Meridia: The New Anti- Obesity Drug

Anjali Shah

Introduction
In today’s society the hegemonic belief surrounding weight is that thin is in and fat is out. With over half of the American population being overweight, the diet craze has swept the nation. However, a bigger player has come into the weight loss scene, the pharmaceutical industry. After the abrupt withdrawal of two anti- obesity drugs from the market in 1997, the pharmaceutical industry has been looking to fill the void in this area of the market. Meridia (sibutramine hydrochloric monohydrate), manufactured by Knoll Pharmaceutical Co, enters with caution what now appears to be a virtually deserted and uncertain anti- obesity market. The drug works to suppress appetite via serotonin (and norepinephrine) re-uptake inhibition.

How Does Meridia Work?
In the fall of 1997, fenfluramine (the fen half of the popular fen-phen drug combination) and Redux (dexfenfluramine) were recalled after the drugs were linked to potentially fatal heart valve abnormalities. In November of 1997, only a few months after the withdrawal of fenfluramine and Redux, the Federal Drug Administration (FDA) approved Meridia. Meridia is a class of drug known as monoamine (serotonin and norepinephrine) re-uptake inhibitors. It falls in the same class of many anti- depressants such as Prozac. Serotonin is a chemical released in the brain after you have eaten a meal, which makes you feel full. When a nerve impulse reaches the end of the nerve (the nerve terminal), the impulse causes the release of chemicals called neurotransmitters. The neurotransmitters are released in the space between the two adjacent neurons, this region is called the synaptic cleft. Usually once the neurotransmitters have bound to their receptors (the neurotransmitter and the receptor fit like a lock and a key) on the adjacent nerve, transport proteins work to reabsorb the extra neurotransmitter back into the nerve terminal so that they can be reused. However, Meridia acts to inhibit the reabsorption of serotonin so the that signal lasts longer, thus giving the sensation that you are full for a longer period of time. This method is thought to effectively reduce the caloric intake of an obese individual due to appetite suppression. For an informational video on the mechanism of action for Meridia visit the world wide web at www.4meridia.com/hcprof/fma.htm.

How is Meridia Different from the Recalled Drugs?
Although Meridia and fenfluramine have similar mechanisms of action (they both affect serotonin), fenfluramine boosts the levels of serotonin into the blood stream. This increase in the levels of serotonin is believed to have caused the heart valve damage seen in some patients. Essentially the difference between the two drugs is that Meridia is more localized, whereas fenfluramine has a systemic effect. Because of this difference, researchers believe that Meridia will not be linked with heart valve damage. As stated by Lawrence Cheskin, M.D., director of the Johns Hopkins Weight Management Center in Baltimore, "Meridia bypasses the heart and acts directly on the brain’s appetite control center. Meridia maintains serotonin levels in the brain, thereby curbing some carbohydrate cravings (Brietzke, 90)". Carbohydrates boost levels of serotonin in the brain, and this impacts appetite and mood so when your brain is running low on the chemical, it tells you to refuel. Meridia keeps serotonin levels elevated, short-circuiting these mentally fueled cravings. The drug also boosts adrenaline levels, curbing overall appetite.

Side Effects
Though Meridia may be safer than other anti- obesity drugs, it still warrants caution. The most troubling side effects include increase in blood pressure, heart rate, and abnormal heart rhythms (arrythmias) seen in some participants during clinical trials. However, most of these side effects were observed in participants who took large doses (more than 15 mg) of the drug (Portyansky, 23). Blood pressure elevations were controlled in these trials with dose adjustments . Those who do have high blood pressure to begin with are urged to weigh the benefits and risks of taking this drug. Meridia’s labeling recommendations calls for blood pressure and pulse measurements prior to therapy initiation and regular monitoring thereafter for all patients. For more information on the increase in blood pressure and heart rate go to www.4meridia.com/hcprof/fsa.htm on the world wide web. The most commonly reported side effects include dry mouth, headache, constipation, and insomnia, "but people seem to find these effects pretty tolerable", according to Cornell Medical Center’s Dr. Louis Aronne (Anonymous, 98).

Who Should Take Meridia?
    Meridia is targeted for the seriously obese and not for those who are looking to lose a few pounds. Linda Mayer, director of communications at Knoll, states, "This is serious medicine, and it is only for certain people. In the past, there has been too much emphasis on cosmetic use of obesity drugs. We’re focusing on the health benefits. It is not about how you look but instead about how your health will improve if you lose weight (Fentress, 33-34)". This drug is recommended only for obese patients with an initial body mass index (BMI) greater or equal to 30 ( a person who is 5’5" and weight 180 pounds), or a BMI of 27 in the presence of other risk factors, such as diabetes, hypertension, arthritis, sleep apnea, or dyslipidemia (low HDL and high triglycerides) (Fentress, 33-34). BMI is a measurement based on height and weight as they relate to body fat. It can be used to determine how much risk people have of developing certain health problems because of their weight. Someone with a BMI of 27 is approximately 20% overweight. The higher the BMI, the greater the risk a person has to develop additional health problems. To calculate your BMI you can go to www.4meridia.com/consumer/archive/bmi.cfm.
    Knoll’s web site (www.4meridia.com/consumer/3200.html#5) states that the drug should not be used by patients who:
· take drugs called monoamine oxidase inhibitors (MAOI’s), which are used for depression, Parkinson’s Disease, and other disorders. This is very important because serious, sometimes even fatal, reactions can occur if Meridia is taken at the same time MAOI’s are taken;
· take other weight loss medicines that act on the brain, such as phentermine. This includes prescription drugs, over- the- counter medicines, and herbal products;
· are allergic to sibutramine;
· have coronary heart disease, angina (heart related chest pain), arrythmias, prior heart attack or congestive heart failure;
· have severe kidney or liver disease;
· have had a stroke or symptoms of a stroke;
· are pregnant, planning to become pregnant, or breast- feeding;
· suffer from anorexia nervosa;
· take drugs for depression; have had seizures;
· have an eye disorder called narrow angle glaucoma;
· are under 16 years of age;
· take other drugs that regulate serotonin. Combining Meridia with other serotonin regulators can cause a rare, but serious condition called "serotonin syndrome", which requires immediate medical attention and may include symptoms such as restlessness, loss of consciousness, confusion, disorientation, tremors, and increased heart rate. Other serotonin regulators include most anti- depressants, , some migraine headache therapies, lithium, tryptophan, and dextromethorphan (cough suppressant).
     A gray area exists between people who should get Meridia, and those who should not. While recommended for people with cardiovascular risk factors (due to obesity), those who have crossed the line into disease are excluded (Chase, B1). But how do you exclude people with undiagnosed heart disease? According to Dr. Michael Schwartz, an obesity researcher at the University of Washington, Seattle, "At minimum, careful history and a physical exam are required to pinpoint unacceptable risk. For some a treadmill test could help", he further states, "Among the obese with high cholesterol and hypertension, a certain percentage will have coronary heart disease and not know it. In such people, a drug which raises blood pressure and pulse could trigger angina, so anyone who experiences chest pain on Meridia should be advised to stop the drug (Chase, B1)". It seems slightly ironic because people who have hypertension and high blood pressure (due to obesity) are the ones who are most likely to want the drug, yet these are the people who are urged not to take it.

The Effectiveness of Meridia
And now the million dollar question, "how much weight can you lose"? In the Knoll clinical studies, overweight patients on Meridia and a reduced calorie diet, in combination with lifestyle modifications, achieved an average of 5 to 10 percent weight reduction from their initial weight at various dosage levels. In one 12 month study, patients who took 10 mg of Meridia daily lost an average of 10 pounds, while those taking 15 mg daily lost an average of 14 pounds. The average weight loss in people on only a reduced calorie diet was 3.5 pounds. Study participants lost most of their weight in the first six months and maintained statistically significant weight losses for up to a year (Fentress, 33-34). Although Meridia’s efficacy profile is modest, the drug’s sustained actions are advantageous since obesity tends to be a chronic condition. Timothy Seaton, M.D., senior medical director at Knoll claims, "the maintained amount of weight loss is enough to reduce obesity- related health risks, including diabetes, osteoarthritis, hypertension and certain types of cancer (Portyansky, 23)".
For those who are trying to lose weight, it is often difficult to stay focused on lifestyle changes and motivated to exercise when all they can think about is food. Knoll claims that Meridia is designed to solve that problem. "Meridia helps patients comply better with an improved lifestyle", said Mayer (director of communications at Knoll), "one patient I spoke with said it felt like she had eaten a bag of popcorn, so she wasn’t so hungry that all she could do was think about food". Mayer warns, "It is important for people to have realistic expectations, Meridia should be used as part of a comprehensive lifestyle management program" (Fentress, 33-34). While Meridia takes your mind of food, Knoll is stressing that it is not likely to be a magic bullet for weight problems.

Clinical Studies
     In a randomized, placebo controlled, double blind study done in Denmark , the group evaluated the effect of sibutramine on energy expenditure and appetite during chronic (8 weeks) treatment without dietary restriction on 32 (seven male, 25 female) healthy obese patients with a BMI of about 34. The results show that sibutramine does cause a significant weight loss as compared to the placebo (2.4 kg vs. 0.3 kg). The 24 hour energy expenditure also decreased significantly less in the treated group, as well as significantly decreased hunger and anticipated food consumption, and increased satiety scores. The study concluded that the weight reducing effect of sibutramine is caused by a dual mechanism: reduction of energy (calorie) intake by increasing satiety and decreasing hunger and prevention of the decline in energy expenditure that follows weight loss (Hansen et al, 1016-24).
     In another study 19 obese female patients receives sibutramine treatment for 12 weeks while the control group received a placebo, both groups were offered dietary advice. This study tested the hypothesis that an increase in energy expenditure contributes to weight loss, and the effects of sibutramine on heart rate and cardiac output were also assessed. The results showed that those on the sibutramine treatment reduced their weight by about 8.1 % in 12 weeks as opposed to the placebo group who reduced their weight by about 5.1%, and there were no significant cardiovascular changes between the two groups. The group concluded that the increase in energy expenditure is associated with weight loss, and this could allow greater numbers of people to maintain a greater degree of weight loss (Walsh et al, 1009-15).
     A study conducted, at the University of Colorado Health Sciences Center in Denver assessed the effects of sibutramine on metabolism and weight loss in overweight women. Forty- four overweight women were randomized given either a placebo or sibutramine for eight weeks and both groups were restricted to a 1200 calorie a day diet. Sibutramine did reduce body weight as compared to the placebo group, however there was no change in the metabolic rate between the two groups. Another finding was that after the patients were taken off medication, they were able to keep their weight stable for another 4 weeks (Seagle et al, 115-21).
     In a study done by a Knoll Pharmaceuticals lab in France, the group tested the efficacy and tolerability of sibutramine in obese patients in a multi- center, double- blind, and placebo- controlled study. 235 subjects, aged 18-65 and a BMI within the range of 27-40 were randomized to receive placebo or sibutramine treatment over a 12 week period, advice on diet and behavior modification was provided. The group mean weight loss at the end of the study for the treated group was 2.4 kg for the 5 mg/day dose, 5.1 kg for 10 mg/day dose, and 4.9 kg for 15 mg/day dose. The incidence and type of adverse events and the rate of withdrawal, were not significantly different in the four groups. No changes in blood pressure were found, but a significant increase in heart rate (4 beats/min) was found in patients who received 10 mg or 15 mg sibutramine compared with placebo Hanotin et al, 32-8).
    Also another study conducted in conjunction with a Knoll scientist (Dr. Timothy Seaton, medical director at Knoll) found "Small mean increases in blood pressure and pulse rate (with considerable individual variability) were observed in patients treated with sibutramine. Most of the adverse events observed on sibutramine are related to its pharmacology, including small mean increases in blood pressure and heart rate" (Bray et al, 189-98). These studies may slightly down play the increase in blood pressure and heart rate finding because these studies were associated with Knoll pharmaceuticals. However, Knoll does acknowledge this problem and addresses it through dosage adjustments.
     In a clinical trial in France, a group conducted a 1 year treatment with sibutramine (10 mg) or placebo on patients who had a BMI greater than 30. These patients were also put on a very low calorie diet. This study also found a significant increase in weight loss, with 86% of the sibutramine patients losing at least 5% of their weight compared to 55% of those in the placebo group. Similarly, at month 12, 75% of subjects in the sibutramine group maintained at least 100% of the weight loss achieved with a very low calorie diet, compared with 42% in the placebo group. The group concluded that following a very low calorie diet, sibutramine is effective in maintaining and improving weight loss for up to a year Apfelbaum et al, 179-84).

Conclusion
After reviewing these studies and evaluating the claims set forth by Knoll Pharmaceuticals, it seems that Meridia is a sufficient tool for weight loss. The amount of weight loss that one can expect is about 5 to 10 percent weight reduction from their initial weight at various dosage levels (5, 10, and 15 mg), however, 10 mg is the most common dosage prescribed. Though this drug is effective there are some dangerous side effects including elevated blood pressure, increased heart rate and prevalence of arrythmias. Robert H. Eckel, M.D., vice chairperson of the American Heart Association’s Nutrition Committee and professor of medicine at the University of Colorado Health Sciences Center states, "Before definitive data are available, patients and their physicians should carefully weigh the benefits vs. the risks of using this new medication. It is especially important that this drug be considered only for people for whom obesity poses a health risk"(http://www.americanheart.org/Whats_News/AHA_News_Releases/974832.html). Also, this drug is not expected to cause heart valve damage as was observed in previous anti- obesity drugs. But it is best to be cautious about Meridia because no long term studies have been done, a least not beyond a year. Once again, this drug is for the purposes of treating obesity, therefore only people with a BMI of 30 (or 27 in the presence of other risk factors) should be taking this drug. The primary goal of this drug is not necessarily to make you look better, but to help you lose enough weight to eliminate health risks associated with obesity. People taking Meridia or considering it should also be reminded that Meridia must be used in conjunction with major lifestyle changes, such as increasing physical activity and eating right. Those who have a BMI under 30 with no risk factors are encouraged to maintain a healthy lifestyle.

References

Apfelbaum, M., Vague, P., Ziegler, O., Hanotin, C., Thomas, F., Jones, SP., Leutenegger, (1999). Long- term maintenance of weight loss after a very- low calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine. American Journal of Medicine, Feb; 106(2): 179-84.

Bray, GA., blackburn, GL., Ferguson, JM., Greenway, FL., Jain, AK., Mendel, CM., Mendels, J., Ryan, DH., Schwartz, SL., Scheinbaum, ML., Seaton, TB. (1999). Sibutramine produces dose- related weight loss. Obesity Research, Mar; 7(2): 189-98.

Brietzke, Carol. (1998). Phen- Fen all over again?. Cosmopolitan, August: 90.

Chase, Marilyn. (1998). A New Diet Drug Hits the Marketplace, With Potential Risks. Wall Street Journal, March 2: B1.

Fentress, Debbie. (1998). New anti- obesity drug comes to market. Diabetes Forecast, June; 51(6):33-34.

Hanotin, C., Thomas, F., Jones, SP., Leutenegger, E., Drouin, P. (1998). Efficacy and Tolerability of Sibutramine in Obese Patients: A Dose- Ranging Study. International Journal of Obesity Related Metabolism Disorders, Jan; 22(1): 32-8.

Hansen, DL., Toubro, S., Stock, MJ., Macdonald, IA., Astrup, A. (1999). The effect of sibutramine on energy expenditure and appetite during chronic treatment without dietary restriction. International Journal of Obesity Related Metabolism Disorders, Oct; 23(10): 1016- 24.

Portyansky, Elena. (1998). A near empty diet market welcomes new anti- obesity drug. Drug topics, Jan; 142(1): 23.

Seagle, HM., Bessesen DH., Hill, JO. (1998). Effects of sibutramine on resting metabolic rate and weight loss in overweight women. Obesity Reseach, Mar;6(2):115-21.

Walsh, KM., Leen, E., Lean, ME. (1999). The effect of sibutramine on resting energy expenditure and adrenaline- induced thermogenesis in obese females. International Journal of Obesity Related Metabolism Disorders, Oct;23(10):1009-15.

Anonymous. (1998). Beyond Phen- Fen: Are the new diet pills for you? Woman's Day, May 12, 61(9): 98.

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