Antidiabetic Drugs

Posts Tagged ‘Xenical’

Three basic pharmacologic approaches to treating obesity are treatments that: 1) reduce food intake; 2) alter metabolism; and 3) increase energy expenditure or thermogenesis. All obese patients should be under the care of a physician; this is particularly important for the patient with type 2 diabetes. Many of the drugs used to treat obesity can have deleterious effects which may be more pronounced in a person with diabetes or any other underlying metabolic disease. Additionally, many of the therapies recommended for weight reduction have not specifically been studied in patients with diabetes and should be used with caution. Patients should be monitored frequently for any adverse effects (see TABLE 4).

Treatments That Reduce Food Intake

Drugs used to reduce food intake tend to work on the noradrenergic or serotonergic systems in the body. These drugs are known as appetite suppressants, anorectants or anorexiants.

Stimulation of alpha-1 and beta-receptors may cause a decrease in food intake. Phenylpropanolamine (PPA), the common nasal decongestant, is an over-the-counter medicine that works by activating adrenergic receptors. This drug causes the release of norepinephrine (NE) from neuronal storage sites with subsequent adrenergic receptor stimulation. PPA has been shown to induce weight loss by 0.23–0.73 kg per week, in studies lasting 2–12 weeks.This drug can also raise blood pressure and should be used cautiously in patients with pre-existing hypertension. Additionally, it should be used judiciously in patients with diabetes, as drugs that stimulate adrenergic receptors can raise blood glucose levels. Another drawback with this medication is that weight reduction tends to be temporary and tolerance to the weight-reducing effects may occur.

Serotonin receptor activation can also result in decreased food intake. The selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine, sertraline) are known to decrease appetite. Currently, the SSRIs are not recommended or FDA approved for the treatment of obesity.

Phentermine (Ionamin, Fastin) is an amphetamine that is used short-term for weight loss. It works by stimulating the release of norepinephrine (NE). Side effects include insomnia, hypertension, and restlessness. Phentermine may also impair mental alertness and motor coordination.

Fenfluramine (Pondimin) and dexfenfluramine (Redux) contribute to appetite suppression, but are no longer available.

Another drug that may suppress food intake and is currently under review by the FDA is sibutramine. This drug works by inhibiting the reuptake of both norepinephrine (NE) and serotonin (5-HT). Although not specifically studied in patients with diabetes, sibutramine has been shown to reduce average weight over an eight-week period by 2.9–5.0 kg. Because sibutramine is a sympathomimetic it may increase heart rate and blood pressure, both of which need vigilant monitoring in patients with diabetes. Other receptors such as the dopaminergic, histaminergic, and gamma-aminobutyric may play a role in modulating food intake. There are no specific anti-obesity agents currently available that work exclusively on these receptor systems in the body.

Drugs That Alter Metabolism

Drugs that alter metabolism delay digestion, absorption, or both, in the gastrointestinal (GI) tract. These drugs need to be taken close to meal time to impart their clinical effect. Side effects associated with decreased digestion include flatulence, diarrhea, and bloating.

The alpha-glucosidase inhibitor acarbose decreases digestion of starch and disaccharides and has not been found to have significant effects on weight. Additionally, the frequent occurrence of GI side effects and the requirement for a slow, prolonged titration period limits its use in patients with type 2 diabetes.

Orlistat (Xenical), currently under review for FDA approval, inhibits the action of pancreatic lipase. Pancreatic lipase is the enzyme responsible for the hydrolysis of triglycerides and absorption of fat from the GI tract. When this enzyme is inhibited, fat passes through the body undigested. In one study, orlistat induced a 4.3 kg weight loss over 12 weeks. Side effects include increased defecation, oily spotting, steatorrhea, and fecal urgency. Additionally, malabsorption of the fat soluble vitamins (A, D, E, K) and beta-carotene may occur. If patients take orlistat, they may need vitamin supplementation to prevent vitamin deficiencies.

The effects of orlistat have been studied in obese patients with type 2 diabetes. In a 57-week study, patients receiving sulfonylureas were placed on a hypocaloric diet and either placebo or orlistat. Mean weight loss in those taking orlistat was 6.2 kg versus 4.2 for placebo. Nearly half of the orlistat group lost 5% of their weight compared to only 23% of those on placebo. The mean HbA1c in the placebo group was 8.2%, and 8.05% for the orlistat group. At the end of the study period, the average HbA1c was 7.57% for placebo and 7.22% for patients treated with orlistat. Orlistat-treated patients whose HbA1c levels were over 8% at the beginning of the study experienced a 0.53% decrease in those levels. Additionally, the mean insulin levels in the orlistat group returned to normal, indicating a lessening of insulin resistance. The lipid profile improved in the orlistat group. Study results showed that triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol decreased, and LDL/HDL (high-density lipoprotein) ratios improved.

Thermogenic Drugs

Thyroid hormone is a thermogenic drug that increases protein catabolism, accelerates calcium loss from bone, and increases the risk of cardiovascular side effects. These potentially serious side effects can be seen when this hormone is improperly used for weight reduction in patients who do not have hypothyroidism. This hormone is neither recommended nor approved for weight reduction. Drugs that affect the beta-2 and beta-3 adrenergic receptors are thermogenic and decrease body fat in some experimental animals. Several experimental drugs that stimulate these receptors have been studied in humans, but most did not produce clinically significant weight loss or have been plagued with side effects. The thermogenic asthma drug terbutaline may produce weight loss but is not approved or recommended for weight reduction.

In general, thermogenic drugs are not utilized to induce weight loss. As the importance and the role of the beta-3 receptor and its actions on fat metabolism are discovered, beta-3 active anti-obesity drugs may become more clinically relevant.

Obesity Overview

Obesity is now looked at as being a long-term energy storage disease. Over the last 200 years there has been a progressive increase in the size and height of humans, while before that time, height had remained stable. Since the availability and balance of energy affects growth, the overall greater availability of calories has in large part resulted in this increase in the stature of mankind. However, as lifespan has progressively increased (from about 40 years in 1890 to 50 years in 1960 and to about 80 years today), this “extra time” has given people more leisure time. Unfortunately, we have not been particularly good at using this time effectively in terms of exercise. Rather, we have become more sedate as a species. This is reflected in the trend toward increasing weight as we age. For example, in 1960, about 25% of men and women were considered to be “obese” and that number has risen to 33% today.

One measure of how large we are is the Body Mass Index (BMI); when a persons BMI is very high (usually over a value of 25-26kg/m2), that person’s risk of developing serious weight- related illnesses (such as heart disease and diabetes) and of dying prematurely from these illnesses, is increased.

BMI is calculated by taking a person's weight in kg (kg = pounds/2.2) and dividing by the person's height in meters (meters = inches x 0.0254), squared.

One way to cut the risk of illness from weight-related conditions is to maintain an ideal body weight. Weight reduction has physiologic benefits that improve our overall health status, but as anyone who has ever dieted knows, it is very difficult to “normalize” body weight, and this is especially difficult in persons with long-standing obesity. Therefore, experts are now looking into the benefits of modest weight loss (10-15% of body weight) by adjusting the balance of caloric intake and caloric loss. By taking in only as many calories as are required to maintain a normal body weight, there is little chance of becoming overweight. The strategies used to maintain this caloric balance are varied and include behavior modification, diets, appetite suppressants, exercise, thermogenic drugs and in severe cases of obesity, surgery. For example, one Swedish study found that a 28kg loss in body weight resulted in a 32- fold decrease in the risk for developing diabetes.

Pharmacologic Agents in Managing Diabetes

Many experts now consider being overweight as being in a pre-diabetic stage. Once above the normal Body Mass Index (BMI) rate of 25 kg/m2, the overall risk for developing diabetes and for dying prematurely increases. For example, a person with a BMI of 30 kg/m2 has a 20 times greater risk of developing diabetes than if their BMI were 25. As BMI increases, insulin sensitivity drops dramatically causing an increase in insulin levels and a subsequent increase in fat stores in the gut (also called visceral adipose tissue). It is known that if you lose 10% of body weight, you will lose 1/3 of your visceral fat. Even small amounts of weight loss will have beneficial effects because the intra-abdominal fat is greatly reduced.

A number of new drugs are being used and developed for the management of obesity. Among the most popular of the newer agents is Redux (dexfenfluramine). In one typical study, after 1 year use of Redux, 52% of patients lost more than 10% of body weight and 72% lost at least 5% body weight. Only 30% of patients using placebo lost more than 10% and only 64% of placebo-treated patients lost greater than or equal to 5%. The investigators found that if a person lost more than 4 lb. during the first month of treatment, they had more than a 75% chance of losing more than 10% of their body weight over the next year. This reduction in weight also helped to decrease HbA1c (hemoglobin A1C) levels indicating that blood sugar control was improved as weight reduction occurred.

Sibutramine (Meridia) blocks the reuptake of norepinephrine and serotonin and had similar results to Redux in one study; about 50% of patients lost 10% of body weight after one year. Those who lost the most weight, also had the greatest reduction in HbA1c levels. Sibutramine also causes a decrease in total glucose level.

Orlistat (Xenical) is a new drug that is a pancreatic lipase inhibitor; it causes a 35% inhibition of fat absorption and is correlated with a slight decrease in HbA1c and LDL cholesterol levels. Given during meals, it is well tolerated. When used with a low-calorie diet, patients lost 10% of body weight as compared to 6% among those treated with placebo and patients gained back less weight over the next year when diet was liberalized.