Arya M. Sharma, MD

Regular readers will be aware that we currently have virtually no effective drugs for the treatment of obesity (which, interestingly, leaves the field wide open for the snake oil pedlars, who, in addition, enjoy an apparently ‘free-for-all’ unregulated scam-artist utopia).

That said, one can only wonder why, despite billion dollar investments, the pharma industry has not been able to bring a single new anti-obesity drug to market in North America since 1999. Is perhaps the regulatory bar simply too high?

This issue is the subject of a discussion paper by Morgan Downey (author of the Downey Obesity Report), Christopher Still (Geisinger Obesity Institute) and myself, published in the latest issue of Current Opinions in Endocrinology, Diabetes & Obesity.

As we point out, since July 2010, the FDA’s Endocrine and Metabolic Advisory Committee has reviewed three new drug applications and one previously approved drug for the treatment of obesity - all three new drug applications were declined while the one existing drug (sibutramine) was ‘voluntarily’ pulled from the market despite a split vote by the Advisory Committee.

In this paper we examine in detail the Advisory Committee’s consideration of the risk–benefit equation of the four drugs, especially in light of its decision on sibutramine and the results of the SCOUT study.

Currently, the FDA’s criteria for effectiveness for anti-obesity drugs has two alternatives: The first is a mean efficacy defined as medication-associated weight reduction of 5%. The alternative criteria is a categorical efficacy endpoint defined as a significantly greater proportion (at least 35%) of those individuals receiving the medication, compared with controls, maintaining a 5% weight loss from their initial weight. Demonstrating the resolution of any obesity associated comorbidities is not a requirement (although, it perhaps should be - see below).

These effectiveness criteria are certainly not the rate limiting step - at least one of these effectiveness criteria was met by all of the existing or newer medications.

The problem appears to lie rather in the FDA’s apparent ‘zero-tolerance’ for adverse effects, clearly holding anti-obesity drugs to far higher standards than any other prescription medications currently on the market.

Curiously enough, while the components in two of the combination medications (Qnexa and Contrave), have been around for decades and are widely used for depression or smoking cessation (bupropion), seizures or migraines (topiramate), narcotic and alcohol dependency (naltrexone), or short-term weight loss (phentermine), these drugs were deemed too ‘dangerous’ for the treatment of obesity.

Unless, the Advisory Committee (which notably lacked any members with clinical expertise in obesity management), does indeed believe that obesity in itself is not a condition worthy of pharmacological treatment, one can only speculate whether the FDA and its advisors believe that both health professionals and obese patients are largely incompetent when it comes to ascertaining risk/benefit rations for themselves or in following prescription information.

Thus, as we point out:

“…panelists expressed doubts as to the reliability of physicians to prescribe an antiobesity drug appropriately, the reliability of patients to take the drug as prescribed, the limited value of the label information, the limited value of primary care providers to work with patients on complex problems like obesity, the lack of predictability that a REMS program, or a program of limited distribution would be successful and whether insurance companies would reimburse for the drug.”

This, attitude unfortunately reeks of bias and discrimination against both health professionals who treat obesity, as well as people who have this problem.

After all, for every other indications, the FDA appears perfectly happy with approvals that include all kind of warnings and caveats - apparently these ‘warnings’ work fine for other indications like high blood pressure, diabetes, or heart failure - it is only when used for obesity treatment that suddenly all these regulatory measures are ineffective.

“One can ask, therefore, whether this skepticism extends to other areas of medical practice or are these concerns sui generis to obesity. If so, are they based on evidence or assumptions about the behavior of patients with obesity and the doctors who treat them?”

On the other hand, it may simply be that the FDA

“…currently does not view obesity as a serious disease and so any risk is too great.”

If this is indeed the case, our recent publication of the Edmonton Obesity Staging System may provide a ready solutions - as our studies show, while for some individuals carrying a few (or even substantially more) extra pounds may have little or no health risk, for others obesity related health problems pose very severe risks, shortening 20 year survival by 10 years!

So while ‘no-risk’ is acceptable for using drugs to treat obesity in ‘healthy’ overweight or obese individuals, considerable risk (as long as it is less than the natural risk of this condition) may well be acceptable for patients with higher Stage obesity.

In addition, as pointed out before, much needs to be done to prospectively define specific target populations based on an etiological framework rather than simply on the presence of excess body fat.

Will the FDA and other regulators change their views on this?

I don’t know. What I do know is that until that happens, few pharma companies will dedicate the necessary resources or invest in the large and extensive trials needed to bring new anti-obesity drugs to market.

In the meantime the beneficiaries of this lack of insight will be the snake oil pedlars on the one hand and bariatric surgeons on the other. The clear losers will be the millions of people struggling with obesity and its consequences.

AMS
Calgary, Alberta

Disclaimer: I have received speaking and consulting honoraria from makers of anti-obesity drugs.

Downey M, Still C, & Sharma AM (2011). Is there a path for approval of an antiobesity drug: what did the Sibutramine Cardiovascular Outcomes Trial find? Current opinion in endocrinology, diabetes, and obesity, 18 (5), 321-7 PMID: 21878755

As readers of these pages are well aware, there is currently only one prescription drug (orlistat) for the long-term management of obesity and recent applications for new anti-obesity drugs have run into considerable obstacles with licensing agencies, not least the US Food and Drug Administration.

Thus, despite meeting criteria for efficacy, recent applications for new anti-obesity drugs were rejected due to safety concerns, the argument being that the expected widespread use of these drugs warrants higher standards of safety than for drugs in other therapeutic areas.

This may well be true, if anti-obesity drugs are indeed to be made freely available (even on prescription) and are to be used without careful consideration of the risk/benefit ratio.

As discussed previously in the context of bariatric surgery, the risk side of this equation is not limited to the ‘risk’ associated with treatment but must also include the ‘risk’ associated with not treating the condition.

As our recent papers on the Edmonton Obesity Staging System (EOSS) clearly show, the ‘risk’ associated with obesity varies considerably - from virtually no risk for patients with EOSS 0 to very significant and immediate risk for patients with EOSS 3.

So, while even the smallest treatment-related risk may be unacceptable for treating obesity in a patient with EOSS 0, a higher level of risk would be certainly be acceptable with higher EOSS stages - or in other words - the greater the risk of not treating, the greater the acceptable risk for a potentially beneficially treatment (which, for e.g., is why cancer warrants the considerable treatment risks of chemotherapy).

Of course, this would mean that rather than having to prove the safety and efficacy of anti-obesity drugs in anyone with a BMI over 30, it may be enough to show that these drugs are effective and safe enough to warrant their use in people with higher EOSS stages (2/3) - the greater the risk of the target population, the greater the acceptable risk of treatment.

This should not be difficult. We know that many of the conditions that patients with EOSS 2/3 present with can be ameliorated even with rather modest weight loss. For these patients, the 5-10% sustainable reductions in body weight that can be achieved with anti-obesity drugs, can have very significant health benefits, which would easily outweigh and justify a reasonable risk of adverse effects - a risk that may be unacceptable in patients presenting with EOSS 0/1 obesity.

This, of course means rewriting some of the approval criteria and guidelines for anti-obesity drugs, but also requires redesigning pharmacological trials to focus on the high-risk EOSS 2/3 patients rather than on the low-risk EOSS 0/1 patients.

I certainly look forward to following how this discussion evolves and wether or not we can indeed find a way out of the current impasse of anti-obesity drug development and approval.

AMS
Toronto, Ontario

Padwal RS, Pajewski NM, Allison DB, & Sharma AM (2011). Using the Edmonton obesity staging system to predict mortality in a population-representative cohort of people with overweight and obesity. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne PMID: 21844111

Kuk JL, Ardern CI, Church TS, Sharma AM, Padwal R, Sui X, & Blair SN (2011). Edmonton Obesity Staging System: association with weight history and mortality risk. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme PMID: 21838602

Over the past two days, I have been discussing the role of leptin in the physiology of human energy regulation.

I discussed the fact that much of the hypometabolic and orexegenic response to weight loss can be attributed to a fall in leptin levels below a leptin ‘threshold’.

I also discussed findings that replacing leptin can attenuate the hypometabolic and orexogenic response to weight loss, thereby potentially making it easier to keep weight off.

So how good is the evidence from leptin treatment studies and why has leptin not found its way into clinical use for obesity management?

First of all, this is not because leptin is not available or ineffective in humans.

Leptin is highly effective in promoting weight loss in rare individuals with congenital leptin deficiency and can dramatically correct diabetes and other metabolic problems in individuals, who lack leptin due to lipodystrophy.

But, as discussed in yesterday’s post, simply injecting leptin (even at higher doses) in obese individuals does not necessarily result in appreciable weight loss - so leptin alone cannot be a ‘weight-loss’ treatment.

Rather, if at all, it would have a role in the prevention of weight regain.

This idea was nicely demonstrated by Leibel and colleagues in a now classic paper published in the Journal of Clinical Investigation in 2005.

In this study, 10 inpatient subjects (5 males, 5 females [3 never-obese, 7 obese]) were examined under 3 sets of experimental conditions:

(a) maintaining usual weight by ingesting a liquid formula diet;
(b) maintaining a 10% reduced weight by ingesting a liquid formula diet; and
(c) receiving twice-daily subcutaneous doses of leptin sufficient to restore 8 am circulating leptin concentrations to pre-weight-loss levels and remaining on the same liquid formula diet required to maintain a 10% reduced weight.

During leptin administration, energy expenditure, skeletal muscle work efficiency, sympathetic nervous system tone, and circulating concentrations of thyroxine and triiodothyronine returned to pre-weight-loss levels.

In a subsequent study from Leibel’s lab also published in the Journal of Clinical Investigation in 2008, leptin was shown to reverse the increased neuronal activity in brain areas known to be involved in the regulatory, emotional, and cognitive control of food intake.

Thus, together, these studies strongly suggest that the weight-reduced state may be regarded as a condition of relative leptin insufficiency and that prevention of weight regain might be achievable by reversing this leptin-insufficient state, in this case by replacing leptin.

This idea was taken a step further by Amylin and Takeda, who partnered in a clinical development program on a combination of pramlinitide, an analogue of the hormone amylin, released by the pancreatic beta cell and involved in glucose homeostasis and satiety, and metreleptin, a recombinant leptin analogue.

After promising results in early studies (with about 13% weight loss), this program recently ran into problems due to the appearance of antibodies to metreleptin in a couple of trial participants. It is not clear when or if this development program will continue.

This, in short, is the current status of leptin as a treatment for obesity and one will have to see how this development program moves forward.

Nevertheless, it also seems prudent to determine whether there could in fact be a regulatory pathway to license a drug for weight-loss maintenance.

I, for one, have no doubts that many individuals who have lost serious amounts of weight would probably be quite open to the idea of having to resort to daily injections to keep the weight off and would perhaps even prefer injections to having bariatric surgery.

AMS
Edmonton, Alberta

Disclosure: I have received consulting honoraria from Amylin/Takeda the makers of pramlintide/metreleptin

Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, Gallagher D, Mayer L, Murphy E, & Leibel RL (2005). Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. The Journal of clinical investigation, 115 (12), 3579-86 PMID: 16322796

Rosenbaum M, Sy M, Pavlovich K, Leibel RL, & Hirsch J (2008). Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli. The Journal of clinical investigation, 118 (7), 2583-91 PMID: 18568078

Yesterday, I posted about the presentation of Columbia University’s Rudy Leibel on how losing weight results in a hypometabolic and orexogenic response mediated largely by a fall in plasma leptin levels that, as a rule, accompany any attempt at reducing fat stores.

This post elicited a number of responses that I will try to address in this follow-up post.

Several readers wanted to know whether there is a way to readjust your ‘leptin sensitivity’ so that the brain no longer wants to restore body weight to pre-weight loss levels.

The short answer is ‘no’. Although there are several proposed strategies (special diets, refeeding days, exercise strategies, etc.) floating around in the popular literature, there is very little scientific evidence that this can actually be done. The sad fact is that anyone, who has ever lost weight, has to continue with efforts to keep it off - this includes people who have had bariatric surgery, who if they ever decide to reverse their surgery - will rapidly gain their weight back (even after years of keeping it off). This, by the way, is why bariatric surgery has to be seen as a definitive and permanent solution and why temporary devices like gastric balloons, which have to be eventually removed, are not a permanent treatment for obesity.

Another reader wanted to know, that if this was true, why some people are successful in maintaining long-term weight loss.

The answer to this is that these individuals somehow manage to continue their efforts (whatever those may be) in the long-term. The best studied group of individuals who have succeeded in the long-term are perhaps those represented by the National Weight Control Registry, who, using various strategies manage to reduce their caloric intake to about 1400 KCal (the same amount that is effectively eaten by successful post-bariatric surgery patients) combined with considerable amounts of exercise (upto 400 KCal worth every day). Such ongoing efforts are clearly beyond what most people can do without completely changing their lives. So, what the NWC participants actually demonstrate, is not so much that sustaining weight loss is possible but rather that this requires an almost ’superhuman’ effort (some would say ‘obsession’) - indeed the NWC registrants represent a rare minority of people attempting to lose weight by diet and exercise alone (the NWC registry has a few thousand registrants compared to the tens of millions who try losing weight every year).

Finally, some readers wondered about ‘leptin resistance’, a term often used to describe the fact that obese people apparently need higher circulating levels of leptin (hyperleptinaemia) to suppress their appetite and burn more calories than lean people.

In his talk, Leibel made clear that ‘resistance’ may not be the best way to describe this phenomenon.

Rather, he preferred to refer to an elevated leptin ‘threshold’, implying that there is an upward shift in the levels of leptin required to suppress the orexogenic and hypometabolic response elicited by caloric restriction.

Leibel prefers the term threshold, because even in people with a high threshold (i.e. obesity), once you have administered enough leptin to restore baseline levels and suppress the orexogenic response that follows weight loss, there is no further decrease in appetite, even at higher leptin doses. This is why simply injecting additional leptin into a person who is at their usual weight (i.e. prior to weight loss) has little to no effect on appetite, which incidentally, is exactly why leptin does not produce weight loss and would not meet thergulatory criteria for as a weight-loss drug (the rare exception being in individuals who are born with a genetic lack of leptin).

Perhaps the difference between ‘resistance’ and ‘threshold’ can best be understood by comparing leptin to insulin. In people who are resistant to insulin (e.g. patients with type 2 diabetes), you can ‘overcome’ this resistance by simply injecting increasing amounts of insulin. Even in the most insulin-resistant individual, you can eventually lower blood glucose levels by injecting more insulin - if you inject too much, these individuals will experience hypoglycemia, i.e. experience the physiological impact of too much insulin.

In contrast, the hypometabolic and orexogenic state following weight loss will respond to leptin injections only up to a dose that is just high enough to restore pre-weight-loss levels (the threshold level) - adding additional leptin will not increase metabolism or suppress appetite further.

Thus, while people with insulin resistance will respond to increasing doses of insulin to the point of hypoglycemic shock, people with an elevated leptin threshold will achieve a maximum metabolic and anorexogenic response (albeit at higher levels than people with a lower threshold) beyond which leptin has no further effect.

This may seem like a ’semantic’ distinction but from a treatment perspective (and the science behind it), this difference is substantial and explains why high doses of insulin can always be used to treat diabetes even in the most insulin-resistant individual whereas leptin only works upto the point where it restores levels to the respective (pre-weight loss) threshold.

Obviously, the key question is why some people have a higher leptin threshold or rather why this threshold (that can also be thought of as the famous ’set point’) only seems to move in one direction (namely to higher levels) and then becomes permanent (unless it is moved to even higher levels by weight gain).

As Leibel explained, the reason that this leptin threshold appears permanent, may be due to the fact that it becomes ‘hardwired’ into the brain - a process that is essentially irreversible (perhaps with the exception of patients with cancer cachexia). It is therefore perhaps not surprising that it actually takes neurosurgery (in animal experiments) to ‘reverse’ this threshold - an approach that is clearly not feasible in humans.

Several readers also asked whether leptin is available and whether it works in humans to help keep weight off - more on this topic tomorrow.

In the meantime, here is a link to a previous post on Leibels ‘Threshold Theory‘.

AMS
Edmonton, Alberta

One of the concerns of undergoing gastric bypass surgery is the impact on gut absorption of essential nutrients.

Although, with modern gastric bypass surgery, the length of gut that is bypassed is rather limited (around 80-120 cms) and all known nutritional deficiencies are generally manageable with dietary monitoring and supplementation, the impact of this surgery on medications is less well known.

Thus, although most patients undergoing gastric bypass surgery will experience substantial improvement or even remission of many obesity related comorbidities, they may still require to take medications for conditions that persist, reoccur with subsequent weight regain, or are unrelated to excess weight in the first place.

This is also true for diabetes medications. While most patients can often discontinue their diabetes medications after gastric bypass surgery, this is not true for all patients and some, despite experiencing marked improvement in the first few years after surgery, may find diabetes creeping back (which is why it is fairer to use the term ‘remission’ rather than ‘cure’ in this context).

This means that there will always be patients who have undergone gastric bypass surgery who may require to continue on or restart their diabetes medications over time.

One of the most widely used oral medications for type 2 diabetes is metformin, a drug that activates the enzyme AMP-kinase and primarily acts by reducing sugar production in the liver (gluconeogensis). In addition, metformin has positive effects on insulin sensitivity, glucose uptake and fatty acid oxidation.

Unfortunately, however, metformin also has rather low bioavailability and slow, incomplete gastrointestinal absorption. It is therefore reasonable to assume that gastric bypass surgery may further limit the absorption of this drug.

We now tested this hypothesis in a study, the results of which were just published by Raj Padwal and colleagues (University of Alberta, Edmonton) in DIABETES CARE.

We performed a nonblinded, single-dose pharmacokinetic study in 16 nondiabetic post-gastric bypass patients and 16 sex- and BMI-matched control subjects (mean age 40 years and BMI 39.2 kg/m(2))

Plasma metformin levels and urinary excretion were measured over 24 hours following the administration of two 500-mg metformin tablets.

Compared with control subjects, gastric bypass subjects has a 20% increase in area-under-the-curve consistent with a 50% increase in bioavailability of metformin (41.8 vs. 27.8%).

Thus gastric bypass surgery, rather unexpectedly, increases metformin absorption, a finding which may have implications on dosing and risk for toxicity in such patients.

Limitations of the study include the use of a single dose and perhaps the fact that all patients were non-diabetic.

Nevertheless, our findings suggest that clinicians should be aware of this paradoxical increased bioavailability of metformin after gastric bypass surgery and may need to adjust doses and monitor patients accordingly.

AMS
Edmonton, Alberta

Padwal RS, Gabr RQ, Sharma AM, Langkaas LA, Birch DW, Karmali S, & Brocks DR (2011). Effect of Gastric Bypass Surgery on the Absorption and Bioavailability of Metformin. Diabetes care PMID: 21478461