Anti-Diabetes and Anti-Obesity Medications: Effects on Weight in People with Diabetes

Home , Anorectic

In Brief From Research to Practice / The Art and Science of Obesity Management 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 diabetes, 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 From Research to Practice / The Art and Science of Obesity Management thereby increasing insulin secretion. face of abnormal glucose levels. These production in the liver may have Currently, three agents are available in drugs are given before meals and some effect in terms of adipose cre- the United States: glyburide, glipizide, decrease postprandial glucose levels. ation. Some patients do have adverse and glimepiride. The three drugs are Weight gain is seen with both gastrointestinal symptoms with met- fairly similar in action, and in a drug- drugs. These drugs cause a decrease formin, such as cramping, diarrhea, naïve patient may lower glucose by in urinary glucose excretion that may and nausea. Whether those symptoms up to 1.5%. There is some evidence play the major role in weight gain. may have an effect on food intake is that glipizide and glimepiride may Although the action of both classes of unclear, but it has been suggested that be associated with less hypoglycemia drug is glucose dependent, hypogly- such symptoms may play a role in the than glyburide. Unlike the action of cemia can occur. With insulin secreta- weight neutrality or weight loss seen other classes of available insulin gogues, efficacy and weight gain often with metformin therapy.29 secretagogues, which are glucose de- have a linear relationship. Rosenstock Several trials have been conducted pendent, sulfonlyureas are not. The et al.27 reported a 6-month study that to determine the role of metformin sustained effect on the b-cell contrib- compared nataglinide to repaglinide in the treatment of early and pre- utes both to the degree of efficacy and therapy. A1C fell by 1.57% for the diabetes. Metformin was part of the also to the rate of hypoglycemia seen repaglinide group versus 1.0% for the Diabetes Prevention Program, in with this class. nataglinide group. Respective weight which it was compared to lifestyle for All three drugs have been associ- gain was 3.9 versus 1.54 lb. prevention of diabetes in patients with ated with weight gain, whether given impaired glucose tolerance.30 Individu- as monotherapy or in combination Metformin als treated with metformin lost 2.5% with other classes of oral agents or Metformin is an interesting drug and of their basal body weight compared insulin.3,23–26 In the UKPDS, patients difficult to categorize. It was intro- with a 7.5% loss in the lifestyle group. on glibenclamide gained 5.7 lb more duced in 1957 in Europe but was not The ADA algorithm published in than patients on nutrition therapy approved in the United States until 2006 recommended metformin as the over a 10-year period.3 Hermann et 1995, after two major registration best choice for initial therapy in type 2 al.24 found in a 6-month study that trials. Initially thought to act on both diabetes and recommended that it be glyburide treatment in drug-naïve the peripheral insulin resistance and started along with lifestyle therapy at patients resulted in a 5.7-lb weight abnormal hepatic glucose output that the time of diagnosis.6 gain, along with a 1.3% decrease characterize type 2 diabetes, it is now in A1C. Recently, the study known thought to have its main effect on Thiazolidinediones as A Diabetes Outcome Progression normalizing hepatic glucose output. Thiazolidinediones are a class of drugs Study (ADOPT) followed patients Treatment with metformin may actu- that activate the peroxisome prolif- for a mean of 4 years in a sequential ally result in weight loss or at least erator-activated receptor-g (PPAR-g). three-arm study to evaluate glycemic weight neutrality. In clinical trials in Activation of this receptor decreases durability.25 Mean A1C at the start which the comparator of treatment is insulin resistance and promotes of the study was 7.3%. Weight gain an insulin secretagogue, less weight glucose uptake by the cell in patients of 3.5 lb in the sulfonylurea arm of gain has been seen in the metformin with type 2 diabetes. Drugs that are the study at the end of 1 year was group. This result was found in the currently available in this class include correlated with a decrease in A1C of UKPDS, with the metformin group rosiglitazone and pioglitazone. 0.9%. No further increase in weight gaining only 1.1–2.2 lb over a 10- The improved glucose control seen was seen during the remainder of the year period.4 This finding was echoed with these drugs may result in weight treatment period. Increased and sus- by a 6-month study by Hermann et gain and in some cases substantial tained insulin secretion, along with al.24 in which drug-naïve patients weight gain.31–35 The cause of this decreased glycosuria and increased treated with metformin lost 1.4–3.3 weight gain is unclear. Decreased gly- hypoglycemia, are thought to fuel the lb and A1C dropped by 1.6%. When cosuria may play a role, but these drugs weight gain seen with this drug class. metformin was added to patients appear to also have a direct effect on Sulfonylureas are not believed to treated with diet in registration stud- the PPAR receptors on the adipocyte have independent effects on adipose ies on metformin, the 29-week mono- and thus stimulate adipogenesis.36 deposition or appetite. therapy study saw an 8.4-lb decrease Most of the increase in adipose tissue in weight and a 1.6% decline in is in the subcutaneous fat depot, and Repaglinide and Nateglinide A1C.28 When metformin was added visceral fat may actually decrease. Often described as being in the same to patients treated with glyburide, Flux in fluid balance may also occur class of drugs, repaglinide and nat- an additional 1.7% decrease in A1C in patients, as signified by peripheral eglinide actually have very different was observed, with only a 0.88-lb edema. In a study by Phillips et al.32 chemical backgrounds but have simi- weight gain. In the ADOPT study, of monotherapy with rosiglitazone, lar mechanisms of action. Repaglinide patients treated with metformin lost weight gain of 7.2 lb was seen when is a meglitinide, and nateglinide is 2.9 kg during the first year and were compared to placebo; A1C decreased a D-phenylalanine derivative. Both stable over the remaining time of the 1.5% from a baseline of 9.0%. The drugs fall into the category of insulin study;25 A1C declined by 0.6%. greatest increase in weight is usually secretagogues and have their effect by The weight effect of metformin seen when these agents are combined stimulating the b-cell. The action of may result from a number of mecha- with insulin secretagogues or insulin both drugs is glucose dependent, and, nisms. It does not stimulate insulin and in patients who are mark- in contrast to the sulfonlyureas, they production, hypoglycemia is rare to edly hyperglycemic. Raskin et al.35 Diabetes Spectrum Volume 20, Number 3, 2007 161 reported a weight gain of 11.7 lb in a another DPP-IV inhibitor, is currently system–mediated effects on appetite. study in which 8 mg of rosiglitazone being evaluated by the FDA. Trials of Nausea is the most common side was added to insulin therapy. Hol- both drugs have been shown to lower effect of exenatide but apparently lander et al.37 saw a lesser weight gain blood glucose.45–47 Six-month studies does not correlate with weight loss. of 7.0 lb in a 6-month study of 4 mg with sitagliptin, both as monotherapy of rosiglitazone in patients on insulin and in combination with metformin Pramlintide therapy; A1C decreased 0.4% from and pioglitazone, have shown aver- Pramlintide is an analog of amylin, a baseline of 8.5%. In the ADOPT age A1C decreases of 0.6–8.0%. a hormone cosecreted by the b-cell trial, an increase of 5.2 lb was seen Both sitagliptin and vilgliptin with insulin. Amylin has been shown in the rosiglitazone arm at 1 year, and have been shown to have a neutral to suppress prandial glucagon pro- A1C fell by 0.5%. At study end, mean effect on weight gain. Moreover, duction and slow gastric emptying. weight gain was 10.6 lb.25 both drugs can be considered insulin Abnormalities in the production of secretagogues. The usual effect of amylin in conjunction with insulin a-Glucosidase Inhibitors this class on weight gain may be abnormalities have been seen in both a-Glucosidase inhibitors include the offset by the other effects of GLP-1. type 1 and type 2 diabetes.55,56 Pram- drugs acarbose and miglitol. Their Hypoglycemia is also rare with these litide is given as an injection at each method of action is to delay the break- drugs and also may play a role in meal and has been shown to decrease down of polysaccharides by blocking diminution of expected weight gain. postprandial glucose. It has been a series of enzymes in the gut, thereby studied extensively in patients with decreasing the postprandial glucose Exenatide type 1 or type 2 diabetes and has spike.38 Because of their mechanism of Exenatide is a GLP-1 mimetic and is been shown to produce significant action, they are taken with each meal. given as an injection. It is a synthetic lowering of A1C in both groups.57–59 The major side effects—flatulence version of extendin-4, a protein Decrease in body weight has been and loose stools—are the result of secreted in saliva of the Gila monster. seen in studies of both type 1 and type the delayed uptake of carbohydrate, It mimics some of the actions of natu- 2 diabetic patients.58,59 In a 1-year which allows increased opportunity rally secreted GLP-1 by binding to and study in patients with type 2 diabetes for bacterial fermentation. stimulating the GLP-1 receptors.48 on insulin therapy, Hollander et al.57 Variable effects on weight have Combination studies in patients found that patients on pramlitide been seen with this drug.39–41 In a with type 2 diabetes on oral agent lost an average of 3.1 lb, associated 3-month dose titration study of acar- monotherapy and combination oral with a 0.8% improvement in A1C bose in patients with type 2 diabetes, agent therapy have shown reduction compared to the group treated with no weight gain was seen in the three in A1C and in weight.49–51 Ratner et placebo. Ratner et al.59 also found treatment groups when compared al.49 reported a weight loss of 6.6 similar effects in a 13-week study to placebo.41 In a 6-month type 1 lb accompanied by a 1.1% decrease in patients with type 1 diabetes. In diabetes study of acarbose, an A1C in A1C in a 30-week study of this group, treated patients had a decrease of 0.48% was observed, exenatide in patients on metformin. 1.05% decrease in A1C along with with a weight increase of 0.44 lb The weight loss is progressive and a decrease in weight. Because of the compared to a 0.22-lb weight gain occurs regardless of baseline weight, effect of pramlintide on weight loss in the placebo group.42 although the greatest weight loss is in patients with diabetes, it has been seen in the most obese patients. An studied as a weight-loss drug in non- Dipeptidyl peptidase-IV (DDP-IV) 82-week extension study of a partial diabetic obese individuals with some Inhibitors cohort of patients from the initial success. Its mechanism of action for DDP-IV inhibitors are one of the new- 1-year study found a mean decrease weight loss may relate to its effect on est classes of drugs to be introduced of 10.1 lb associated with sustained gastric emptying and thereby satiety. for the control of blood glucose. To A1C reduction. A 28-week trial that Studies on food intake in patients understand the mechanism of action compared the addition of exenatide treated with pramlintide have shown of these drugs, it is important to or glargine to patients already on a reduction in caloric intake.60 understand the role of glucagon-like oral agents found an equal decrease peptide 1 (GLP-1), which is secreted in A1C, with weight gain in the insu- Obesity Drugs in the gut after food ingestion. GLP-1 lin cohort of 2.8 lb and weight loss in Weight loss is considered an important stimulates insulin production by the the exenatide cohort of 4.6 lb.52 An aspect of therapy for patients with b-cell, regulates glucagon secretion, 82-week extension study of a partial diabetes. Excess weight places greater may slow gastric emptying, and cohort of patients from the initial direct demand on the b-cell and also can affect the appetite center in the 1-year study found a mean decrease aggravates insulin resistance. Numer- hypothalamus, resulting in feelings of 9.9 lb.53 However, when overall ous studies have shown that weight of satiety. DPP-IV is an enzyme in trial data are analyzed, a responder loss in patients with diabetes can result the blood that inactivates the GLP-1 pattern in terms of weight loss is seen in improvement in glucose levels.61–63 peptide. DPP-IV inhibitors slow the in the extension studies, and not all Weight loss appears to be more breakdown of GLP-1 and thereby treated patients lose weight.54 difficult for patients with diabetes extend its metabolic effects.43,44 Sev- Exenatide is resistant to the effect than for those without diabetes. This eral drugs in this class are in develop- of DPP-IV and thus can exhort a phenomenon has been shown in stud- ment, and sitagliptin has recently been prolonged possible supraphysiologi- ies of lifestyle therapy, drug therapy, approved by the U.S. Food and Drug cal effect on the GLP-1 receptors, and even bariatric surgery. The Look Administration (FDA). Viligliptin, especially on the central nervous Ahead trial, a 11.5-year study of 162 Diabetes Spectrum Volume 20, Number 3, 2007 lifestyle, behavioral, and drug therapy in the group treated with sibutramine gorithm for the treatment of type From Research to Practice / The Art and Science of Obesity Management in patients with type 2 diabetes on versus the group treated with placebo, 2 diabetes7 suggested starting drug variable treatment regimens may show the improvement in glucose control treatment at diagnosis and also different results.64 An interim report of was found only in patients who lost introducing insulin earlier in the pro- its results has shown a fairly impres- 5 or 10% of basal body weight and gression of disease. The focus of this sive weight loss of 8% of basal body was not seen when the intention-to- algorithm is glycemic control and weight and a decrease in mean A1C treat group was analyzed. not weight. Metformin, however, is from 7.25 to 6.6% at 1 year in the Rimonabant, a selective can- recommended as the drug of choice treatment group,whereas the control nabinoid (CB1) receptor inhibitor, for initiation of therapy, and it does group lost 0.4% of basal body weight decreases appetite and affects energy have a favorable effect on weight. with a decrease in A1C of 0.15%. balance. Although CB1 receptors The second tier of the algorithm sug- A limited number of drugs have have been identified on numerous gests the choices of basal insulin, sul- been approved by the FDA for the body organs, the major effect of this fonylurea, or a thiazolidinedione in treatment of obesity. Phenteramine drug appears to be on the central addition to metformin as the second is the oldest and most commonly nervous system. Rimonabant has step in treatment. All three of these prescribed anti-obesity drug. It has been shown to cause significant agents are associated with variable been studied in two small 3- and weight loss and decrease in A1C in weight gain. 4-month studies for weight loss in a year-long study in patients with The consensus algorithm does patients with type 2 diabetes.65,66 type 2 diabetes who were on either not include the newer drugs, such as Weight loss of up to 7.9–8.3 lb was metformin or sulfonylurea therapy.74 pramlitide, extenatide, sitaglitin, or reported, but no effect was found on Average weight loss was 8.1 lb over inhaled insulin. Do these drugs offer glucose as measured by fasting blood the placebo group and was associated advantages over the older drugs? All glucose level. Sibutramine, a central with a decrease in A1C of 0.7% from four appear to have a neutral effect nervous system appetite suppres- a baseline of 8.5%. No differences in on weight gain or to actually cause sant, and orlistat, a lipase inhibitor, weight loss or A1C change were seen weight loss. Pramlitide has been have both been studied in patients between the metformin group and the studied both in type 1 and type 2 with type 2 diabetes. Rimonabant, group on sulfonlyureas. More recent diabetes and has been associated a cannabinoid antagonist, has also data have become available from a with modest weight loss. Extenatide been studied in patients with type 2 6-month study in drug-naïve patients has been shown to cause weight diabetes. It has been approved in the that also showed similar results: a loss in patients along with sustained European Community and approval mean A1C decrease of 0.8% from a decrease in A1C. Less weight gain is pending in the United States. baseline of 7.9% in the treated group has been seen with inhaled insulin in The three drugs studied in patients as opposed to a 0.3% decline in A1C patients on basal-bolus therapy, and with type 2 diabetes work by quite for the placebo group.75 Mean body the DPP-IVs have been associated different mechanisms. Orlistat blocks weight declined by 14.7 lb in the with weight neutrality. triglyceride uptake in the gut and may rimonabant group versus 5.9 lb in The decision to initiate or add any cause loose stools and flatulence.67 It the placebo group. In terms of side drug to the diabetes regimen rests has been studied along with lifestyle effects of the cannabinoid inhibitor, on a number of factors, including therapy in combinations with sulfo- there may be minor risk for increase efficacy, side effects, weight consider- nylureas, metformin, and insulin in in development or aggravation of ations, patient acceptance, and cost. 12-month trials in patients with type depression. Therapy must always be directed to 2 diabetes.68–70 Similar decreases in the individual patient. Weight gain both A1C and weight were observed. Summary does not have to be an inevitable In a 1-year study by Hollander et al.69 Weight gain is an undesirable result of result of diabetes treatment. Optimi- in patients treated with sufonylureas, treatment for patients with type 1 or zation of therapy to limit weight gain a 0.48% decrease in A1C from base- type 2 diabetes. Multiple medications requires understanding the effect of line was seen, in conjunction with a are now available to lower blood the drug in question on weight and weight loss of 13.6 versus 9.5 lb in the glucose, but as the goal of near- its effect on efficacy. In climbing the placebo group. normal glycemia is sought, weight gain ladder of increasingly complex dia- Sibutramine, a serotonin and nor- often ensues. Unfortunately, weight betes therapy for patients with type adrenaline reuptake inhibitor, in- gain can be associated with poor 2 diabetes, successful combination fluences satiety and may increase cardiovascular outcomes and other therapy may be best attained through thermogenic energy. Side effects of morbidity and leads to increasing the synergy of adding a weight-loss this drug include increases in blood insulin resistance in both type 1 and promoting or weight-neutral drug to pressure and tachycardias. Studies type 2 diabetes.76–78 Concerns about one that promotes weight gain. The have shown sibutramine to cause weight gain should not discourage importance of implementing nutri- weight loss and an accompanying advancement of therapy, however. tion therapy to neutralize decreases decrease in glucose level.71–73 In a The choice of treatment for patients in glycosuria is also a key point in study reported by Serrano-Rios et depends on the degree of progression limiting weight gain for all patients. al.,71 a mean weight loss of 9.9 lb of their diabetes. Insulin is always the and a decrease in A1C of 1.0% from first choice for the treatment of type 1 References a baseline of 9.0% was seen.71 In a diabetes, but there are multiple treat- study by McNulty et al.,73 although ment choices for patients with type 1The DCCT Research Group: The effect of in- overall mean A1C reduction was seen 2 diabetes. The ADA consensus al- tensive treatment of diabetes on the develop- Diabetes Spectrum Volume 20, Number 3, 2007 163 ment and progression of long-term complica- gain over 12 months in comparison to NPH metformin in patients with non-insulin-de- tions in insulin-dependent diabetes mellitus. insulin. Diabetes Obes Metab 7:73–82, 2005 pendent diabetes mellitus. N Engl J Med N Engl J Med 329:977–986, 1993 333:541–549, 1995 16Rosenstock J, Schwartz SL, Clark CM Jr, Park 2Okwa H, Khishkawa Y, Araki E, Takao M, GD, Donley DW, Edwards MB: Basal insulin 29Lee A, Morley JE: Metformin decreases Isami S, Motoryoshi S, Kojima Y, Furuyoshi N, therapy in patients with type 2 diabetes: 28-week food consumption and induces weight loss in Shichiri M: Intensive insulin therapy prevents comparison of insulin glargine (HOE 901) and subjects with obesity with type II non-insulin- the progression of diabetic microvascular com- NPH insulin. Diabetes Care 24:631–636, 2001 dependent diabetes. Obes Res 6:47–53, 1998 plications in Japanese patients with NIDDM: a 17Anderson JH Jr, Brunelle RL, Keohane P, 30The DPP Research Group: Reduction in randomized prospective six year study. Diabe- Koivisto VA, Trautmann ME, Vignati L, Di- the incidence of type 2 diabetes with lifestyle tes Res Clin Pract 28:103–117, 1995 Marchi R: Mealtime treatment with insulin intervention or metformin. N Engl J Med 3U.K. Prospective Diabetes Study Group: Inten- analog improves postprandial hyperglycemia 346:393–403, 2003 sive blood-glucose control with sulphonylureas and hypoglycaemia in patients with non-insu- 31Aronoff S, Rosenblatt S, Braithwaite S, Egan or insulin compared with conventional treat- lin-dependent diabetes mellitus. Arch Intern JW, Mathisen AL, Schneider RL: Pioglitazone ment and risk of complications in patients with Med 157:1249–1255, 1997 hydrochloride monotherapy improves glyce- type 2 diabetes. Lancet 352:837–853, 1998 18Shober E, Shoenie E, Van Dyk J, Wernicke- mic control in the treatment of patients with 4U.K. Prospective Diabetes Study Group: Panten K, Pediatric Study Group of Insulin type 2 diabetes: a 6-month randomized place- Effect of intensive blood glucose control Glargine: Comparative trial between insulin bo-controlled dose-response study. Diabetes with metformin on complications in over- glargine and NPH insulin in children and ad- Care 23:1605–1611, 2000 weight patients with type 2 diabetes. Lancet olescents with type 1 diabetes. Diabetes Care 32Phillips LS, Grunberger G, Miller E, Pat- 352:854–865, 1998 24:2005–2006, 2001 wardhan R, Rapparport EB, Salzman A, Rosi- 5The DCCT/EDIC Research Group: Intensive 19Holleman F, Schmitt H, Rottiers R, Rees A, Sy- glitazone Clinical Trials Study Group: Once- diabetes therapy and cardiovascular disease manowski S, Anderson JH: Reduced frequency and twice-daily dosing with rosiglitazone im- in patients with type I diabetes. N Engl J Med of severe hypogylcemia and coma in well-con- proves glycemic control in patients with type 353:2643–2653, 2005 trolled IDDM patients treated with insulin lis- 2 diabetes. Diabetes Care 24:308–315, 2001 pro. Diabetes Care 20:1827–1832, 1997 6Nathan D, Buse J, Davidson M, Heine R, 33Fonseca V: Effect of thiazolidinediones on Holman R, Sherwin R, Zinman B: Manage- 20Hollander PA, Blonde L, Rowe R, Mehta body weight in patients with diabetes melli- ment of hyperglycemia in type 2 diabetes: a AE, Milburn JL, Hershon KS, Chiasson JL, tus. Am J Med 115:42S–48S, 2003 consensus algorithm for the initiation and ad- Levin SR: Efficacy and safety of inhaled insu- 34Rosenstock J, Rosiglitazone Clinical Trials justment of therapy: a consensus statement lin (exubera) compared with subcutaneous in- Study Group: A randomized trial of rosigli- from the American Diabetes Association and sulin therapy in patients with type 2 diabetes: tazone therapy in patients with inadequately the European Association for the Study of Di- results of a 6-month, randomized compara- controlled insulin-treated type 2 diabetes. Di- abetes. Diabetes Care 29:1963–1972, 2006 tive trial. Diabetes Care 27:2356–2362, 2004 abetes Care 254:1226–1232, 2001 7American Diabetes Association: Standards 21Skyler J, Jovanovic L, Klioze S, Reis J, Dug- 35Raskin P, Rendell M, Riddle M, Dole J, of medical care in diabetes—2007. Diabetes gan W, for the Exubera 1022 Study Group: Freed M, Rosenstock J, Rosiglitazone Clini- Care 29 (Suppl. 1):S4–S47, 2007 Sustained efficacy and tolerability of inhaled cal Trials Study Group: A randomized trial of insulin (Exubera) therapy over 2-years: pa- 8Harris M, Flegal D, Cowie CC, Eberhardt rosiglitazone therapy in patients with inade- tients with type 1 diabetes. Diabetologia 49 MS, Goldstein DE, Little RR, Wiedmeyer quately controlled insulin-treated type 2 dia- (Suppl. 1):118, 2006 HM, Byrd-Holt DD: Prevalence of diabetes, betes. Diabetes Care 254:1226–1232, 2001 impaired fasting glucose and impaired glucose 22Rosenstock J, Klioze S, Foyt H, Ogawa M, 36Ahima RS: Adipose tissue as an endocrine tolerance in U.S. adults: the Third Nation- St. Aubin L, Duggan W, for the Exubera 1029 organ. Obesity 14:242S–249S, 2006 al Health and Nutrition Examination Study, Study Group: Inhaled human insulin (Exu- 1988–1994. Diabetes Care 21:518–524, 1998 bera) therapy shows sustained efficacy and is 37Hollander P, Dahong Y, Chou H: Low-dose well tolerated over a 2-year period in patients rosiglitazone in the treatment of type 2 diabe- 9Scnell A, Gregg E, Bowman B, Morris S, Zhang with type 2 diabetes (T2DM) [Abstract]. Dia- tes. Arch Intern Med 167:1284-1290, 2007 X, Avenell A, Gregg E, Bowman B, Schmid C, betes 55 (Suppl. 1):A109, 2006 Lau J: Long-term effectiveness of weight-loss in- 38Lebovitz HE: Alpha-glucosidase inhibitors. terventions in adults with pre-diabetes: a review. 23Groop LC: Sulfonylureas in NIDDM. Dia- Endocrinol Metab Clin North Am 26:539– Am J Prev Med 28:126–139, 2005 betes Care 15:737–754, 1992 551, 1997 10The DCCT Research Group: Weight gain 24Hermann LS, Schersten B, Bitzen PO, Kjell- 39Delgado H, Lehmann T, Bobbioni-Harsch associated with intensive therapy in the Dia- ström T, Lindgarde F, Melander A: Therapeu- E, Ybarra J, Golay A: Acarbose improves in- betes Control and Complications Trial. Dia- tic comparison of metformin and sulfonyl- directly both insulin resistance and insulin se- betes Care 11:567–573, 1988 urea, alone and in various combinations: a cretion in obese type 2 diabetic patients. Dia- double-blind controlled study. Diabetes Care betes Metab 28:195–200, 2002 11Bagg W, Plank L, Gambe G, Drury P, Sharpe 17:1110–1119, 1994 N, Braatvedt KGD: The effects of intensive 40Segal P, Feig PU, Schernthaner G, Ratzmann glycaemic control on body composition in pa- 25Lins PE, Lundblad S, Persson-Trotzig E, Ad- KP, Rybka J, Petzinna D, Berlin C: The efficacy tients with type 2 diabetes. Diabetes Obes amson U: Glibenclamide improves the response and safety of miglitol therapy compared with Metab 3:410–416, 2001 to insulin treatment in non-insulin-dependent glibenclamide in patients with NIDDM inade- diabetics with second failure to sulfonylurea quately controlled by diet alone. Diabetes Care 12Strachan MW, Ewing FM, Frier BM, Harper therapy. Acta Med Scand 223:171–179, 1988 20:687–691, 1997 A, Deary IJ: Food cravings during acute hypoglycaemia in adults with type 1 diabetes. 26Kahn SE, Haffner SM, Heise MA, Her- 41Coniff R, Sharpiro J, Robbins D, Kleinfield R, Physiol Behav 80:675–682, 2004 man W, Holman RR, Jones NP, Kravitz BG, Seaton T, Beiswenger P, McGill J: Reduction of Lachin JM, O’Neill M, Aninman B, Viberti G, glycosylated haemoglobin and postprandial hy- 13Kersten KS: Mechanisms of nutritional and ADOPT Study Group: Glycemic durability of perglycemia by acarbose in patients with NID- hormonal regulation of lipogenesis. EMBO rosiglitazone, metformin, or glyburide mono- DM. Diabetes Care 18:831–843, 1995 Rep 2:282–286, 2001 therapy. N Engl J Med 355:2427–2443, 2006 42Hollander P, Pi Sunyer X, Coniff R: Acar- 14Schwartz MW, Woods SC, Porte D Jr, Seeley 27Rosenstock J, Hassaman DR, Madder RD, bose in the treatment of type 1 diabetes. Dia- RJ, Baskin DG: Central nervous system control Brazinsky SA, Farrell J, Khutoryansky N, Hale betes Care 20:248–254, 1997 of food intake. Nature 404:661–671, 2000 P, Repaglinide Versus Nateglinide Comparison 43Drucker DJ: Enhancing incretin action for 15De Leeuw I, Vague P, Selam JL, Skeie S, Study Group: Repaglinide versus nateglinide the treatment of type 2 diabetes. Diabetes Lang H, Draeger E, Elte JW: Insulin detemir monotherapy: a randomized multicenter study. Care 26:2929–2940, 2003 used in basal-bolus therapy in people with Diabetes Care 27:1265–1270, 2004 type 1 diabetes is associated with a lower risk 44Ahrén B, Landin-Olsson M, Jansson PA, 28DeFronzo RA, Goodman AM: Efficacy of of nocturnal hypoglycaemia and less weight Svensson M, Holmes D, Schweizer A: Inhibi-

164 Diabetes Spectrum Volume 20, Number 3, 2007 tion of dipeptidyl peptidase-4 reduces glyce- 56Koda JE, Fineman M, Rink TJ, Dailey GE, domized double-blind study. Diabetes Care mia, sustains insulin levels, and reduces gluca- Muchmore DB, Linarelli LG: Amylin concen- 21:1288–1294, 1998 From Research to Practice / The Art and Science of Obesity Management gon levels in type 2 diabetes. J Clin Endocri- trations and glucose control. Diabetes Care 70Kelly D, Bray G, Pi-Sunyer FX, Klein S, Hill nol Metab 89:2078–2084, 2004 339:1179–1180, 1992 J, Miles J, Hollander P: Clinical efficacy of 45Scott R, Wu M, Sanchez M, Stein P: Effica- 57Hollander PA, Levy P, Fineman MS, Maggs orlistat therapy in overweight and obese pa- cy and tolerability of the dipeptidylpeptidase- DG, Shen LZ, Strobel SA, Weyer C, Kolter- tients with insulin-treated type 2 diabetes: a 4 inhibitor sitagliptin as monotherapy over man OG: Pramlintide as an adjunct to insu- 1-year randomized controlled trial. Diabetes 12 weeks in patients with type 2 diabetes. Int lin therapy improves long-term glycemic and Care 25:1033–1041, 2002 J Clin Pract 61:171–180, 2007 weight control in patients with type 2 diabe- 71Serrano-Rios M, Melchionda N, Moreeno- tes: a 1-year randomized controlled trial. Dia- 46Aschner P, Kipnes MS, Lunceford JK, San- Carretero E: Role of sibutamine in the treat- betes Care 26:784–790, 2003 chez M, Mickel C, Williams-Herman DE: Ef- ment of obese type 2 diabetic patients receiv- fect of the dipeptidyl peptidase-4 inhibitor si- 58Hollander P, Maggs DG, Ruggles JA, Fine- ing sulphonylurea therapy. Diabetes Med tagliptin as monotherapy on glycemic con- man M, Shen L, Kolterman OG, Weyer C: Ef- 19:119–124, 2002 trol in patients with type 2 diabetes. Diabetes fect of pramlintide on weight in overweight 72Sanchez-Reyes L, Fanghnel G, Yamamoto Care 29:2632–2637, 2006 and obese insulin-treated type 2 diabetes pa- J, Martnez-Rivas L, Campos-Franco E, Ber- tients. Obes Res 12:661–668, 2004 47Charbonnel B, Karasik A, Liu J, Wu M, ber A: Use of sibutramine in overweight adult Meininger G: Efficacy and safety of the dipep- 59Ratner RE, Dickey R, Fineman M, Maggs Hispanic patients with type 2 diabetes melli- tidyl peptidase-4 inhibitor sitagliptin added to DG, Shen L, Strobel SA, Weyer C, Kolterman tus: a 12 month, randomized, double-blind, ongoing metformin therapy in patients with OG: Amylin replacement with pramlintide as placebo-controlled clinical trial. Clin Ther type 2 diabetes inadequately controlled with an adjuct to insulin therapy improves long- 26:1427–1435, 2004 metformin alone. Diabetes Care 29:2638– term glycaemic and weight control in type 1 73McNulty S, Yr E, Williams G: A random- 2643, 2006 diabetes mellitus: a 1-year, randomized con- ized trial of sibutramine in the management trolled trial. Diabet Med 21:1204–1212, 2004 48Nielsen LL, Young AA, Parkes D: Pharma- of obese type 2 diabetic patients treated with cology of exenatide (synthetic exendin-4): a 60Chapman I, Parker B, Foran S, Feinle-Biss- metformin. Diabetes Care 26:125–132, 2003 potential therapeutic for improved glycemic set C, Wixhart J, Strobel S, Wang Y, Burns 74Scheen AJ, Finer N, Hollander P, Jensen M, control of type 2 diabetes. Regul Pept 117:77– C, Lush C, Weyer C, Horowitz M: Effect Van Gaal LF, RIO-Diabetes Study Group: Ef- 88, 2004 of pramlintide on satiety and food intake in ficacy and tolerability of rimonabant in over- obese subjects and subjects with type 2 diabe- 49Ratner RE, Maggs D, Nielsen LL, Stone- weight or obese patients with type 2 diabetes. Diabetologia 48:838–848, 2005 house AH, Poon T, Zhang B, Bicsak TA, tes: a randomised controlled study. Lancet Brodows RG, Kim DD: Long-term effects of 61Maggio CA, Pi- Sunyer FX: The preven- 368:1660–1672, 2006 exenatide therapy over 82 weeks on glycaemic tion and treatment of obesity. Diabetes Care 75Iranmanesh A, Rosenstock J, Hollander P, control and weight in over-weight metformin- 20:1744–1766, 1997 SERENADE: Rimonabant monotherapy for treated patients with type 2 diabetes mellitus. 62Pascale RW, Wing RR, Butler BA, Mullen the treatment of multiple cardiometabolic risk Diabetes Obes Metab 8:419–428, 2006 M, Bonon P: Effects of a behavioural weight factors in treatment-naïve patients with type 50Buse JB, Henry RR, Han J, Kim DD, Fine- loss program stressing calorie restriction ver- 2 diabetes [Abstract]. Diabet Med 23 (Suppl. man MS, Baron AD, Exenatide-113 Clinical sus calorie plus fat restriction in obese individ- 4):230, 2006 Study Group: Effects of exenatide (exendin-4) uals with NIDDM or a family history of dia- 76Purnell JQ, Hokanson JE, Marcovina SM, on glycemic control over 30 weeks in sulfo- betes. Diabetes Care 128:1241–1248, 1995 Steffes MW, Cleary PA, Brunzell JD: Effect nylurea-treated patients with type 2 diabetes. 63Wing RR: Use of very-low calorie diets in of excessive weight gain with intensive thera- Diabetes Care 27:2628–2635, 2004 the treatment of obese person with non-in- py of type 1 diabetes on lipid levels and blood 51Kendall DM, Riddle MC, Rosenstock J, Ah- sulin-dependent diabetes mellitus. J Am Diet pressure: results from the DCCT. JAMA kuang D, Kinm DD, Fineman MS, Barron AD: Assoc 95:569–572, 1995 280:140–146, 1998 Effects of exenatide (exendin-4) on glycemic 64Pi-Sunyer FX: Look Ahead (Action for 77Yki-Jarvienen H, Ryysy L, Kauppila M, Ku- control over 30 weeks in patients with type 2 Health In Diabetes) study. Oral presentation jansuu E, Lahti J, Marjanen T, Niskanen L, diabetes treated with metformin and a sulfonyl- at the American Diabetes Association annual Rajala S, Salo S, Sppala P, Tulokas T, Viikari urea. Diabetes Care 28:1083–1091, 2005 meeting and scientific sessions, June 2006. J, Taskinen MR: Effect of obesity on the re- 52Heine RJ, Van Gaal LF, Johns D, Mihm Available online from www.internal medicine- sponse to insulin therapy in non-insulin-de- MJ, Widel MH, Brodows RG, GWAA Study news.com pendent diabetes mellitus. J Clin Endocrinol Group: Exenatide versus insulin glargine in Metab 82:4037–4043, 1997 65Greshberg H, Kane R, Hulse M, Pensgen E: patients with suboptimally controlled type 2 Effects of diet and an anorectic drug (phen- 78Anderson JW, Kendall CW, Jenkins DJ: Im- diabetes: a randomized trial. Ann Intern Med termine resin) in obese diabetics. Ther Res portance of weight management in type II di- 143:559–569, 2005 22:814–820, 1977 abetes: review with meta-analysis of clinical 53Blonde L, Klein EJ, Han J, Zhang B, Mac studies. J Am Col Nutr 22:331–339, 2003 66Campbell CJ, Bhalla IP, Stell JM, Duncan SM, Poon TH, Taylor KL, Trautmann ME, LJ: A controlled trial of phentermine in obese Kim DD, Kendall DM: Interim analysis of the diabetic patients. The Practioner 218:851– effects of exenatide treatment on A1C, weight 855, 1977 Priscilla Hollander, MD, is medical and cardiovascular risk factors over 82 weeks director at the Baylor University in 314 overweight patients with type 2 diabe- 67Guerciolini R: Mode of action of orlistat. tes. Diabetes Obes Metab 8:436–447, 2006 Int J Obes Relate Metab Disord 21 (Suppl. Medical Center Ruth Collins 3):S12–S23, 1997 Diabetes Center in Dallas, Texas. 54Ratner RE, Maggs D, Nielsen LL, Stone- house AH, Poon T, Zhang B, Bicsak TA, 68Berne C; Orlistat Swedish Type 2 Diabetes Brodows RG, Kim DD: Long-term effects of Study Group: A randomized study of orlistat exenatide therapy over 82 weeks on glycaemic in combination with a weight management Note of disclosure: Dr. Hollander control and weight in over-weight metformin- programme in obese patients with type 2 di- has recieved honoraria for speaking treated patients with type 2 diabetes mellitus. abetes treated with metformin. Diabet Med engagements from Merck, Pfizer, Diabetes Obes Metab 8:419–428, 2006 22:612–618, 2005 and Sanofi-Aventis and has served 55Young AA, Vine W, Gedulin BR, Pittner R, 69Hollander PA, Elbein SC, Hirsch IB, Kelley on advisory boards for these compa- Janes S, Gaeta LS, Percy A, Moore CX, Koda D, McGiIl J, Taylor T, Weiss SR, Crockett SE, nies and for Roche Pharmaceuticals, JE, Rink TA, Beaumont K: Preclinical phar- Kaplan RA, Comstock J, Lucas CP, Lodewick all of which manufacture pharma- macology of pramlintide, in the rat: compar- PA, Canovatchel W, Chung J, Hauptman J: isons with human and rat amylin. Drug Dev Role of orlistat in the treatment of obese pa- ceutical products for the treatment Res 37:231–248, 1996 tients with type 2 diabetes: a 1-year ran- of diabetes.

Diabetes Spectrum Volume 20, Number 3, 2007 165