Anti-Diabetes and Anti-Obesity Medications: Effects on Weight in People with Diabetes
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In Brief to Practice / The Art and Science of Obesity Management Research From Choosing medications for people with diabetes involves consideration of a number of factors, including effects on weight. Improvements in glucose control are often linked to weight gain, but this does not have to be the inevitable result of diabetes treatment. Adding a drug that either promotes weight-loss or is weight neutral to one that promotes weight gain and pro- viding medical nutrition therapy can be considered. Anti-Diabetes and Anti-Obesity Medications: Effects on Weight in People With Diabetes The current approach to the treatment trials of intensified diabetes therapy of both type 1 and type 2 diabetes is in both type 1 and type 2 diabetes, Priscilla Hollander, MD to achieve the best possible glucose most notably the Diabetes Control control. Past clinical trials have shown and Complications Trial (DCCT), the that glycemia plays a key role in the Kumamoto Study, and the U.K. Pro- prevention of both macro- and micro- spective Diabetes Study (UKPDS).1–3 vascular complications.1–5 The current One of the main factors in weight American Diabetes Association (ADA) gain in patients who intensify therapy guidelines suggest a glycemic goal of is the reduction in glycosuria. If having a hemoglobin A1c (A1C) < 7%, patients do not reduce caloric intake but also state that an A1C of ≤ 6% to match the change in calorie loss, should be a goal if it can be achieved they will usually gain weight. Mecha- without risk of complications.6,7 nism of action and glucose-lowering During the past 20 years, a number potential certainly must be considered of new medications to control blood as playing major roles in the effect glucose have been introduced, and of an anti-hyperglycemic drug on new approaches to the use of older weight, but other considerations such medications have been developed. In as direct effects on the adipocyte, prescribing any medication, however, gastrointestinal system, and appetite one must consider benefits versus risks. center may play a role. In terms of the treatment of hypergly- Currently, there are nine different cemia, certainly toxic side effects are classes of drugs available to control of concern, as is hypoglycemia. One blood glucose. Effects on weight gain, major area of concern, however, is the weight maintenance, and weight loss effect of such drugs on weight. vary among the classes of medica- Weight and diabetes, especially tions and in fact may vary somewhat type 2 diabetes, are closely related. within each class. This review will Obesity is a major risk factor for the describe the individual classes of development of type 2 diabetes, and drugs and their effects on weight in the current increase in obesity in our patients with type 2 diabetes and, society has fueled a major increase where pertinent, on patients with type in the expression of this disease.8 1 diabetes. Representative studies will Not only does weight, through the be used to highlight the key points of mechanism of insulin resistance, each class. Table 1 lists the nine drug aggravate hyperglycemia, it also classes and their effects on weight and increases the risk for hypertension, A1C. In addition to drugs that have hyperlipidemia, and other conditions indications for treatment of type 2 that lead to cardiovascular disease.9 diabetes, several anti-obesity drugs Improvement in glucose control have been studied in patients with has been linked to weight gain. This type 2 diabetes, for their effects on effect has been demonstrated in both weight and glucose control. This Diabetes Spectrum Volume 20, Number 3, 2007 159 article also reviews the weight and stems from the decrease in glycos- nature of the analog action profiles, glycemic control effects of approved uria when insulin therapy is started including basal insulins glargine and drugs for the treatment of obesity. or intensified. In a small study on detemir and bolus insulins lispro, intensification in type 2 diabetes, aspart, and glulisine, allow for a more Insulin metabolic factors were measured physiological approach to therapy Abnormalities in insulin production, closely.11 A1C decreased from 12.9 than the older insulin formulations. release, and effectiveness underlie to 9.6%, with a weight gain of 5.7 Provision of lower basal insulin levels the major pathophysiology of both lb. Fat mass increased by 5.2 lb, and and more direct and limited capture of type 1 and type 2 diabetes. Insulin 70% of the gain was attributed to prandial glucose excursions by rapid- therapy was first introduced in 1921 correction of glycosuria. Weight gain acting insulins could decrease hypo- and completely changed the course may be minimized in most patients glycemia and better utilize calories, of diabetes treatment. The ability to by reduction in calorie intake. Unfor- thereby decreasing weight changes. optimize insulin therapy, however, tunately, patients often do not get Results of such studies have been arose in the 1980s, with the introduc- the adequate nutrition therapy and variable depending on the comparison tion of blood glucose self-monitoring education needed to complement regimens and whether both groups technology and the A1C assay. Before their change in medical therapy. were intensified to the same degree.15–19 then, glucose control was often Another factor that has been De Leeuw et al.15 compared NPH suboptimal and excess weight gain shown to fuel weight gain with insu- versus detemir as basal insulin in an was generally not a major problem. lin therapy is hypoglycemia. Frequent intensified regimen for patients In fact, many type 1 diabetic patients hypoglycemia and treatment, often with type 1 diabetes, patients on the were basically malnourished and overtreatment, can cause weight determir regimen had a mean weight had difficulties gaining weight. The gain.12 Frequency of hypoglycemia loss of 0.22 lb, whereas the NPH results of the DCCT and the Kuma- and increase in weight were linked in group gained 2.6 lb. Rosenstock et moto trial not only validated the the intensified group in the DCCT.10 al.16 performed a 28-week study of glycemic hypothesis, but also helped There is also evidence that insulin glargine versus NPH regimens in a the diabetes community better use may play a direct role in fat creation treat-to-target trial of basal insulins in insulin in a more physiological man- and deposition.13 Moreover, it has type 2 diabetes. A1C declined 0.7% in ner to achieve better glucose control. long been debated whether insulin, both groups from an average of 8.5%, Weight gain was associated with especially supraphysiological levels but the glargine-treated group gained improved glycemic control in both of insulin, may have a direct effect 0.88 lb versus 3.0 lb in the group studies. Weight gain was also seen on receptors in the central nervous treated with NPH. A 28-week study by in the insulin-therapy group of the system that govern appetite.14 Anderson et al.17 compared lispro and UKPDS, which gained 8.8 lb more The early landmark studies that regular insulin at mealtimes and found than the conventional diet-treated tested the glycemic hypothesis were no difference in weight gain between group during a 10-year period.3 Aver- done using human DNA insulins, the two groups of patients with type age weight gain in the DCCT during including regular, NPH, and ultralente 2 diabetes. Reduction in A1C also did the first year of therapy was 11.2 lb insulins. During the past 15 years, new not differ between the two groups. in the intensified group, versus 5.7 lb injectable analog insulins have been The insulin delivery method may in the conventional group.1,10 introduced, and more recently inhaled also play a role in weight gain. In a A major factor in weight accrual insulin has become available. The 6-month study by Hollander et al.20 involving patients with type 2 dia- betes, patients on a multiple daily Table 1. Anti-Diabetes Medications With Their Reductions injection insulin regimen were ran- in A1C and Effects on Weight domized either to continue their current therapy or to switch to a regi- Reductions in men of inhaled insulin and ultralente Drug Class Weight Effects (lb) A1C (%) insulin. A1C decreased by 0.7% in both groups. No weight gain was Insulin > 2.5 +8.8–11.0 seen in the patients using inhaled insulin, whereas a gain of 2.8 lb was Inhaled insulin 1–2 +2.2–4.4 seen in the patients on subcutaneous Sulfonylureas 1.6 +3.5–5.7 insulin. Data from 2-year safety studies on patients with type 1 or Repaglinide and nateglinide 0.8–1.5 +1.54–3.9 type 2 diabetes also found less weight gain in the inhaled insulin treatment Metformin 1.5 −10.1–+0.88 groups versus patients treated with Thiazolidinediones 0.8–1.0 +9.2–10.6 subcutaneous insulin.21,22 a-Glucosidase inhibitors 0.5–0.8 +0.0–0.44 Sulfonylureas DPP-IV inhibitors 0.5–1.0 +0.0–0.88 Sulfonylureas are a class of oral hypo- glycemic agent that has been used GLP-1 mimetic 0.6–0.8 -2.8–6.6 for the treatment of type 2 diabetes for more than 50 years. They are Amylin analogs 0.6 −3.1 described as insulin secretagogues and 160 Diabetes Spectrum Volume 20, Number 3, 2007 act on a set of receptors on the b-cell, stimulate insulin secretion only in the nonexistent, and normalizing glucose to Practice / The Art and Science of Obesity Management Research From thereby increasing insulin secretion.