June 15, 2021

Drugs For Obesity

by mert in Metabolic Health

At this point I believe that short of bariatric surgery, most people who have overweight or obesity will need medication to keep the weight off.  FDA approved treatments for obesity are indicated when BMI reaches 30 (or over 27 with complications related to obesity).  Even before drugs, though, the first step is to make sure you’re not taking other prescription medications that cause weight gain.  Some of the bad actors in this realm include sulfonylureas for diabetes, certain antidepressants and antipsychotics, carbamazepine and valproate, beta-blockers and some other medications.

And before we launch on a discussion of medications, let me suggest that obesity should never be treated with just medications.  You need to establish healthy and enduring habits of nutrition and activity, you need to attend to muscle growth and maintenance, you need to transform the microbiome.  In the best scenario, the treatment of obesity can be a springboard for globally improved health.

What follows is a list of the FDA-approved therapies along with my thoughts about each.  Ultimately, the decision to start medication and which one to choose is one you should make with your doctor, and it depends on each drug’s advantages and disadvantages as well as your own medical history and physiology.

    1. PHENTERAMINE:  is a stimulant, a schedule IV controlled substance, and so I’m naturally biased against it, and though there’s evidence that it is not habit-forming1, it can raise blood pressure.  It works because it reduces appetite but may be associated with anxiety, insomnia, and palpitations.  One plus is that phentermine is relatively inexpensive.  Nevertheless, there are better drugs available and I do not prescribe it.  In some health systems, insurance companies require patients to fail a trial of phentermine before they will cover other more expensive drugs.
    2. PHENTERMINE / TOPIIMATE ER (QSYMIA): here we add topiramate, an anti-seizure drug with appetite suppressive properties to phentermine.  The combination is more effective than either alone and you can expect to lose about 10% of body weight after a year.   Maybe I’m less set against this one because the phentermine dose does not get as high, nevertheless, I’ve do not prescribe it.  Topiramate by itself has some weight loss effects, but there’s a reason people call it “dopiramat.”  It makes you spacey and you can get tingling in your extremities.  Maybe once upon a time it made sense to try this medication, but now with third generation meds, I don’t see the rationale.
    3. ORLISTAT: here’s one that’s fairly safe, it inhibits the absorption of dietary fat, so this is a good adjunct to a low carb diet.  You can buy it in a lower dose without a prescription on Amazon, so what’s not to love?  Well, urgent, explosive, greasy stools, for one.  When you inhibit the metabolism of lipids, the fat passes through your system and changes your bathroom experience.  But if you have chronic constipation, then this might be a serendipitous plus. A second consideration is that it takes your fat-soluble vitamins with it (A,D,E,K), so you really need to supplement with a multivitamin if you’re going to take this medicine.  Most patients do not like this drug.
    4. NALTREXONE / BUPROPION (CONTRAVE): this is a fascinating drug that works by reducing hunger cravings in the brain.  Let us nerd out on the mechanism for a moment.  Bupropion is an anti-depressant that has the unexpected effect of stimulating the cleavage of a large molecule called POMC.  One of the cleavage products is a-MSH, which activates the melanocortin-4-receptor (MC4R), which reduces appetite and increases energy expenditure.  Another cleavage product of POMC, beta-endorphin, feeds-back to inhibit cleavage of POMC.  But that’s where naltrexone comes in, it blocks the inhibition of POMC cleavage, resulting in unopposed stimulation of MC4R.  Beware though that naltrexone blocks the action of opiates more broadly, so if you take opiate pain medication, this drug is definitely not for you. However, Contrave does seem to have a role in attenuating addictive pathways in the brain, so it might be an appropriate choice for someone who wants to cut down on smoking and/or drinking.
    5. GLP1 RECEPTOR AGONISTS (LIRAGUTIDE, SEMAGLUTIDE): these drugs are now both FDA approved for weight loss and they work very well.  Semaglutide has gotten a lot of press as a “game-changer” and it’s true—it’s a once-a-week drug that has been associated with loss of up to 20% of body weight.  The drugs imitate the effect of a molecule called GLP-1, which has a range of effects including delaying emptying of the stomach, reducing appetite, and increasing the secretion of insulin.  One would think that increased insulin is bad, but in one meta-analysis, GLP-1RA’s were associated with fewer strokes, fewer cardiovascular events, and lower all-cause mortality in a diabetic population.2  We’ll find out soon whether there is a decreased risk of major events for non-diabetics as well, but it makes this a very appealing medicine.  In mice, a recent article suggests GLP1RA’s reduce brain aging.3  What are the negatives?  First, the cost.  They’re expensive, but if your insurance covers them, you’re lucky.  If not, there are some other tricks to getting it at lower cost.  Second, semaglutide, while once a week, is delivered as an injection–which is a bridge too far for some.  Most importantly, when you take these medications, you lose muscle mass at the same time that you lose fat.  But if you stop taking them, you gain fat.  This effect is especially pronounced in people who are lean, so if you’re taking this medication to lose a few pounds in order to fit into a bathing suit, or a dress, you’re going to ultimately replace fat-free mass or muscle with fat.  So mantra is that if you take this class of drugs you need to lift weights and develop your muscle mass, particularly lower extremity, buttocks, trunk and core muscles.  Finally, even though the official account is that these drugs are not associated with pancreatitis, I’ve had one patient on semaglutide develop a severe case, so that experience sits in the back of my mind.  Nevertheless, these seem to be a class of agents that represent a great leap forward and a great option for people who can afford them.  Liraglutide has quickly gone the way of the Betamax because you have to take it every day, but it’s an option for people whose insurance doesn’t cover other GLP1RA’s.
    6. GLP1/GIP agonists (Tirzepatide):  Mounjaro is the first in class of these drugs and it’s remarkably similar to semaglutide in terms of dosing and effect.  From my experience, it seems to effect greater weight loss with fewer side effects.
    7. GLP1/GIP/glucagon agonists:  These are preclinical molecules that show positive effects in mice, they enhance energy expenditure and lower weight in a manner superior to tirzepatide.
    8. Activin receptor type 2B antagonist (Bimagrumab): once-a-month IV monoclonal Ab infusion from Versanis Bio that blocks the activin receptor, has shown 20% loss of total body fat mass with 5% GAIN of lean muscle mass at 48 weeks in diabetics. Now starting phase 2B.

Investigational Drugs (from this Nature Biotechnology article)

Company Approach Stage of development
Aardvark Therapeutics TAS2R agonist: bitter taste receptor agonists Phase 2
Aphaia Pharma Reawakening nutrient-sensing in intestinal lining cells using
glucose capsules
Phase 2
Rivus Pharmaceuticals HU6: mitochondrial uncoupler (DNP pro-drug) Phase 2a/b
Versanis Bio Activin type II receptor agonist: increases lean muscle mass Phase 2b
Ysopia Bioscience Xia1: single-strain biotherapy based on gut bacterium Christensenella minuta,
found to limit weight gain and normalize metabolic markers
Phase 2
LG Chem Oral melanocortin 4 receptor (MC4R) agonist: hypothalamic target Expected to start phase 2/3 for rare genetic obesity in 2023
Scohia Agonist of GPR40 (free fatty acid receptor 1): regulates insulin, GIP and GLP-1 secretion Phase 2-ready
Shionogi Oral monoacylglycerol acyltransferase 2 (MOGAT2) inhibitor: inhibits fat absorption
and suppresses appetite via GLP-1and other gut peptide release
Phase 1
Inversago Pharma Peripheral cannabinoid receptor 1 (CB1R) small-molecule blocker for metabolic syndrome
complicated by obesity and diabetic kidney disease
Phase 1
Novo Nordisk LAGDF15 (growth differentiation factor 15) agonist: reduces food intake via central mechanism Phase 1
Kallyope Gut-restricted small molecules that act via the gut–brain axis to elicit a systemic response Phase 1
Xeno Biosciences XEN-101: delivers oxygen to the lower gut, mimicking microbiota changes induced
by gastric bypass surgery per ‘air hypothesis’: surgery means more oxygen gets to gut,
leading to more aerobic microbes
Approaching phase 1

Beyond these drugs that are FDA approved to treat obesity, there are metformin, SGLT2 inhibitors, and others that will afford you some weight loss and metabolic benefit and may occasionally be appropriate.  Canagliflozin, an SGLT2 inhibitor, has shown promise in the interventions testing protocol conducted by Richard Miller at the National Institute of Health as a longevity drug.  Metformin is also a promising drug for non-diabetics and is being investigated for its purported life-extension properties by Dr. Nir Barzelai.

1 (Hendricks, E. J., et al. “Addiction potential of phentermine prescribed during long-term treatment of obesity.” International journal of obesity 38.2 (2014): 292-298.)
2 Malhotra, Konark, et al. “GLP-1 receptor agonists in diabetes for stroke prevention: a systematic review and meta-analysis.” Journal of neurology 267.7 (2020): 2117-2122.
3Li, Zhongqi, et al. “Systemic GLP-1R agonist treatment reverses mouse glial and neurovascular cell transcriptomic aging signatures in a genome-wide manner.” Communications biology 4.1 (2021): 1-6.


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