risk factors [8]. For example, in a follow-up bolic syndrome [3,4]. CVD risk factors include study of 1292 women with coronary heart dis- insulin resistance, low high-density lipoprotein ease (CHD), higher levels of bodyweight within cholesterol, increased triglyceride levels, small the ‘normal’ range, as well as modest weight dense low-density lipoprotein cholesterol, systo- gain after 18 years of age, increased risks of lic hypertension, absence of nocturnal decline CHD significantly, with a 5–11 kg increase in in pulse and blood pressure, increased oxida- bodyweight associated with a 25–65% increase tive stress and endothelial dysfunction, among in CHD risk [9]. This risk is increased further o thers (BOX 2) [3,4]. with the aggregation of other CVD risk factors, A high prevalence of CVD risk factors asso- such as hypertension and dyslipidemia associ- ciated with obesity has been demonstrated in ated with weight gain [8]. Weight gain has del- large studies. In the Swedish National Diabetes eterious effects on glycemic control and other Register, a cross-sectional ana lysis involving CVD risk factors, including hypertension and 44,042 Type 2 diabetes patients, with a 6-year dyslipidemia, thus limiting the ability of the prospective study of 4468 Type 2 diabetes diabetic patients to comply with the treatment patients, obese patients with diabetes (37%) regimens [8]. Weight gain also sends mixed 10.2217/THY.11.8 © 2011 Future Medicine Ltd Therapy (2011) 8(2), 113–120 ISSN 1475-0708 113 REVIEW Provilus, Abdallah & McFarlane Weight gain associated with antidiabetic medications REVIEW Box 1. Risk factors for Type 2 diabetes. and have resulted in significant reduction and Age >45 years improvement in metabolic outcomes and car- Overweight (e.g., BMI ≥25 kg/m2) diovascular risk [17]. As such, they have been Lifestyle (physical inactivity, high-caloric, made into recommendations by major medical high-fat intake) associations [18]. Family history of Type 2 diabetes (parents or siblings) Benefits of weight loss in diabetes Ethnic minorities The degree of caloric restriction and the mag- Gestational diabetes nitude of weight loss in the diabetic population Hypertension have independent effects on improvements in Dyslipidemia (low HDL-cholesterol, high glycemic control and insulin sensitivity [19], triglyceride levels) particularly with the use of low carbohydrate Impaired fasting glucose (≥100 to ≤125 mg/dl) Impaired glucose tolerance (2 h plasma diets leading some to discontinue antidiabetic glucose ≥140 mg/dl) medications altogether for selected patients [20]. Spouse with Type 2 diabetes mellitus Weight loss improves glycemic control in diabe- tes and, more importantly, decreases the overall messages to the patients who are advised to lose mortality in this patient population above and weight as a major component of their treatment beyond glycemic control [21]. In the American plan in order to gain better glycemic control. Cancer Society’s (ACS) Cancer Prevention Study, a prospective ana lysis with a 12-year Antidiabetic medications mortality follow-up of 4970 overweight dia- & weight gain betic patients aged 40–64 years, intentional Major therapeutic classes of medications used weight loss was reported by 34% of the cohort. for Type 2 diabetes, such as insulin, sulfonyl- After adjustment for initial BMI, sociodemo- ureas (SUs) and thiazolidinediones, have been graphic factors, health status and physical associated with weight gain [10,11], with the activity, weight loss was associated with a 25% potential to offset the beneficial effects of gly- reduction in total mortality and a 28% reduc- cemic control [8]. Landmark trials, such as the tion in CVD and diabetes mortality. In this UK Prospective Diabetes Study (UKPDS) [12], study, weight loss of 9.1–13.2 kg was associ- clearly established the beneficial effects of tight ated with the greatest reductions in mortality glucose control on microvascular complica- (~33%) [21]. These data collectively indicate tions in Type 2 diabetes. In this study, weight that weight loss is not only beneficial in terms gain was significantly higher in the intensive of glycemic control, but is also associated with group (mean: 2.9 kg) compared with the reduced mortality from CVD, the major cause conventionally treated arm (p < 0.001) and of death in diabetes. patients assigned insulin had a significantly higher weight gain (4.0 kg) compared with Antidiabetic medications those assigned chlorpropamide (2.6 kg) or & weight gain g libenclamide (1.7 kg) [12]. n Insulin secretagogs Antidiabetic agents, such as SU, repaglinide Weight reduction & prevention of and nateglinide, are collectively termed insu- Type 2 diabetes lin secretagogs; they act mainly by increasing Weight reduction has been shown to reduce the insulin secretion through stimulation of SU rate of diabetes in high-risk prediabetic popula- receptors [22]. Studies involving SU gener- tions [13,14]. Two major large-scale trials from ally demonstrate a tendency towards weight Finland and the USA (the Finnish Diabetes gain [8]. For example, in the European GlUcose Study and the Diabetes Prevention Program) control in Type 2 diabetes: Diamicron MR ver- have shown consistent results in terms of pre- sus glimEpiride (GUIDE) study, the first large- vention of Type 2 diabetes with lifestyle changes scale, head-to-head comparison of two SUs that included weight loss of approximately 6.8 kg designed for once-daily administration used over 36 months [15,16]. The magnitude of pre- under conditions of everyday clinical prac- vention of Type 2 diabetes with lifestyle inter- tice, 845 patients with Type 2 diabetes were ventions was almost twice that achieved with randomized to either gliclazide or glimepiride medications such as metformin [16]. These strate- in a double-blind, 27-week, parallel-group gies have been shown to be beneficial in people design [23]. A1c was reduced to a similar degree with prediabetes and the metabolic syndrome, in the two groups (by 1.1 and 1%, respectively) 114 Therapy (2011) 8(2) future science group REVIEW Provilus, Abdallah & McFarlane Weight gain associated with antidiabetic medications REVIEW and bodyweight increased by approximately Weight gain of 3.8 kg over a 3-year period 0.6 kg in the two groups [23]. Similarly, weight with the use of pioglitazone was observed in gain