EAST 501 Lecture Notes - Lecture 12: Setmelanotide, Glucose Tolerance Test, Melanocortin 4 Receptor
21 Jun 2018
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L6 – Bernard Mar 2
Treatments for Obesity – Part 2
1
MC4R AGONIST – NEW THERAPY
- Melanocortin agonists act on the MC4R
- new MC4R agonist – Setmelanotide
- Trial:
“Significant weight loss in two POMC-deficient patients treated with a novel MC4R agonist (Setmelanotide)”
o recruited 2 obese patients with POMC LOF unable to make alpha-MSH
o >98th percentile overweight
o treated daily (injection) with Setmelanotide à responded well
o decrease in hunger score and weight (2 participants showed similar results)
• one participant was treated for longer than the other
o doesn’t seem to have the same effect on BP like the other drugs (MC4R agonists) previously had
o in the extension phase of the study they are put back Setmelanotide:
• decline in systolic BP (this is typical when people lose a lot of weight)
• glycemic control increases (seen in both patients)
• the same pattern was observed in both patients (decreasing trend in diastolic BP and HR)
§ diastolic did not decrease as much as systolic
• insulin levels and blood glucose following the glucose-tolerance test were much more stable in
patient 1 in the extension phase than during baseline
- the melanocortin therapies are in phase 2 trials right now
OBESITY TREATMENT STRATEGIES
- not many current drug therapies to treat obesity
- Controlled diet and exercise (this is the start for any weight loss) à always a control in trials of new therapies
- Inhibitors of fat absorption
o Orlistat – oldest of the available drugs
- Appetite suppressants: all have a different action, but do the same thing
o 5-HT2c receptor agonists (Lorcaserin)
o Phentermine/topiramate
o GLP-1 receptor agonists (Liraglutide)
o Naltrexone/bupropion (NB32)
o these drugs are modestly effective in at least a certain proportion of the population in inducing weight
loss but not that much à usually ~3-9% (placebo adjusted weight loss) of body weight is lost with the
drugs
§ this may help with BP and glycemic control and trying to limit development of T2DM, etc.
- Bariatric surgery
EFFICACY BENCHMARKS FOR WEIGHT LOSS DRUGS (FDA)
- In general, a product can be considered effective for weight management if after 1 year of treatment either of
the following occurs:
o The difference in mean weight loss between the active-product and placebo-treated groups is at least 5
percent and the difference is statistically significant
o The proportion of subjects who lose greater than or equal to 5 percent of baseline body weight in the
active-product group is at least 35%, is approximately double the proportion in the placebo-treated
group, and the difference between groups is statistically significant
- for new drugs on the market you want/need to have a certain criterion à there is an FDA document
PHARMACOTHERAPY AND LIFE-STYLE CHANGES WORK BETTER TOGETHER THAN ALONE IN REDUCING BODY WEIGHT
- the point is that pharmacotherapy works better in context of making lifestyle changes than the effect of the
pharmacotherapy alone à reduction in weight is two-fold (combined therapy vs. pharmacotherapy alone)
L6 – Bernard Mar 2
Treatments for Obesity – Part 2
2
- Ranking of most to least weight change
1. Combined therapy
2. Pharmacotherapy + brief lifestyle modification OR Lifestyle modification alone
3. Pharmacotherapy alone
ORLISTAT (XENICAL/ALLI = brand names)
- Pancreatic and GI lipase inhibitor
- Approved in 1999
- 60 or 120mg, 3x daily (before mealtime)
- Available OTC (low dose)
o not in Canada, but in US and Europe
- Inhibits breakdown of dietary fats into FFAs by 30% = lipase inhibitor
o acts on lipases that come from the pancreas and are secreted in the GI tact
o when you ingest your food and there is fat in the diet, lipases from the pancreas chew up TGs into
smaller FFAs that the intestine takes up à this drug blocks the lipase activity, blocking TG breakup and
limits the FFAs from being taken up
- Promotes better glycemic control
- Modest effects on weight loss
o 2-3kg over 1 year compared to controls
- Unwanted effects: abdominal cramping, flatulence; oily, loose stool
ORLISTAT PROMOTES WEIGHT LOSS MORE THAN LIFESTYLE CHAGES ALONE OVER 4 YEAR PERIOD
- Clinical trial:
o in a comparison of Orlistat vs. placebo, Orlistat is more effective than lifestyle change alone
o other the course of the next 3 year, following drug therapy, the weight comes back on
o the big success marker is if the weight doesn’t come back on, but it normally does
ORLISTAT DECREASES INCIDENCE OF DIABETES, ESPECIALLY IN OBESE PATIENTS WITH IMPAIRED GLUCOSE TOLERANCE
- Study (4 years): Evaluated diagnosis of DM
o pre-diabetes can be diagnosed with a glucose tolerance test (prior to the diagnosis of full diabetes)
o they evaluated all patients to determine pre-diabetics and diabetics
o Individuals on Orlistat (+ lifestyle changes) were less likely to develop diabetes over the 4 year study
LORCASERIN (BELVIQ)
- 5-hydroxytryptamine 2c receptor agonist (5-HT2cR)
o Receptor expressed in many brain regions, including hypothalamus
o drug looks like 5HT
- Approved in 2012
o NDA filed in 2009; approval delayed because of cancer in rats, modest efficacy, potential cardiac
valvulopathies
- First weight loss drug approved since 1999
- 11.6x higher affinity than for 5-HT2BR (linked to cardiac valve problems)
- 10mg, 2x daily (before breakfast and dinner)
- promotes modest weight loss
- unwanted effects (limited): HA, dizziness, nausea
- works/act on the brain/related systems and not on the GI tract
- suspected problem was that it might have caused cancer in rats and there was a concern about effects on the
cardiac valves (where there is high expression of 5-HT2BR)
o in fact it doesn’t seem to have an effect on the valves and doesn’t work on the 2B receptor that would
cause the valve problems
Document Summary
Not many current drug therapies to treat obesity. Controlled diet and exercise (this is the start for any weight loss) always a control in trials of new therapies. Inhibitors of fat absorption: orlistat oldest of the available drugs. Ranking of most to least weight change. Mar 2: combined therapy, pharmacotherapy + brief lifestyle modification or lifestyle modification alone, pharmacotherapy alone. 60 or 120mg, 3x daily (before mealtime: not in canada, but in us and europe. Modest effects on weight loss: 2-3kg over 1 year compared to controls. Unwanted effects: abdominal cramping, flatulence; oily, loose stool. Orlistat promotes weight loss more than lifestyle chages alone over 4 year period. Orlistat decreases incidence of diabetes, especially in obese patients with impaired glucose tolerance. Study (4 years): evaluated diagnosis of dm: pre-diabetes can be diagnosed with a glucose tolerance test (prior to the diagnosis of full diabetes) they evaluated all patients to determine pre-diabetics and diabetics.
