APPETITE SUPPRESSANTS















Overview
  • Sympathomimetic amines have been used for a long time to treat obesity
  • Two relatively recent randomized controlled trials that evaluated their effectiveness are detailed below
Phentermine vs Placebo for Weight Loss in Obese Patients, Diabetes, Obesity, and Metabolism (2010) [PubMed abstract]
  • A trial in the Diabetes, Obesity, and Metabolism enrolled 74 obese patients with an average weight of 191 pounds
Main inclusion criteria
  • BMI ≥ 30 or BMI 27 - 30 and treated for type 2 diabetes, hypertension, or dyslipidemia
Main exclusion criteria
  • HgA1C > 7.5%
  • SBP ≥ 140, DBP ≥ 90
  • History of weight loss surgery or medications
  • Psychiatric illness
Baseline characteristics
  • Average age 35 years
  • Average BMI - 33
  • Average weight - 191 lbs (87 kg)
  • Female sex - 74%
  • Average blood pressure - 123/80
Randomized treatment groups
  • Group 1 (37 patients) - Phentermine 30 mg once daily for 12 weeks
  • Group 2 (37 patients) - Placebo for 12 weeks
  • Phentermine was given in a diffuse-controlled release (DCR) capsule
  • All patients were instructed to follow a hypocaloric diet (1500 cal/day for men, and 1200 cal/day for women)
Primary outcome: Change in body weight and waist circumference at 12 weeks
Results

Duration: 12 weeks
Outcome Phentermine Placebo Comparisons
Primary outcome (body weight loss) 17.8 lbs (8.1 kg) 3.74 lbs (1.7 kg) p<0.001
Primary outcome (decrease in waist circumference) 7.2 cm 2.1 cm p<0.001
Dropout rate 19% 27% N/A
  • Insomnia and dry mouth occurred significantly more in Group 1
  • Average blood pressure decreased in both groups over the course of the study, and the difference between groups was not significant [10]

Findings: Short-term phentermine DCR treatment resulted in significant reduction in weight and improvement of metabolic parameters, including waist circumference and some lipid profiles, without clinically severe adverse events. Further study is needed to show long-term efficacy and safety of phentermine DCR in Korean patients with obesity.
Diethylpropion vs Placebo for Weight Loss in Obese Patients, Int J of Obesity (2009) [PubMed abstract]
  • A trial in the International Journal of Obesity enrolled 69 obese patients with an average weight of 211 pounds
Main inclusion criteria
  • BMI ≥ 30 and ≤ 45
Main exclusion criteria
  • Body weight fluctuations > 4 kg in previous 3 months
  • Use of other weight loss medications
  • Diabetes
  • Significant depression, anxiety, or substance abuse disorder
Baseline characteristics
  • Average age 37 years
  • Average BMI - 37
  • Average weight - 211 lbs (96 kg)
  • Female sex - 90%
  • Average blood pressure - 126/72
Randomized treatment groups
  • Group 1 (37 patients) - Diethylpropion SR 50 mg twice a day for six months
  • Group 2 (32 patients) - Placebo for six months
  • All patients were instructed to follow a 600 calorie deficit per day diet
  • EKGs and echocardiograms were performed at baseline, 6 months, and 12 months
Primary outcome: Percent change in body weight at 6 months
Results

Duration: 6 months
Outcome Diethylpropion Placebo Comparisons
Primary outcome (% weight loss) 9.8% 3.2% p<0.0001
Average weight loss at 6 months 20.5 lbs (9.3 kg) 6.8 lbs (3.1 kg) p<0.0001
Dropout rate 19% 31% N/A
Dry mouth (first 3 months) 69.4% 41% p=0.02
Insomnia (first 3 months) 53% 22% p=0.009
  • Average blood pressure decreased in both groups over the course of the study, and the difference between groups was not significant
  • In the diethylpropion group, there were no clinically relevant abnormal findings or worsening of baseline findings in EKGs and echocardiograms over the course of the study
  • At 6 months, patients were enrolled in an open-label extension phase for 6 additional months. At 12 months, the diethylpropion group lost an additional 1.76 lbs (0.8 kg). [2]

Findings: Diethylpropion plus diet produced sustained and clinically significant weight loss over 1 year. It seems to be safe in relation to cardiovascular and psychiatric aspects in a well-selected population.
Summary
  • In the two small studies above, sympathomimetic amines increased weight loss by about 15 pounds over a 3 - 6 month period when compared to placebo
  • In the diethylpropion study, therapy beyond 6 months only led to small amount of additional weight loss (2 lbs)
  • Dry mouth and insomnia were frequent side effects



Overview
  • Topiramate (Topamax®) is a seizure medication that is FDA-approved to treat seizures and prevent migraines. One of the side effects of topiramate is appetite suppression and weight loss.
  • A drug company called Vivus formulated a pill that combines topiramate and phentermine (Qsymia®). In 2010, Vivus applied for FDA approval of Qsymia®, but was denied because of potential side effects in women who might become pregnant (topiramate has been linked to birth defects). In 2011, Vivus reapplied for FDA approval with new labeling that would exclude the use of Qsymia® in women of childbearing age, and the drug was approved.
  • One large randomized controlled trial has evaluated Qsymia® for weight loss. It is detailed below
CONQUER trial - Qsymia® vs Placebo for Weight Loss in Obese Patients, Lancet (2011) [PubMed abstract]
  • The CONQUER trial enrolled 2487 overweight and obese patients with risk factors for heart disease
Main inclusion criteria
  • BMI 27 - 45
  • Two or more of the following: SBP 140-160, DBP 90-100 or taking ≥ 2 blood pressure medications, triglycerides 200-400 mg/dl or taking ≥ 2 lipid lowering drugs, fasting blood sugar > 100 mg/dl or 2-hour glucose load > 140 mg/dl or type 2 diabetes managed with lifestyle or metformin monotherapy
  • Waist circumference ≥ 42 inches for men and 34.6 inches for women
Main exclusion criteria
  • Blood pressure > 160/100
  • Fasting blood sugar > 240 mg/dl
  • Triglycerides > 400 mg/dl
  • Type 1 diabetes
  • Taking diabetes drug other than metformin
  • History of kidney stones
  • Significant depression
  • Taking tricyclic antidepressant or MAO inhibitor
Baseline characteristics
  • Average age 51 years
  • Average BMI - 36
  • Average weight - 227 lbs (103 kg)
  • Female sex - 70%
  • Average blood pressure - 128/80
  • Diabetes or prediabetes - 68%
Randomized treatment groups
  • Group 1 (994 patients) - Placebo once daily for 56 weeks
  • Group 2 (498 patients) - Phentermine CR 7.5 mg + Topiramate 46 mg once daily (Qsymia®) for 56 weeks
  • Group 3 (995 patients) - Phentermine CR 15 mg + Topiramate 92 mg once daily (Qsymia®) for 56 weeks
  • All patients were given diet counseling with instructions to decrease their caloric intake by 500 calories/day
Primary outcome: Coprimary outcomes were the average percentage change in body weight and the proportion of patients achieving at least 5% weight loss
Results

Duration: 56 weeks
Outcome Placebo Qsymia® 7.5/46 Qsymia® 15/92 Comparisons
Primary outcome (percent weight loss) 1.2% 7.8% 9.8% 2 or 3 vs 1 p<0.0001
Primary outcome (percent achieving 5% weight loss) 21% 62% 70% 2 or 3 vs 1 p<0.0001
Weight loss at 1 year 3 lbs 17.82 lbs 22.4 lbs N/A
Dropout rate 43% 31% 36% N/A
Dry mouth 2% 13% 21% 2 or 3 vs 1 p<0.0001
Paresthesia 2% 14% 21% 2 or 3 vs 1 p<0.0001
Taste perversion 1% 7% 10% 2 or 3 vs 1 p<0.0001
Insomnia 5% 6% 10% 3 vs 1 p<0.0001
Dizziness 3% 7% 10% 2 or 3 vs 1 p<0.05
Disturbance in attention <1% 2% 4% 2 or 3 vs 1 p<0.05
  • Blood pressure decreased in all 3 groups over the course of the study and the decrease in Groups 2 and 3 was significantly greater than the decrease in Group 1

Findings: The combination of phentermine and topiramate, with office-based lifestyle interventions, might be a valuable treatment for obesity that can be provided by family doctors.
Summary
  • Phentermine combined with topiramate facilitates weight loss, although the results of the CONQUER trial are not any better than what was seen with appetite suppressant monotherapy (see above). The CONQUER trial was a much larger trial so the results are statistically more robust.
  • A review of topiramate is available here - Topiramate (Topamax®)
  • Dosing guidelines for Qsymia® are available here - Qsymia® dosing
  • Topiramate and phentermine are available as individual drugs that both have generics. Prescribing generic versions of each drug is cheaper than prescribing Qsymia®.
  • Providers and pharmacies must register in the Qsymia REMS program in order to prescribe Qsymia®



Stimulant side effects
Overview
  • Sympathomimetic amines are central nervous system stimulants, and their side effects are related to their stimulant effects
  • Side effect frequencies are not well-defined
Stimulant side effects include the following:
  • Insomnia
  • Dry mouth
  • Unpleasant taste in mouth
  • Palpitations
  • Anxiety or agitation
  • Elevated blood pressure
  • Increased heart rate
  • Drug dependence and addiction
  • Possible precipitation of psychosis in susceptible patients

Valvular heart disease
Valvular heart disease
  • In the past, phentermine was combined with fenfluramine in the popular "Phen-fen" diet pill combination
  • Fenfluramine and another drug called dexfenfluramine were found to induce valvular heart disease in patients who took them for extended periods of time
  • The mechanism of this effect is thought to be caused by their ability to directly stimulate a class of serotonin receptors found in the heart
  • In 1997, the FDA pulled fenfluramine and dexfenfluramine from the market
  • Because phentermine was often taken with fenfluramine, the FDA also placed a warning on all sympathomimetic amines regarding the possibility of valvular heart disease
  • In studies, sympathomimetic amines have not been shown to be associated with valvular heart disease [6,7,8,11]
Summary
  • Fenfluramine and dexfenfluramine were associated with valvular heart disease, and both were subsequently removed from the market
  • Sympathomimetic amines have not been shown to be associated with valvular heart disease

Primary pulmonary hypertension (PPH)







Kidney disease
Benzphetamine
  • Pharmacokinetics are not well-defined
  • Manufacturer makes no specific recommendations [14]
Diethylpropion
  • Diethylpropion is excreted in the urine
  • Kidney disease would be expected to affect diethylpropion clearance
  • The manufacturer recommends caution in kidney disease, but makes no specific dosage recommendations [7]
Phendimetrazine
  • Major route of elimination is by the kidneys
  • Kidney disease would be expected to affect phendimetrazine clearance
  • The manufacturer makes no specific dosage recommendations in kidney disease [15]
Phentermine
  • Phentermine is excreted in the urine
  • Kidney disease would be expected to affect phentermine clearance
  • The manufacturer makes no specific dosage recommendations in kidney disease [12]

Liver disease
Benzphetamine
  • Pharmacokinetics are not well-defined
  • Manufacturer makes no specific recommendations [14]
Diethylpropion
  • The metabolism of diethylpropion is not well-defined
  • Diethylpropion has not been studied in patients with significant liver disease
  • The manufacturer makes no specific dosage recommendations in liver disease [7]
Phendimetrazine
  • The metabolism of phendimetrazine is not well-defined
  • Phendimetrazine has not been studied in patients with significant liver disease
  • The manufacturer makes no specific dosage recommendations in liver disease [15]
Phentermine
  • The metabolism of phentermine is not well-defined
  • Phentermine has not been studied in patients with significant liver disease
  • The manufacturer makes no specific dosage recommendations in liver disease [12]

Hypertension

Hyperthyroidism

Psychiatric illness

Drug abuse

Abrupt discontinuation



Drug Interactions

All sympathomimetic amines

  • MAO inhibitors - MAO inhibitors should not be taken within 14 days of sympathomimetic amines. When taken together, severe hypertension may occur.
  • Medications that work in the central nervous system - any medication that works in the central nervous system (ex. antidepressants, antipsychotics, seizure medications, insomnia drugs, bipolar medications, etc.) may potentially be affected by the stimulant properties of sympathomimetic amines
  • Serotonergic medications - Case reports of serotonin syndrome have been reported in patients taking stimulants with other serotonergic medications

Metabolism and clearance