Traditional therapies for obesity have failed. Dietary and behavior modifications have been unsuccessful. In fact, studies have shown that 61-81% of initial weight loss is regained between 2.5 and 3.5 years. At five years, the numbers are more dismal. Seventy-five to 121% of the initial weight lost with dietary and/or behavior modifications is regained at five years 1. With 34% percent of the adult population in the United States classified as overweight and 27% of the adult population classified as obese 2, other approaches to weight loss are desperately needed. Pharmacotherapy with diet pills serves as a useful adjunct in the treatment of obesity.
Several paradigm shifts must occur when thinking about obesity and its treatment. First of all, obesity is a chronic disease, not a character flaw. Secondly, obesity is not merely cosmetic issue, but a disease with serious public health implications. Finally, weight gain after the cessation of treatment reflects the chronic nature of the disease and does not necessarily mean that the treatment was a failure 1.
The degree of excess weight is measured by the body mass index (BMI). The BMI is obtained by dividing the weight in kilograms by the height in meters squared. Normal BMI is 18.5 to 24.9. Overweight is defined as BMI from 25 to 25.9. Obesity is defined as BMI greater than 30. Obesity is associated with numerous medical conditions including: type II diabetes mellitus, hypertension, dyslipidemia, macrovascular disease, menstrual irregularities, sleep apnea, osteoarthritis, asthma, and certain types of cancer 1, 2, 3.
The National Institutes of Health (NIH) recommends non-pharmacologic weight loss methods for at least six months. If weight loss is less than 0.45 kg/month, weight loss drugs should be considered. Patients with BMIs that are 30 or greater and patients with BMIs that are 27 or greater with at least two obesity related risk factors or diseases are candidates for treatment with weight loss medications 2,3.
Weight loss medications have three main mechanisms of action. They may suppress appetite via central nervous system mechanisms, inhibit digestion, or increase metabolism. The appetite suppressants fall into three categories: noradrenergic agents, serotonergic agents, and the nonadrenergic/serotonergic agents.
Phentermine
Noradrenergic agents activate central alpha or dopamine receptors in the hypothalamus, enhance catecholamine transmission, increase sympathetic activity, and decrease appetite 3. Phentermine is the only FDA approved weight loss medication in this group. It is the “phen” of the “phen-fen” combination, and has been available since 1968. The only long-term, randomized double-blind, placebo controlled study of phentermine was done by Munro et al in 1968. In this study, 108 obese women were randomized to receive either phentermine 30 mg each day, four weeks on phentermine and four weeks off, or placebo. The women were followed for nine months. At the end of the study, the women in the continuous phentermine group lost 12.2 kg; those in the intermittent group lost 13.0 kg; those in the placebo group lost 4.8 kg 1. Side effects included: agitation, insomnia, headache, nervousness, irritability, palpitations, tachycardia, hypertension. Contraindications include: hyperthyroidism, glaucoma, agitated states, advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, and a history of drug abuse 3.
Fenfluramine
Appetite suppressants also act by serotonergic mechanisms. Fenfluramine, an agent in this class, inhibits the uptake of serotonin and releases serotonin in the synaptic cleft. As a result, food-seeking behavior is diminished and the amount of food consumed is decreased 3. Fenfluramine, its active form dexfenfluramine, and the combination phentermine-fenfluramine, “phen-fen”, were withdrawn from the market in 1997. Fenfluramine was shown to cause valvular heart disease. In addition to causing the release of serotonin and inhibiting the uptake of serotonin from the synaptic cleft, fenfluramine acts as a serotonin agonist. It is the agonistic effect that is responsible for valvular heart damage 1. Valvular heart disease is not associated with the selective serotonin reuptake inhibitor class of antidepressants, nor is it seen with the weight loss medication sibutramine. These agents do not have serotonergic agonist properties. They inhibit the uptake of serotonin from the synaptic cleft, and thus are not associated with valvular heart disease 1. Furthermore, use of dexfenfluramine for more than three months was associated with primary pulmonary hypertension 3.
Meridia
Sibutramine (Meridia) inhibits the uptake of serotonin and norepinephrine from the synaptic clefts in the hypothalamus 4. It increases satiety and may increase metabolic rate 5. Several studies have demonstrated the efficacy of sibutramine. A study by Bray et al enrolled 1047 obese subjects with BMIs between 30 and 40. After a two-week run-in period, the subjects were randomized to receive placebo or sibutramine (1mg, 5 mg, 10mg, 15 mg, 20 mg, or 30 mg) for 24 weeks. All subjects were encouraged to exercise by walking 20-30 minutes each day. Information on behavior modification was given. The women received instructions for a 1200 kcal/day diet, and the men received instructions for a 1500 kcal/day diet. After the end of six weeks, the placebo group lost 1.3 kg; 1mg group lost 2.4 kg; 5 mg group lost 3.7 kg; 10mg group lost 5.7 kg; 15mg group lost 7.0 kg; 20 mg group lost 8.2 kg; and the 30 mg group lost 9.0 kg.
The study had a high drop-out rate, with only 65% completing the study. Furthermore, the exclusion criteria were extensive and included: hypertension, cardiovascular disease, diabetes, depression, substance abuse, pulmonary disease, renal disease, hepatic disease, and other serious medical conditions. Adverse effects included dry mouth, insomnia, hypertension, palpitations, tachycardia, and dyspnea 6.
Because obesity is a risk factor for type II diabetes mellitus and so many type II diabetics are obese, Serrano-Rios et al conducted a study testing the efficacy of sibutramine in type II diabetics. The study enrolled 134 patients with stable type II diabetes with BMIs greater than 27 who were taking sulphonylureas. The participants were randomized to placebo or to sibutramine 15 mg per day for six months. At the end of the study, the sibutramine group lost 4.5 kg and the placebo group lost 1.7 kg. In addition to that, those in the sibutramine group who lost more than 10% of their body weight had a 1.8% decrease in their hemoglobin A1C levels. The placebo group’s hemoglobin A1C levels decreased 0.7%. The change in hemoglobin A1C was a result of the weight loss and not an independent drug effect 7.
The above two studies demonstrate the efficacy of sibutramine for a period of six months. A study by James et al shows that sibutramine is effective for long-term weight loss and weight maintenance. Six hundred and five patients with BMIs between 30 and 45 were enrolled in the study. All participants received a diet with a 600 kcal/day deficit and were encouraged to walk thirty minutes daily. All patients received sibutramine 15mg each day for six months. This was the six-month weight loss phase. At the end of six months, patients losing more than five percent of their body weight or regaining less than two kilograms were randomly assigned to placebo or sibutramine 15mg. The dose of sibutramine was increased to 20 mg if more than one kilogram of weight was gained at the end of the initial six months. The weight maintenance phase of the study lasted 18 months. Two hundred sixty one patients completed the study. Of the patients in the sibutramine group, 43% maintained 80% or more of the weight lost during the weight loss phase of the trial. Only 16% of the placebo group was able to do so. Furthermore, of those entering the maintenance phase on sibutramine, 69% maintained more than five percent of weight loss 18 months later, 46% maintained ten percent weight loss and 27% maintained the full weight loss 8 (see figure 1).
These studies demonstrate that sibutramine is effective for weight loss. However, these studies had high drop-out rates averaging about 20%. Patients with medical conditions including hypertension, heart disease, and diabetes (except in the study by Serrano-Rios et al) were excluded from most of the studies of sibutramine. Small increases in blood pressure and pulse are seen with higher doses of sibutramine 2,6. Headache, dry mouth, insomnia and constipation are other side effects 2. Use of sibutramine is associated with improvements in metabolic parameters. Lower LDL, triglyceride, and total cholesterol levels are seen with sibutramine use. Uric acid levels, glucose and hemoglobin A1C levels are lower as well 2,6. The typical starting dose is 10mg per day and may be increased after one month to 15 or 20 mg 3. Use of sibutramine for longer than two years is not recommended.
Xenical
In addition to suppressing appetite, weight loss medications may inhibit digestion as well. Orlistat (Xenical) is the only medication in this group. Orlistat inhibits lipase and thus decreases the absorption of dietary fat, which leads to decreased absorption of calories and decreased body weight. Approximately one-third of the ingested fat is excreted 2,3,9.
Sjostrom et al conducted a two-year study showing that orlistat was effective for weight loss and for slowing the rate of weight regain. Seven hundred forty-three patients with BMIs between 28 and 47 were enrolled. Each patient received a hypo-caloric diet consisting of 30% of the energy as fat. There was a single blind run-in period of four weeks in which each patient received placebo three times daily with meals. At the end of the run-in period, those who were compliant were randomized to placebo or orlistat 120mg three times daily with meals for 52 weeks. At the end of year one, compliant patients were further randomized to continue their current treatment or to switch regimens (see figure 2).
They were also given a eucaloric diet designed to maintain stable weight. Weight loss during year one and weight maintenance during year two were the two main variables. At the end of year one, the orlistat group lost 10.3 kg, and the placebo group lost 6.1 kg. At the end of year two, the placebo to orlistat group lost 3.6 kg; the orlistat to placebo group regained 4% of their weight; the orlistat to orlistat group regained 2% of their weight; and the placebo to placebo group regained 2% of their weight. In patients receiving 2 years of continuous orlistat treatment, 57% maintained a weight loss greater than five percent, compared to 37% of those receiving 2 years of placebo
As with other studies of weight loss medications, the drop-out rate in this study was high at 25%. Furthermore, patients with medical conditions including cardiovascular disease, diabetes, and hypertension were excluded from this study. Adverse effects included greasy stools, increased defecation, abdominal pain, flatulence. These occurred early in treatment and lasted less than four days. Also observed were slightly decreased levels of fat soluble vitamins in those taking orlistat. Sixteen patients in the orlistat group and four patients in the placebo group required supplementation. Orlistat treated patients also demonstrated lower LDL and total cholesterol levels 9.
Orlistat has also shown to be efficacious in diabetic patients. In a study by Hanefeld et al, 492 type II diabetic patients with BMIs greater than 27 who were either receiving treatment with sulphonylureas or no treatment for their diabetes were randomized to receive either orlistat 120 mg three times daily with meals or placebo for 48 weeks. At the end of the study the orlistat group lost 5.7 kg, and the placebo group lost 3.4 kg. Of the orlistat group, 51.3% lost more than five percent of their body weight as opposed to 31.6% of the placebo group. In regards of glycemic control, the hemoglobin A1C level went from 8.6 to 7.7 in the orlistat group, and from 8.6 to 8.1 in the placebo group. Total cholesterol and LDL levels decreased in the orlistat group vs. placebo. Increased levels of HDL were seen in the orlistat group as well 10.
These two studies demonstrate that orlistat is effective in weight loss. Orlistat also has favorable effects on total cholesterol, LDL cholesterol, and glycemic control. Most adverse effects consist of gastrointestinal symptoms. These usually resolve within several days of starting treatment. Furthermore, orlistat may reduce absorption of fat soluble vitamins and supplementation may be necessary 2,3. The usual dose of orlistat is 120 mg three times daily with meals. It may be taken up to one hour after meals 3. Use of orlistat for longer than two years is not recommended.
Ephedrine/Ephedra
In addition to suppressing appetite and inhibiting digestion of fat, weight loss medicines may also work by increasing metabolism. Ephedrine is one such medicine that has thermogenic properties. Ephedrine also suppresses appetite 3. Ephedrine is the synthetic form of ephedra which is found in the botanical Ma Huang 2. Neither ephedrine nor ephedra are FDA approved for weight loss. Despite this, ephedrine and ephedra, either alone or in combination with caffeine, are sold over the counter in the form of several weight loss products. Metabolife is one such product. Each tablet contains 12 mg of ephedra alkaloids and 40 mg of caffeine.
Ephedrine increases the release of norepinephrine which causes diminished food intake. It also acts as a sympathomimetic agent to increase blood pressure, heart rate, and thermogenesis. Caffeine decreases the breakdown of norepinephrine in the synaptic cleft, and thus acts in synergy with ephedrine 3.
A meta-analysis by Shekelle et al evaluated the safety and efficacy of ephedrine and ephedra. In terms of weight loss, they reviewed twenty trials that lasted for eight weeks or more. They reviewed five trials of ephedrine vs. placebo. The treatment groups lost an average of 0.6 kg/month more than the placebo groups. The average weight loss at four months was 11% in the ephedrine group. All trials had a 20% drop-out rate. They also looked at twelve trials of ephedrine and caffeine vs. placebo. These trials lasted between two and four months. The ephedrine-caffeine group lost an average of one kg/month more than the placebo group. The average percent weight loss in the treatment group was 11%. Three trials were reviewed consisting of ephedrine-caffeine vs. ephedrine. The ephedrine-caffeine group lost an average of 0.4 kg/month more than the ephedrine group. The group also reviewed two studies of ephedrine vs. other weight loss medications. No statistical difference was found in ephedrine vs. dexfenfluramine or in ephedrine vs. diethylproprion 11.
Trials of ephedra also demonstrated efficacy in weight loss. In one trial lasting three months patients treated with ephedra lost 0.8 kg/month more than those treated with placebo. In four trials ephedra with herbs containing caffeine vs. placebo, the treatment group lost 1.0 kg/month more weight than the placebo group. The average weight lost in the treatment group was 5.2% at four months 11 (see figure 4).
The meta-analysis by Shekelle et al also examined adverse events associated with ephedrine/ephedra usage. They examined 50 trials and grouped the symptoms into seven categories: psychiatric symptoms, autonomic hyperactivity, upper gastrointestinal symptoms, palpitations, hypertension, and headaches. They found that treatment with ephedrine/ephedra had a 2.2 to 3.6 increased odds for psychiatric symptoms, autonomic hyperactivity, upper gastrointestinal symptoms, and heart palpitations. The increase in blood pressure was not statistically significant. They also reviewed case reports of serious adverse events. They found two deaths, three myocardial infarctions, nine cerebral vascular accidents, three seizures and three psychiatric cases associated with prior ephedra consumption. Prior ephedrine consumption has been linked to three deaths, two myocardial infarctions, two cerebral vascular accidents, one psychiatric case, and one seizure. In the case studies of the serious adverse events, one-half occurred in persons younger than thirty years old 11.
In short, ephedrine and ephedra are effective for short-term (less than six months) weight loss. They are not FDA approved. Side effects include psychiatric disturbances, autonomic hyperactivity, upper gastrointestinal symptoms, and palpitations. There have been case reports of death, myocardial infarctions, strokes, and seizures associated with the use of these products 2,3,11.
Weight loss medications, in addition to diet and exercise, are useful adjuncts in the treatment of obesity. Patients with BMIs greater than 30 or greater than 27 with two obesity-related conditions or risk factors are candidates for treatment. There are only
three FDA approved drugs that have demonstrated efficacy in long-term (greater than nine months) trials: phentermine, sibutramine, and orlistat 1. Ephedrine and ephedra show efficacy, but they are not FDA approved. Unfortunately, the magnitude of weight loss with these medications is not great. However, even a five percent weight loss results in improvement in cardiovascular risk factors 9. Long-term use (greater than two years) is not recommended as there is no data on the safety and efficacy of these drugs for that length of time 2.
Several paradigm shifts must occur when thinking about obesity and its treatment. First of all, obesity is a chronic disease, not a character flaw. Secondly, obesity is not merely cosmetic issue, but a disease with serious public health implications. Finally, weight gain after the cessation of treatment reflects the chronic nature of the disease and does not necessarily mean that the treatment was a failure 1.
The degree of excess weight is measured by the body mass index (BMI). The BMI is obtained by dividing the weight in kilograms by the height in meters squared. Normal BMI is 18.5 to 24.9. Overweight is defined as BMI from 25 to 25.9. Obesity is defined as BMI greater than 30. Obesity is associated with numerous medical conditions including: type II diabetes mellitus, hypertension, dyslipidemia, macrovascular disease, menstrual irregularities, sleep apnea, osteoarthritis, asthma, and certain types of cancer 1, 2, 3.
The National Institutes of Health (NIH) recommends non-pharmacologic weight loss methods for at least six months. If weight loss is less than 0.45 kg/month, weight loss drugs should be considered. Patients with BMIs that are 30 or greater and patients with BMIs that are 27 or greater with at least two obesity related risk factors or diseases are candidates for treatment with weight loss medications 2,3.
Weight loss medications have three main mechanisms of action. They may suppress appetite via central nervous system mechanisms, inhibit digestion, or increase metabolism. The appetite suppressants fall into three categories: noradrenergic agents, serotonergic agents, and the nonadrenergic/serotonergic agents.
Phentermine
Noradrenergic agents activate central alpha or dopamine receptors in the hypothalamus, enhance catecholamine transmission, increase sympathetic activity, and decrease appetite 3. Phentermine is the only FDA approved weight loss medication in this group. It is the “phen” of the “phen-fen” combination, and has been available since 1968. The only long-term, randomized double-blind, placebo controlled study of phentermine was done by Munro et al in 1968. In this study, 108 obese women were randomized to receive either phentermine 30 mg each day, four weeks on phentermine and four weeks off, or placebo. The women were followed for nine months. At the end of the study, the women in the continuous phentermine group lost 12.2 kg; those in the intermittent group lost 13.0 kg; those in the placebo group lost 4.8 kg 1. Side effects included: agitation, insomnia, headache, nervousness, irritability, palpitations, tachycardia, hypertension. Contraindications include: hyperthyroidism, glaucoma, agitated states, advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, and a history of drug abuse 3.
Fenfluramine
Appetite suppressants also act by serotonergic mechanisms. Fenfluramine, an agent in this class, inhibits the uptake of serotonin and releases serotonin in the synaptic cleft. As a result, food-seeking behavior is diminished and the amount of food consumed is decreased 3. Fenfluramine, its active form dexfenfluramine, and the combination phentermine-fenfluramine, “phen-fen”, were withdrawn from the market in 1997. Fenfluramine was shown to cause valvular heart disease. In addition to causing the release of serotonin and inhibiting the uptake of serotonin from the synaptic cleft, fenfluramine acts as a serotonin agonist. It is the agonistic effect that is responsible for valvular heart damage 1. Valvular heart disease is not associated with the selective serotonin reuptake inhibitor class of antidepressants, nor is it seen with the weight loss medication sibutramine. These agents do not have serotonergic agonist properties. They inhibit the uptake of serotonin from the synaptic cleft, and thus are not associated with valvular heart disease 1. Furthermore, use of dexfenfluramine for more than three months was associated with primary pulmonary hypertension 3.
Meridia
Sibutramine (Meridia) inhibits the uptake of serotonin and norepinephrine from the synaptic clefts in the hypothalamus 4. It increases satiety and may increase metabolic rate 5. Several studies have demonstrated the efficacy of sibutramine. A study by Bray et al enrolled 1047 obese subjects with BMIs between 30 and 40. After a two-week run-in period, the subjects were randomized to receive placebo or sibutramine (1mg, 5 mg, 10mg, 15 mg, 20 mg, or 30 mg) for 24 weeks. All subjects were encouraged to exercise by walking 20-30 minutes each day. Information on behavior modification was given. The women received instructions for a 1200 kcal/day diet, and the men received instructions for a 1500 kcal/day diet. After the end of six weeks, the placebo group lost 1.3 kg; 1mg group lost 2.4 kg; 5 mg group lost 3.7 kg; 10mg group lost 5.7 kg; 15mg group lost 7.0 kg; 20 mg group lost 8.2 kg; and the 30 mg group lost 9.0 kg.
The study had a high drop-out rate, with only 65% completing the study. Furthermore, the exclusion criteria were extensive and included: hypertension, cardiovascular disease, diabetes, depression, substance abuse, pulmonary disease, renal disease, hepatic disease, and other serious medical conditions. Adverse effects included dry mouth, insomnia, hypertension, palpitations, tachycardia, and dyspnea 6.
Because obesity is a risk factor for type II diabetes mellitus and so many type II diabetics are obese, Serrano-Rios et al conducted a study testing the efficacy of sibutramine in type II diabetics. The study enrolled 134 patients with stable type II diabetes with BMIs greater than 27 who were taking sulphonylureas. The participants were randomized to placebo or to sibutramine 15 mg per day for six months. At the end of the study, the sibutramine group lost 4.5 kg and the placebo group lost 1.7 kg. In addition to that, those in the sibutramine group who lost more than 10% of their body weight had a 1.8% decrease in their hemoglobin A1C levels. The placebo group’s hemoglobin A1C levels decreased 0.7%. The change in hemoglobin A1C was a result of the weight loss and not an independent drug effect 7.
The above two studies demonstrate the efficacy of sibutramine for a period of six months. A study by James et al shows that sibutramine is effective for long-term weight loss and weight maintenance. Six hundred and five patients with BMIs between 30 and 45 were enrolled in the study. All participants received a diet with a 600 kcal/day deficit and were encouraged to walk thirty minutes daily. All patients received sibutramine 15mg each day for six months. This was the six-month weight loss phase. At the end of six months, patients losing more than five percent of their body weight or regaining less than two kilograms were randomly assigned to placebo or sibutramine 15mg. The dose of sibutramine was increased to 20 mg if more than one kilogram of weight was gained at the end of the initial six months. The weight maintenance phase of the study lasted 18 months. Two hundred sixty one patients completed the study. Of the patients in the sibutramine group, 43% maintained 80% or more of the weight lost during the weight loss phase of the trial. Only 16% of the placebo group was able to do so. Furthermore, of those entering the maintenance phase on sibutramine, 69% maintained more than five percent of weight loss 18 months later, 46% maintained ten percent weight loss and 27% maintained the full weight loss 8 (see figure 1).
These studies demonstrate that sibutramine is effective for weight loss. However, these studies had high drop-out rates averaging about 20%. Patients with medical conditions including hypertension, heart disease, and diabetes (except in the study by Serrano-Rios et al) were excluded from most of the studies of sibutramine. Small increases in blood pressure and pulse are seen with higher doses of sibutramine 2,6. Headache, dry mouth, insomnia and constipation are other side effects 2. Use of sibutramine is associated with improvements in metabolic parameters. Lower LDL, triglyceride, and total cholesterol levels are seen with sibutramine use. Uric acid levels, glucose and hemoglobin A1C levels are lower as well 2,6. The typical starting dose is 10mg per day and may be increased after one month to 15 or 20 mg 3. Use of sibutramine for longer than two years is not recommended.
Xenical
In addition to suppressing appetite, weight loss medications may inhibit digestion as well. Orlistat (Xenical) is the only medication in this group. Orlistat inhibits lipase and thus decreases the absorption of dietary fat, which leads to decreased absorption of calories and decreased body weight. Approximately one-third of the ingested fat is excreted 2,3,9.
Sjostrom et al conducted a two-year study showing that orlistat was effective for weight loss and for slowing the rate of weight regain. Seven hundred forty-three patients with BMIs between 28 and 47 were enrolled. Each patient received a hypo-caloric diet consisting of 30% of the energy as fat. There was a single blind run-in period of four weeks in which each patient received placebo three times daily with meals. At the end of the run-in period, those who were compliant were randomized to placebo or orlistat 120mg three times daily with meals for 52 weeks. At the end of year one, compliant patients were further randomized to continue their current treatment or to switch regimens (see figure 2).
They were also given a eucaloric diet designed to maintain stable weight. Weight loss during year one and weight maintenance during year two were the two main variables. At the end of year one, the orlistat group lost 10.3 kg, and the placebo group lost 6.1 kg. At the end of year two, the placebo to orlistat group lost 3.6 kg; the orlistat to placebo group regained 4% of their weight; the orlistat to orlistat group regained 2% of their weight; and the placebo to placebo group regained 2% of their weight. In patients receiving 2 years of continuous orlistat treatment, 57% maintained a weight loss greater than five percent, compared to 37% of those receiving 2 years of placebo
As with other studies of weight loss medications, the drop-out rate in this study was high at 25%. Furthermore, patients with medical conditions including cardiovascular disease, diabetes, and hypertension were excluded from this study. Adverse effects included greasy stools, increased defecation, abdominal pain, flatulence. These occurred early in treatment and lasted less than four days. Also observed were slightly decreased levels of fat soluble vitamins in those taking orlistat. Sixteen patients in the orlistat group and four patients in the placebo group required supplementation. Orlistat treated patients also demonstrated lower LDL and total cholesterol levels 9. Orlistat has also shown to be efficacious in diabetic patients. In a study by Hanefeld et al, 492 type II diabetic patients with BMIs greater than 27 who were either receiving treatment with sulphonylureas or no treatment for their diabetes were randomized to receive either orlistat 120 mg three times daily with meals or placebo for 48 weeks. At the end of the study the orlistat group lost 5.7 kg, and the placebo group lost 3.4 kg. Of the orlistat group, 51.3% lost more than five percent of their body weight as opposed to 31.6% of the placebo group. In regards of glycemic control, the hemoglobin A1C level went from 8.6 to 7.7 in the orlistat group, and from 8.6 to 8.1 in the placebo group. Total cholesterol and LDL levels decreased in the orlistat group vs. placebo. Increased levels of HDL were seen in the orlistat group as well 10.
These two studies demonstrate that orlistat is effective in weight loss. Orlistat also has favorable effects on total cholesterol, LDL cholesterol, and glycemic control. Most adverse effects consist of gastrointestinal symptoms. These usually resolve within several days of starting treatment. Furthermore, orlistat may reduce absorption of fat soluble vitamins and supplementation may be necessary 2,3. The usual dose of orlistat is 120 mg three times daily with meals. It may be taken up to one hour after meals 3. Use of orlistat for longer than two years is not recommended.
Ephedrine/Ephedra
In addition to suppressing appetite and inhibiting digestion of fat, weight loss medicines may also work by increasing metabolism. Ephedrine is one such medicine that has thermogenic properties. Ephedrine also suppresses appetite 3. Ephedrine is the synthetic form of ephedra which is found in the botanical Ma Huang 2. Neither ephedrine nor ephedra are FDA approved for weight loss. Despite this, ephedrine and ephedra, either alone or in combination with caffeine, are sold over the counter in the form of several weight loss products. Metabolife is one such product. Each tablet contains 12 mg of ephedra alkaloids and 40 mg of caffeine.
Ephedrine increases the release of norepinephrine which causes diminished food intake. It also acts as a sympathomimetic agent to increase blood pressure, heart rate, and thermogenesis. Caffeine decreases the breakdown of norepinephrine in the synaptic cleft, and thus acts in synergy with ephedrine 3.
A meta-analysis by Shekelle et al evaluated the safety and efficacy of ephedrine and ephedra. In terms of weight loss, they reviewed twenty trials that lasted for eight weeks or more. They reviewed five trials of ephedrine vs. placebo. The treatment groups lost an average of 0.6 kg/month more than the placebo groups. The average weight loss at four months was 11% in the ephedrine group. All trials had a 20% drop-out rate. They also looked at twelve trials of ephedrine and caffeine vs. placebo. These trials lasted between two and four months. The ephedrine-caffeine group lost an average of one kg/month more than the placebo group. The average percent weight loss in the treatment group was 11%. Three trials were reviewed consisting of ephedrine-caffeine vs. ephedrine. The ephedrine-caffeine group lost an average of 0.4 kg/month more than the ephedrine group. The group also reviewed two studies of ephedrine vs. other weight loss medications. No statistical difference was found in ephedrine vs. dexfenfluramine or in ephedrine vs. diethylproprion 11.
Trials of ephedra also demonstrated efficacy in weight loss. In one trial lasting three months patients treated with ephedra lost 0.8 kg/month more than those treated with placebo. In four trials ephedra with herbs containing caffeine vs. placebo, the treatment group lost 1.0 kg/month more weight than the placebo group. The average weight lost in the treatment group was 5.2% at four months 11 (see figure 4).
The meta-analysis by Shekelle et al also examined adverse events associated with ephedrine/ephedra usage. They examined 50 trials and grouped the symptoms into seven categories: psychiatric symptoms, autonomic hyperactivity, upper gastrointestinal symptoms, palpitations, hypertension, and headaches. They found that treatment with ephedrine/ephedra had a 2.2 to 3.6 increased odds for psychiatric symptoms, autonomic hyperactivity, upper gastrointestinal symptoms, and heart palpitations. The increase in blood pressure was not statistically significant. They also reviewed case reports of serious adverse events. They found two deaths, three myocardial infarctions, nine cerebral vascular accidents, three seizures and three psychiatric cases associated with prior ephedra consumption. Prior ephedrine consumption has been linked to three deaths, two myocardial infarctions, two cerebral vascular accidents, one psychiatric case, and one seizure. In the case studies of the serious adverse events, one-half occurred in persons younger than thirty years old 11.
In short, ephedrine and ephedra are effective for short-term (less than six months) weight loss. They are not FDA approved. Side effects include psychiatric disturbances, autonomic hyperactivity, upper gastrointestinal symptoms, and palpitations. There have been case reports of death, myocardial infarctions, strokes, and seizures associated with the use of these products 2,3,11.
Weight loss medications, in addition to diet and exercise, are useful adjuncts in the treatment of obesity. Patients with BMIs greater than 30 or greater than 27 with two obesity-related conditions or risk factors are candidates for treatment. There are only
three FDA approved drugs that have demonstrated efficacy in long-term (greater than nine months) trials: phentermine, sibutramine, and orlistat 1. Ephedrine and ephedra show efficacy, but they are not FDA approved. Unfortunately, the magnitude of weight loss with these medications is not great. However, even a five percent weight loss results in improvement in cardiovascular risk factors 9. Long-term use (greater than two years) is not recommended as there is no data on the safety and efficacy of these drugs for that length of time 2.
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