Orlistat Enhances Diabetes Therapy

Studies confirm benefits in losing weight, lowering plasma glucose, and reducing need for insulin

Obesity is a major risk factor for a number of debilitating conditions like cardiovascular disease and diabetes mellitus. In fact, diabetes mellitus has an "obese" classification, which is why there is a general idea that being obese also means being diabetic.

    And obesity is one major reason for the rise in the incidence of diabetes mellitus, according to Prof. Arthur Campfield, PhD, head of the Department of Food Science and Human Nutrition at the College of Applied Human Sciences in Colorado. Prof. Campfield was the main speaker in a symposium on the Role of Orlistat in the Management of Obese Diabetic Patients organized by the Philippine College of Physicians.

    Establishing the link between obesity and diabetes, Dr. Campfield said that as a person's body mass index (BMI) increases, his risk for diabetes, hypertension, and dyslipidemia also rises. Obesity could also give rise to impaired glucose tolerance, cardiovascular disease, stroke, sleep apnea, gallbladder disease, osteoarthritis, reduced fertility, and some cancers.

    A person is considered overweight if his BMI is from 23.0 to 24.9, and obese if the BMI is 25 or greater. Another measure would be waist circumference, which is an indicator of visceral fat, excess of which constitutes an independent predictor of risk factors. Men are considered high-risk if their girth is greater than 35 inches; women if the waistline exceeds 31 inches.

    Thus, treatment of obesity should seek to prevent weight gain, induce weight loss, or maintain the ideal weight. The ways to achieve these would include modifying lifestyle (healthy eating, physical activity, and behavioral changes), pharmacotherapy, and surgery. Dr. Campfield likens the management of obesity to a three-legged stool: The legs correspond to physical activity, healthy eating, and medication. Though some patients can lose weight and maintain them by using only two "legs" of the stool (physical activity and healthy eating), a good majority of obese patients need the third "leg," which is using medications like orlistat (Xenical). "Orlistat provides the extra support and stability to achieve weight loss and maintain ideal weight," said Dr. Campfield.

    Orlistat works by blocking pancreatic lipase, which is the prime mover in the hydrolysis of fat and triglycerides in the intestines. In the presence of orlistat, part of the process of fat hydrolysis and absorption is blocked. "So around a third of the food's fat content leaves the body as unaltered triglycerides," said Dr. Campfield.

    In a study of normal subjects maintained on a normal diet, the mean fecal fat content was increased after treatment with orlistat. "In this study, Xenical allowed one-third of the fat content--about 25 g/day-to be excreted," Dr. Campfield noted.

    Dr. Campfield observed that this is orlistat's main action, not just a side effect like that of other drugs; it was "designed to cause a deficit or decrease in fat absorption, to cause a net energy deficit, to cause weight loss." Compared with diet alone, orlistat induces 70 percent more weight loss. Moreover, the weight loss "starts early and is sustained," he said, pointing out that there is no weight regain after one year of treatment .

    Dr. Campfield, however, stressed that the overall weight management program should include a balanced hypocaloric diet, dietary counseling, behavior modification, and regular consultation. "Even if patients take orlistat, but eat whatever they can possibly put in their mouth, they will gain weight," he said, emphasizing that it is important that they reduce their caloric intake and engage in physical activity, in short, modify their behavior. He urged physicians to maintain regular contact with their patients, noting that one of the major predictors of weight management has been frequent contact with a caring, concerned, interested, and involved physician. Said Dr. Campfield: "You have the ability to influence them. Having your patients come back to see you on a regular basis is extremely critical in lowering their risk and improving the management of their existing conditions like diabetes or hypertension."

Efficacy and Tolerability of Orlistat

    A lot of studies have been done to prove the efficacy of orlistat not only among normal obese patients but also among diabetics. Dr. Campfield presented data on the addition of orlistat to the present standard therapy for Type-2 diabetes. An early study by Pricilla Hollander using orlistat in patients with diabetes showed a significant reduction in body weight, about 45 percent greater compared with diet alone. And the effect was sustained for up to 18 months.

    "So not only does orlistat cause weight loss, it supports weight maintenance. That is probably the strongest feature in either preventing chronic disease or improving the management," said Dr. Campfield. And there were twice as many patients who lost more than five percent or ten percent of their weight with Xenical than those put on diet alone.

    Another positive feature with orlistat therapy is the significant reduction in the waist circumference. Again, compared with dieters alone, patients on orlistat had almost twice the reduction in waist circumference (Figure 1). "The first wonderful benefit when you are trying to lose weight is felt when it is easier to button your pants," said Dr. Campfield as he suggested that doctors encourage their patients to wear a belt at the start of therapy and tighten it as they go through therapy until they reach the last hole and it becomes necessary to punch a new hole.

    Studies have also associated orlistat with lowering of cholesterol independent of weight loss. LDL cholesterol is lowered two times more in patients put on diet and orlistat than those put on diet alone because cholesterol leaves the body along with the unabsorbed fat. "This alone makes Xenical a true innovation in the management of chronic disease," said Dr. Campfield.

    Orlistat also reduces blood pressure (BP) better than diet alone, and significantly lowers blood glucose and HbA1c levels in patients maintained on either metformin or insulin, far better than with diet alone. Dr. Campfield said "this is a good reason to add orlistat to the management of Type 2 diabetes mellitus, especially if the patients' BMIs indicate that their weight is either decreasing the potency of their current diabetic medications, or weight loss is indicated to bring them to the normal therapeutic ranges." Even the dosage or need for concurrent medications (such as sulfonylureas) can be reduced after orlistat treatment.

    "Now this is not a drug interaction, but a form of better glucose control, so there is the need to reduce the dose of the sulfonylureas," he said. Consequently, it also lessens the need for insulin (Figure 2).

    More importantly, Orlistat's safety profile is comparable to that of placebo. The only side effect would be the gastrointestinal (GI) adverse events, which were generally mild and transient, and goes away after long-term use. "This is not an adverse event per se, but the local action of orlistat in the intestinal lumen," Dr. Campfield clarified. He said most of the GI adverse events occur within the first 12 weeks of treatment. After a year, the incidence would decline. Patients get used to the treatment; their intestines and bowel movement adapt, and they would be eating less fat, he added.

    Dr. Campfield said that orlistat could play a major role in the management of Type 2 diabetes. An application is now pending before the US Food and Drug Administration for a new labeling for orlistat as an adjunct treatment in Type 2 diabetes.

    He reminded physicians to keep track of the modifiable predictors of long-term outcome of weight management program. These include keeping a record of the patient's weight, diet and exercise; access to correct diet and nutrition information; behavioral and cognitive strategies for better patient compliance with the program; enough physical activity; frequent physician follow; and most important, early response to the problem of obesity.

    "Early response is a key to see if the program is working, and to test also if the patient is at risk," Dr. Campfield ended.