Posts Tagged ‘Pondimin’
Treating Obesity in Patients with type 2 Diabetes: Pharmacologic Treatments of Obesity
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).
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Table 4. Drugs Used to Treat Obesity |
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| Drug | Mechanism of Action | Side Effects | FDA Approved for Weight Loss/Studied in Patients with Type 2 Diabetes |
| Phenylpropanolamine | Norepinephrine release | Hypertension, nervousness, insomnia, headache | No/No |
| SSRIs | Selective serotonin reuptake inhibitors | Nausea, vomiting, insomnia, somnolence | No/No |
| Fenfluramine | Serotonin reuptake inhibitor/serotonin receptor blocker | Dry mouth, insomnia | Withdrawn/No |
| Dexfenfluramine | Serotonin reuptake inhibitor/serotonin receptor blocker | Dry mouth, insomnia, diarrhea, primary pulmonary hypertension (rare) | Withdrawn/No |
| Phentermine | Norepinephrine release | Insomnia, hypertension, restlessness | Yes/No |
| Sibutramine | Inhibits reuptake of serotonin and norepinephrine | Tachycardia, hypertension, dry mouth, insomnia | Pending/No |
| Orlistat | Pancreatic lipase inhibitor | Diarrhea, steatorrhea, oily spotting, malabsorption of fat soluble vitamins | Pending/Yes |
| Phen/Fen Combination | See above | See above, heart valve defects | No/No |
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.
| Manufacturers withdraw weight loss drugs |
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On September 15, 1997, the Food and Drug Administration announced the withdrawal of two appetite suppressants, fenfluramine (Pondimin) and dexfenfluramine (Redux), from the market. Recently, some physicians have prescribed fenfluramine or dexfenfluramine in combination with phentermine to manage obesity. Although fenfluramine and phentermine were approved for short-term use, doctors have been prescribing the combinations fen-phen and dexfen-phen for extended periods. On July 8, 1997, the FDA issued a Public Health Advisory in response to a report from the Mayo Clinic about 24 patients who had developed heart valve disease after taking fen-phen. There were also reports of heart valve disease in patients taking only f enfluramine or dexfenfluramine. The FDA decided to recommend the withdrawal of fenfluramine and dexfenfluramine based on screenings of 291 patients who had received fen-phen or dexfen-phen. Approximately 30% of these patients had abnormal echocardiograms even though they had no symptoms of heart disease. According to the FDA, this unexpectedly high percentage of abnormal test results indicates that the drugs present an unacceptable risk to patients. Phentermine has not been pulled from the market because no cases of heart valve disease meeting FDA’s case definition (mild to severe aortic valve regurgitation and moderate to severe mitral valve regurgitation) have been reported with phentermine alone. Analysis of the data indicates an association of heart valve disease with fenfluramine and dexfenfluramine. No studies were presented to the FDA to demonstrate either the effectiveness or safety of the drugs taken in combination. Combinations of phentermine with any of the selective serotonin reuptake inhibitor (SSRI) antidepressants are likewise off-label uses and have not been studied adequately to permit a recommendation by FDA for combined use. |
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.