LIPASE INHIBITORS





Acronyms


DRUGS IN CLASS


MECHANISM OF ACTION


FDA-APPROVED INDICATIONS


WEIGHT LOSS


RCT
Orlistat vs Placebo for Weight Loss in Obese Patients, Obesity Research (2000) [PubMed abstract]
  • The trial enrolled 729 patients with an average BMI of 35
Main inclusion criteria
  • Age ≥ 18 years
  • BMI 28 - 43
Main exclusion criteria
  • Lost > 4 kg of body weight in previous 3 months
  • History of weight loss surgery
  • Drug-treated diabetes
  • Uncontrolled hypertension
Baseline characteristics
  • Average age 44 years
  • Average weight - 215 lbs (98 kg)
  • Average BMI - 35
Randomized treatment groups
  • Group 1 (239 patients) - Orlistat 60 mg three times a day
  • Group 2 (242 patients) - Orlistat 120 mg three times a day
  • Group 3 (237 patients) - Placebo
  • There was a 4-week run-in period before randomization where patients had to comply with a 600 calorie deficit/day diet
  • Patients were instructed to continue the diet after randomization. After the first year, the diet was adjusted for patients who lost ≥ 3 kg to 10% calorie deficit/day.
Primary outcome: Weight loss at two years
Results

Duration: 2 years
Outcome Orlistat 60 Orlistat 120 Placebo Comparisons
Percent weight loss 6.8% 7.6% 4.5% 1 vs 3 p=0.005 | 2 vs 3 p<0.001
Actual weight loss 14.5 lbs 16.3 lbs 9.5 lbs N/A
Dropout rate 42% 35% 44% N/A
Fatty/oily stools 24% 32% 5% N/A
Fecal urgency 10% 14% 5% N/A
Oily spotting 13% 15% 1% N/A

Findings: Orlistat administered for 2 years promotes weight loss and minimizes weight regain. Additionally, orlistat therapy improves lipid profile, blood pressure, and quality of life.

RCT
Orlistat vs Placebo for Weight Loss in Obese Adolescents, JAMA (2005) [PubMed abstract]
  • The study enrolled 539 obese adolescents aged 12 - 16 years
Main inclusion criteria
  • Age 12 - 16 years
  • BMI ≥ 2 units above the 95th percentile for age and sex
Main exclusion criteria
  • BMI ≥ 44
  • Body weight ≥ 286 lbs or ≤ 121 lbs
  • Psychiatric disease
  • Active GI disorder
  • Use of dexamphetamine or methylphenidate
Baseline characteristics
  • Average age 13.5 years
  • Average weight - 211 lbs (96 kg)
  • Average BMI - 35
  • Female sex - 67%
Randomized treatment groups
  • Group 1 (181 patients): Placebo
  • Group 2 (352 patients): Orlistat 120 mg three times daily
  • All participants were given guidance on a hypocaloric diet, exercise, and behavioral modification
Primary outcome: Change in BMI from baseline to study end (or study exit)
Results

Duration: 54 weeks
Outcome Placebo Orlistat Comparisons
Primary outcome (BMI change) +0.31 -0.55 p=0.001
Body weight change +6.9 lbs (3.14 kg) +1.2 lbs (0.53 kg) p<0.001
Fatty/oily stool 8.3% 50.3% N/A
Oily spotting 3.9% 29% N/A
Oily evacuation 1.7% 23.3% N/A
Abdominal pain 11% 21.9% N/A
Fecal urgency 11% 20.7% N/A
Flatus with discharge 2.8% 19.9% N/A
Study dropouts 36% 35% N/A

Findings: In combination with diet, exercise, and behavioral modification, orlistat statistically significantly improved weight management in obese adolescents compared with placebo. The use of orlistat for 1 year in this adolescent population did not raise major safety issues although gastrointestinal adverse events were more common in the orlistat group.


CHOLESTEROL EFFECTS



DIABETES PREVENTION


RCT
XENDOS trial - Orlistat vs Placebo for the Prevention of Type 2 Diabetes, Diabetes Care (2004) [PubMed abstract]
  • The XENDOS trial enrolled 3305 patients with a BMI ≥ 30 and an average body weight of 242 pounds
Main inclusion criteria
  • 30 - 60 years of age
  • BMI ≥ 30
  • Normal blood sugar or impaired glucose tolerance (FBS of < 120 mg/dl and OGTT of 120 - 180 mg/dl)
Main exclusion criteria
  • Diabetes
  • Cardiovascular disease
  • Gastrointestinal disease
Baseline characteristics
  • Average age 43 years
  • Average weight - 242 pounds (110 kg)
  • Average BMI - 37
  • Average fasting blood sugar - 83 mg/dl
  • Patients with impaired glucose tolerance - 21%
Randomized treatment groups
  • Group 1 (1640 patients) - Orlistat 120 mg three times a day + weight loss counseling
  • Group 2 (1637 patients) - Placebo + weight loss counseling
  • All patients were prescribed a diet with a caloric deficit of 800 calories a day
  • 2-hour OGTT was performed every 6 months
Primary outcome: Time to onset of type 2 diabetes and change in body weight after 4 years
Results

Duration: 4 years
Outcome Orlistat Placebo Comparisons
Primary outcome (diabetes) 6.2% 9% HR 0.63, 95% CI [0.46 - 0.86], p=0.0032
Primary outcome (weight loss) 12.8 lbs 6.6 lbs p<0.001
Dropouts 48% 66% p<0.0001
LDL cholesterol (% decrease from baseline) 12.8% 5.1% p<0.01
GI side effects (during year 1) 91% 65% N/A
GI side effects (during year 4) 36% 23% N/A
  • Orlistat-treated patients had significant decreases in vitamins A, K, E, and D compared to placebo. However, the average level of each vitamin remained within the normal reference range throughout the study.
  • Diabetes prevention was only significant in patients with impaired glucose tolerance. In euglycemic patients, diabetes incidence was too low to detect a significant difference.

Findings: Compared with lifestyle changes alone, orlistat plus lifestyle changes resulted in a greater reduction in the incidence of type 2 diabetes over 4 years and produced greater weight loss in a clinically representative obese population. Difference in diabetes incidence was detectable only in the impaired glucose tolerance subgroup; weight loss was similar in subjects with impaired glucose tolerance or normal glucose tolerance.


SIDE EFFECTS

  • Reference [10]
GI side effects with orlistat 120 mg three times a day
Side effect First year of use Second year of use
Oily rectal spotting 26.6% 4.4%
Flatus with Discharge 23.9% 2.1%
Fecal Urgency 22.1% 2.8%
Oily Evacuation 20% 5.5%
Fatty/Oily stool 17.1% 4.9%
Increased defecation 10.8% 2.6%
Fecal Incontinence 7.7% 1.8%





CONTRAINDICATIONS


PRECAUTIONS





DRUG INTERACTIONS


LONG-TERM SAFETY


DOSING


BIBLIOGRAPHY