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When Will We Bridge The Pharmacological Treatment Gap in Obesity?



Readers will recall my recent post on how even modest sustained weight loss (in the 3-10% range) can reduce cardiovascular events in high-risk obese patients (Stage2/3).

Unfortunately, in clinical practice, most patients are unable to sustain even this rather modest degree of weight loss by lifestyle interventions alone. Indeed, the typical long-term weight-loss seen with lifestyle interventions alone is in the 3-5% range, even under the rather artificial (and generally more intense) setting of a clinical trial.

In contrast, patients requiring sustainable weight loss of 20% or greater, may, more often than not, need to seriously consider bariatric surgery.

This leaves a wide ‘therapeutic gap’ for patients requiring sustainable weight-loss in the 5-20% range, which lies beyond what can be generally achieved with lifestyle intervention alone but well below the degree of weight loss that would suggest the need for surgery.

Addressing this ‘gap’ is now widely recognised as one of the most pressing unmet needs in chronic disease management, a need that recently prompted the US Senate’s Appropriations Committee to declare itself  “concerned with the absence of novel medicines to treat obesity” and call the lack of obesity drugs “a significant unmet medical need”.

Unfortunately, thus far, the pharmacological options that may help bridge this gap remain sparse.

One of the few options on the horizon may be Qnexa, a fixed-dose combination of phentermine and controlled-release topiramate, that recently refiled for FDA approval after being sent back to the drawing board in 2010, mainly due to lingering concerns around the potential teratogenicity of topiramate.

However, despite these concerns, Qnexa may be one of the few agents that could potentially help address this therapeutic gap in obesity management.

A recent publication on Qnexa by Timothy Garvey and colleagues, in the American Journal of Clinical Nutrition, certainly allows room for guarded optimism.

This paper presents the results of SEQUEL, a 52-week extension of CONQUER, a previously published 56-week placebo-controlled, randomised double-blind study of placebo, 7.5 mg phentermine/46 mg controlled-release topiramate (7.5/46), or 15 mg phentermine/92 mg controlled-release topiramate (15/92)] in addition to lifestyle modification. Of 866 eligible subjects from CONQUER, 676 (76%) elected to continue for a second year SEQUEL on their assigned treatments.

Overall sustained weight-loss over the extension was –1.8%, –9.3%, and –10.5% for placebo, 7.5/46, and 15/92, respectively, with almost 80% of participants in the 15/92 treatment arm achieving at least 5% weight reduction, 50% achieving 10% reduction, and 15% achieving an over 20% reduction in body weight.

Thus, Qnexa clearly has the potential to bridge that elusive 5-20% therapeutic weight-loss gap between lifestyle intervention and surgery.

Notably, active treatment was also associated with improvements in cardiovascular and metabolic variables and even reduced rates of incident diabetes (annualised event rates dropping from 3.7 on placebo to 0.9 on 15/92).

While the participants randomised to active treatment did experience more drug-related adverse (‘side’-) effects (e.g. constipation, paresthesia, dry mouth, etc.), these were fully consistent with the known profile of the respective drugs (phentermine and topiramate), both of which have been on the market as single agents for decades (phentermine for weight loss and topiramate for migraines and convulsive disorders).

But then, nobody really expects anti-obesity drugs to be completely free of side-effects. As with bariatric surgery, the question ultimately comes down to a risk/benefit assessment — the question is never whether a treatment is risky or not — the question is always whether or not risk of treatment outweighs the risk of not treating.

While for a low-risk obese individual (Stage 0/1), even the seemingly safest obesity treatment (including diet and exercise) may sometimes outweigh the risk of doing nothing, in high-risk obese individuals (Stage 2-4), even the risk of surgery (still far greater than the risk of any obesity medications to date) may appear well worth taking.

I believe it is fair to say that no anti-obesity drug will ever be safe enough to be used by people who don’t need it — this, however, does not mean we should continue denying effective treatments to those who do.

AMS
Dallas, TX

Disclaimer: I have received consulting and speaking honoraria from various pharmaceutical companies, including Vivus, the maker of Qnexa.

ResearchBlogging.orgGarvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, Schwiers M, Day WW, & Bowden CH (2011). Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. The American journal of clinical nutrition PMID: 22158731

5 Comments

  1. I’m in that range, and I would consider taking a drug that hasn’t been tested for decades riskier than staying the size I am. It’s my belief that being moderately physically active is more important for my health than being a bit smaller. But then, I’m fine with the way I look.

    I think that most people my size who want weight loss drugs are either wrongly blaming their low level of fitness on their weight rather than on their habits, or are more concerned about their appearance than their health (though most would never admit it).

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  2. The two novel drug class I am optimistic about is PTP1b inhibitors, which a phosphatase which its substrates are tyrosine-phosphorylated residues on the IRS (insulin-response substrate) proteins and the insulin receptor, and JNK1 inhibitors.

    IRS2 is the second messenger for the POMC (anorexigenic) neurons in the arcuate nucleus in the hypothalamus, which receive input from leptin and insulin. Inhibiting PTP1b increases the life-time of the second message and prolongs signaling, much like how sildenafil (Viagra) increases NO signaling (promoting vasodilation in the penis) by preventing the degradation of the second messenger cGMP. PTP1b mice knockouts have no adverse side-effects, suggesting this class is a viable target in humans.

    How are those drugs coming alone?

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  3. Lol, my comment is up for moderation, presumably because it mentioned a name of a popular pfizer drug and a male anatomical organ.

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  4. One side effect of topiramate not mentioned here is cognitive difficulties. So much, that I’ve seen it dubbed “Dopamax,” Stupamax” and the “Barbie Doll Drug” because it makes you skinny and stupid. The weight loss is a bug, not a feature. I would never in a million years recommend someone take this drug just to lose weight. Every time this one comes up, I want to tear my hair out.

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  5. Black_Rose – thanks for your information and the important rationale behind why you support this new class of inhibitors. While insulin is obviously not the only problem, it’s definitely one of the main antagonists in the story.

    And yes, what’s the news on the progress on of such inhibitors?

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