CLINICAL DIABETES CASE STUDIES Case Studies: Weight Gain in Two Troglitazone-Treated Patients With Improved Glycemic Control Marguerite Ragone, C-NP, CDE, and Howard M. Lando, MD, FACP, FACE Presentation
For 12 years, she was treated with combinations of regular and NPH insulin up to 56 U twice daily after oral hypoglycemic agents failed to lower her blood glucose levels. The results were suboptimal, and her HbA1c was rarely below 8.5% (normal <6.1%). Two years ago, she was placed on troglitazone (Rezulin) 400 mg/day, which was subsequently increased to 600 mg/day, with gradual reduction and eventual elimination of insulin therapy. In addition to her troglitazone, she now takes a sulfonylurea, an angiotensin-converting enzyme (ACE) inhibitor and a lipid-lowering medication. Her HbA1c levels now run from 6.6 to 7.4%, but she has gained 30 lb since starting troglitazone. During this time, B.L. claims not to have changed her eating habits, which have often included indulging her sweet tooth, eating out up to 4 times a week, and snacking frequently. She has an irregular sleep pattern and does not exercise. She refuses dietary counseling, stating that she "knows what needs to be done" but she "just doesn't want to live that way." The improvement in her blood glucose levels once troglitazone was started was the first sign that any progress had been made in her treatment. * * * J.A. is a 58-year-old woman with type 2 diabetes for 6 years, who was put on insulin after her blood glucose levels were not controlled on maximum doses of a sulfonylurea. Like B.L., her other medical problems are hypertension and dyslipidemia. When first seen, she was on 36 U of NPH insulin in the morning, which was gradually increased to 40 U of NPH in the morning and 20 U in the evening. She was put on troglitazone 2 years ago when her HbA1c was 8.9% (normal <6.1%). Her HbA1c slowly decreased to 5.5% at her recent follow-up visit. She is now off of insulin. Her dyslipidemia is now controlled by diet and exercise. She remains on an ACE inhibitor for her blood pressure. J.A. weighed 259 lb at the onset of treatment with troglitazone. The following year, despite now being off of insulin completely, she weighed 279 lb. She claims never to have been a "light weight," but was appalled at the weight gain. In November 1998, she started a sensible weight loss and exercise program, and at her last visit she weighed 241 lb. Questions
2. Are there strategies to lessen weight gain associated with troglitazone therapy? Commentary
Weight gain associated with improved glycemic control was evident in the Diabetes Control and Complications Trial, which studied patients with type 1 diabetes,2 and to a lesser degree in the U.K. Prospective Diabetes Study, which studied type 2 diabetes patients.3 With improved glycemic control, weight gain may result from decreased glycosuria, fluid retention, and increased adiposity associated with the retention of calories previously lost in the urine. Some of this weight gain was also attributed to patients eating more in order to treat or prevent the hypoglycemia associated with intensive treatment. In addition, we see that, with improvement in daily blood glucose levels, patients often feel they have the ability to "cheat" on their meal plans more often. The reduction in risk factors for complications was so overwhelming that the weight gain was not considered a significant contradiction to improving glycemic control. Not all studies of troglitazone have shown weight gain as an adverse effect in treated patients versus those on placebo. A few studies have shown minimal but statistically significant weight gain in treated patients. However, study participants were encouraged to follow weight maintenance diets rather than weight reduction diets so as not to attribute improvement in glycemic control to weight loss.4-7 It also should be noted that these studies were not of long duration, with most being 12 weeks. Since troglitazone "demonstrates both an acute (minutes-to-hours) and chronic (days-to-weeks) onset of action,"8 and because dosages may be increased slowly over months, this increased weight can take many months to be apparent and, therefore, may have been minimized in most of these short-term studies. Studies have shown improved HbA1c levels, decreased insulin resistance, reduced hyperinsulinemia, and improved lipid profiles in most patients treated with troglitazone (although some studies show a modest rise in low-density lipoprotein cholesterol).6 Improved glycemic control (and lessening of glycosuria) cannot alone cause the weight gain seen in troglitazone-treated patients over the long term. In studies of metformin (Glucophage), for instance, improved HbA1c levels were seen along with weight maintenance or modest weight loss.9,10 Recently, the combination of metformin and insulin has been shown to be associated with weight loss.11 This seems to be mostly due to a decrease in food intake associated with metformin's use (anorexic effect), despite a decrease in basal metabolism rate and glucosuria noted with improved control. One wonders, though there is no proof of this, if the decrease in gluconeogenesis, which metformin causes, may also play a role in the decrease in calories available for utilization. We know that improved blood glucose levels reduce the risk of retinopathy, nephropathy, neuropathy, and probably cardiovascular events. In most patients, these benefits outweigh the health risks of obesity. Patients like B.L., who are not likely to be controlled in any other way and who already show signs of retinopathy and proteinuria, will benefit. (Because B.L. has a rising creatinine level, she would not be a good candidate for metformin.) The possibility of stopping troglitazone was discussed with J.A., but she was so thrilled with not having to take insulin that she decided to maximize her diet and exercise regimen and continue her medication. She now realizes that she will have to maintain this lifestyle always if her goals of weight loss and insulin-free treatment are to be met.
Oral antihyperglycemic drugs work to decrease blood glucose levels by stimulating insulin secretion, decreasing glucose availability, or increasing glucose disposal (Figure 1). All of the agents known to increase weight in diabetic patients (insulin, sulfonylureas, repaglinide [Prandin], troglitazone) do so by either increasing insulin production or availability or by increasing peripheral utilization by decreasing insulin resistance. Either way, this will increase stored calories, i.e., weight. Diet, by decreasing total caloric intake, or metformin, by decreasing calories from gluconeogenesis in the liver, obviously can have a similar beneficial effect on HbA1c and blood glucose levels, yet a positive effect on weight loss. Therefore, if peripheral utilization agents are to be used most effectively, we must look not just at euglycemia as an endpoint, but also at decreasing glucose production/absorption to prevent weight gain. The hallmarks of diet and exercise, long known to be the first-line treatment for many health problems, including diabetes, will become more, not less, important as treatments such as troglitazone become available. Treatment with troglitazone does not necessarily mean weight gain, but patients must be warned about these potential side effects and be even more vigilant in their dietary regimens. Our excitement over new options to treat diabetes must be tempered with the reality that we still must choose treatments carefully, inform patients of the risks, and involve them in the decision-making process. Clinical Pearls
REFERENCES 1Rezulin (troglitazone) package insert. Parke-Davis, Division of Werner-Lambert Company, February 1998. 2The DCCT Research Group: The effect of intensive treatment of diabetes mellitus on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-86, 1993. 3U.K. Prospective Diabetes Study Group: Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type II diabetes (UKPDS 33). Lancet 352:837-53, 1998. 4Schwartz S, Raskin P, Fonseca V, Graveline JF: Effect of troglitazone in insulin-treated patients with type II diabetes mellitus. N Engl J Med 338:861-66, 1998. 5Iwamoto Y, Kosaka T, Adanuma Y, Shigeta Y, Kaneko T: Effect of combination therapy of troglitazone and sulfonylureas in patients with type II diabetes mellitus who were poorly controlled by sulfonylurea therapy alone. Diabetic Med 13:365-70, 1996. 6Kumar S, Boulton AJM, Beck-Nielsen H, Berthezene F, Muggeo M, Persson B, Spinas GA, Donoghue S, Littes S, Stewart-Longo P: Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Diabetologia 39:701-709, 1996. 7Nolan J, Ludvik B, Beerdsen P, Joyce M, Olefsky J: Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 331:1188-93, 1994. 8Henry R: Thiazolidinediones: current therapies for diabetes. Endocrinol Metab Clin North Am 26:553-73, 1997. 9DeFronzo R, Goodman A, the Multicenter Metformin Study Group: Efficacy of metformin in patients with non-insulin dependent diabetes mellitus. N Engl J Med 333:541-49, 1995. 10Nathan DM: Treating type 2 diabetes with respect. Ann Intern Med 130:440-41, 1999. 11Makimattila S, Nikkila K, Yki-Jarvinen H: Causes of weight gain during insulin therapy with and without metformin in patients with type 2 diabetes mellitus. Diabetologia 42:406-12, 1999. Marguerite Ragone, C-NP, CDE, is a nurse practitioner and certified diabetes educator with a private endocrinology practice in Alexandria and Reston, Va. Howard M. Lando, MD, FACP, FACE, is an endocrinologist in private practice in Alexandria and Reston, Va. He is also an associate clinical professor of medicine and endocrinology at George Washington University in Washington, D.C. Note of disclosure: Dr. Lando has received honoraria for speaking engagements from Hoechst-Marion Roussel, Bayer, Novo Nordisk, Schering Corp., Eli Lilly and Co., Bristol-Myers Squibb, and Parke-Davis/Sankyo. Editor's note:It is clear that sulfonylureas, meglitinides, insulin, and thiazolidinediones all cause weight gain. What is not yet clear is how this latter group, our newest class, results in weight gain. The weight gain may be dramatic,1 and may not be the same for all of the agents in this class. By the end of this year, we will likely have three thiazolidinediones available for our use, and the agent chosen for an individual patient may be related to which drug causes less weight gain. What is unique about these agents that may eventually result in massive weight gain? Stimulation of the peroxisome proliferator activated receptor (PPAR) gamma with compounds such as troglitazone results in adipocyte differentiation from adipose precursor cells (adipoblasts).2 Lipoprotein lipase is induced by PPAR gamma, which causes an increase in availability of free fatty acids, which in turn results in triglyceride particles that accumulate within the fat cell.2 Perhaps just as important is the fact that edema may occur with these agents. Plasma volume increases 68% in human volunteers.3 It is impossible to predict who will develop the severe weight gain, but clinicians need to be aware that this is a possibility with these agents. Furthermore, these agents should not be used in patients with pre-existing congestive heart failure. As new agents continue to be developed, we must remember that although there is now universal agreement that hyperglycemia is responsible for a tremendous amount of the morbidity and mortality in patients with type 2 diabetes, it is at least possible that individual agents or classes of agents do not result in improving all of the endpoints. For example, in obese patients in the U.K. Prospective Diabetes Study, compared to insulin and sulfonylureas, metformin resulted in an improvement of any diabetes-related endpoints (P = 0.0034) and all-cause mortality (P = 0.021).4 Although speculative, these results could be explained by the lack of weight gain with metformin compared to the other two groups. What is clear is that trials examining these final endpoints (such as mortality) are needed for all new agents. REFERENCES 1Gorson DM: Significant weight gain with Rezulin therapy (letter). Arch Intern Med 338:861, 1999. 2Schoonjans K, Staels B, Auwerx J: The peroxisome proliferator activated receptors (PPARs) and their effects on lipid metabolism and adipocyte differentiation. Biochem et Biophys Acta 1302:93-101, 1996. 3Rezulin (troglitazone) package insert. Parke-Davis, Division of Werner-Lambert Company, July 1998. 4UK Prospective Diabetes Study Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854-65, 1998. Copyright © 1999 American Diabetes
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