Gibbs Biomedical Consulting

The popular idea that drinking red wine may hold the key to a longer lifespan has come under renewed skepticism according to data in an article published recently in Nature 477:482-485 (Sept. 2011, http://www.nature.com/nature/journal/v477/n7365/full/nature10296.html).  Data reported in this article by senior authors David Gems and Linda Partridge at University College London “… cast doubt on the robustness of the previously reported effects of sirtuins on lifespan in C. elegans and Drosophila.”  The relevance of this work to the ‘red wine/longevity hypothesis’ is that the Nature study presents compelling evidence that sirtuins, the putative target at which certain compounds in red wine exert their beneficial effect, are not involved in the aging hypothesis.  If sirtuins are not involved in affecting the aging process, then the hope that activating this pathway by drinking red wine will not be of benefit.

Nicolas Wade published an interesting commentary on the sirtuin controversy in The New York Times (Sep. 21, 20011, http://www.nytimes.com/2011/09/22/science/22longevity.html?_r=1&hpw) in which he briefly summarizes the opinions of the authors of the current work as well as the lead author of the original work that implicated sirtuins in the aging process, Leonard Guarente of the Massachusetts Institute of Technology.  The two research groups have markedly different opinions about conclusions of all of the sirtuin studies.  The universal nature of the topic of aging has made this a fertile field of research over the last decade and the ultimate conclusion about whether activating the sirtuin pathway by drinking red wine or another method will await more definitive research.  Red wine is still meant to be enjoyed, but the hope that it might add years to ones life by activating the sirtuin pathway has been dealt a serious blow.

As reported by Andrew Pollack in The New York Times on Feb. 1, 2010 (http://www.nytimes.com/2011/02/02/business/02drug.html?ref=health) the Food and Drug Administration declined to approve yet another new prescription medication for the treatment of obesity.  On Dec. 7, 2010 the F.D.A. advisory committee had voted 13-7 in favor of approval of the drug, Contrave (Orexigen Therapeutics, San Diego, CA). In despite of this positive  recommendation, the F.D.A. decided to reject approval of Contrave, pending positive results being obtained in a long-term cardiovascular outcomes clinical trial.  Somewhat surprisingly, the F.D.A. ruled that this study would have to be conducted prior to approval of Contrave.

Contrave was the third obesity drug that the F.D.A. has declined to approve in the last few months, and this action sends a clear message that safety is of paramount concern for the agency to approve future drugs for this indication.  The time and cost of conducting cardiovascular outcomes trials before approval will surely cause Pharmaceutical and Biotech companies to reassess their plans for continued investment in this area of great unmet medical need.

See the article directly below for further perspective on Contrave and anti-obesity therapies.

As reported in The New York Times on Dec. 7, 2010 (http://prescriptions.blogs.nytimes.com/2010/12/07/f-d-a-panel-backs-new-diet-pill/?ref=health), an F.D.A. advisory committee recommended approval of the weight loss drug, Contrave (Orexigen Therapeutics, San Diego, CA), by a voting margin of 13 to 7.  While not required to do so, the F.D.A. usually follows the committee’s advice and is expected to formally approve Contrave by Jan. 31, 2011.  Contrave is a combination of two currently marketed drugs, the opiate antagonist, naltrexone, which is used to treat alcohol and opiate addiction, and the antidepressant, buproprion, which is also marketed as an aid to help quit smoking.

While this author agrees that diet and exercise should be the first strategy for weight control, this common sense approach has been spectacularly unsuccessful in today’s industrialized society as current obesity rates in the U.S. approach 30%, and at least 60% of American adults are overweight.  In light of these grim statistics, a safe and effective weight-loss medication would be extremely beneficial in combating the serious morbidities associated with obesity (e.g. diabetes and heart disease).

It is not clear that Contrave will meet this unmet medical need as only one of two efficacy standards for F.D.A. approval for a weight-loss medication were achieved in the four clinical trials conducted by Orexigen.  Patients taking Contrave in these trials lost an average of 4.2% of body weight compared to those patients taking a placebo pill;  the F.D.A. suggested standard is a minimum of 5% weight loss greater than that observed in the placebo group.  Contrave did meet the second F.D.A. standard in that twice as many patients on Contrave lost at least 5% of their body weight as patients on placebo. In addition to producing only modest efficacy, small increases in blood pressure and pulse rate were observed in these clinical trials. Because of these cardiovascular signals, a large post approval trial designed specifically to assess cardiovascular morbidity and mortality will be required.

Safety results from this large clinical trial combined with additional efficacy results post-approval when larger numbers of patients will take Contrave will determine how much benefit this therapy will provide in the obesity epidemic.  In addition to the current strategies of diet/exercise, bariatric surgery, and Xenical (Roche, Nutley, NJ), a fourth option for the treatment of obesity should be available in the near future.  Clearly, more options are still necessary and research in this field should remain a top priority for funding by the NIH and at pharmaceutical and biotech companies.

Almost a quarter of a century ago, Dr. Bruce Spiegelman and his colleagues at the Dana-Farber Cancer Institute (Boston, MA) first identified a fat-cell specific nuclear regulatory element (Cell 49:835-847, 1987) that was subsequently shown to bind the transcriptional activator, peroxisome proliferator-activated receptor gamma (PPAR-g).  While the findings of Dr. Spiegelman’s laboratory were of major academic interest at the time, there was no connection made between his seminal work and the ongoing drug discovery efforts in many pharmaceutical companies that had identified various thiazolidinedione molecules as potential antidiabetic and/or hypolipemic drugs in the late 1980’s and early 1990’s using animal models as primary screening tools.  As drug-discovery efforts advanced, the biochemical mechanism of action for the efficacy of this class of compounds remained a mystery.  The classical empirical drug-discovery approach yielded results as multiple compounds reached the clinic, and three drugs  eventual were approved by the FDA for the treatment of type 2 diabetes, troglitazone (Rezulin®), pioglitazone (Actos®), and rosiglitazone (Avandia®) (Current Pharmaceutical Designs 2:85-102, 1996).

It was only during the middle stages of these drugs’ development that it was discovered that at least one of their major mechanisms of action was binding to, and activating PPAR-g (J.Biol.Chem. 270:12953-12956. 1995). At this time, advances on the basic science front from Dr. Spiegelman’s laboratory as well as a host of others merged quite nicely with the classical drug discovery efforts of multiple pharmaceutical companies and the identification of potentially life-changing drugs were being discovered.  However, as borne out by clinical results, the early promise was tempered as Rezulin® was withdrawn from the US market in 2000 due to idiosynchratic liver toxicity, and Avandia® may soon be withdrawn due to cardiac toxicity.  The third drug of this class to be approved, Actos®, remains on the market for treatment of type 2 diabetes.

Excitingly, a very recent report from Dr. Speigelman’s laboratory (Nature 466:451-456, 2010) has demonstrated that PPAR-g activators also have another key biochemical action that likely contributes to their beneficial antidiabetic effects.  These recent results demonstrate that PPAR-g activators inhibit phosphorylation of PPAR-g by various stimuli that contribute to increased obesity.  Importantly, inhibition of PPAR-g phosphorylation levels are not directly associated with transcriptional activation of the nucleus.  Still more importantly, analysis of clinical results strongly suggest that inhibition of PPAR-g phosphorylation in fat correlates with antidiabietic efficacy.  These crucial findings have led to the obvious conclusion that identification of specific inhibitors of PPAR-g phosphorylation may yield efficacacious antidiabetic drugs devoid of the myriad of the deleterious effects of PPAR-g transcriptional activators, as recently summarized by Drs. Riekelt Houtkooper and Johann Auwerx (Nature 466:443-444, 2010)

Thus by a long and circuitous route, and after over two decades of continued pursuit of fat-cell transcriptional activators, results produced in Dr. Spielgelman’s laboratory may yet lead to an efficacious, and safe antidiabetic therapy.  Lets all hope for such a rewarding conclusion.

A recent article by Dr. Ranit Mishori in the popular lay news magazine ‘Parade” (http://www.parade.com/health/2010/05/can-this-surgery-cure-diabetes.html) brought the question of whether bariatric surgery might be a cure for type 2 diabetes to the public’s attention.  Her article was timely in that the Diabetes Surgery Summit’s (DSS) consensus recommendations on the use of bariatric surgery to treat patients with type 2 diabetes was just published by Dr. Francesco Rubino and his co-delegates in the “Annals of Surgery” (March 2010, Vol. 251, No. 3, pp 399-405).  For the first time, this consensus statement provides the criteria and safety standards needed to guide the use and further development of bariatric surgery (i.e., gastric bypass, Roux-en-Y, laparoscopic gastric banding, or similar procedures) for the treatment of obese type 2 diabetics.  While this type of surgery is currently only an option for obese patients, further advances in surgical techniques and obtaining a better understanding of the mechanisms responsible for the improvement in glucose control should make this promising therapy more commonplace in an expanded patient population.

Succinctly, the two major DSS recommendations are:

1)                  Bariatric surgery is recommended as a “reasonable treatment option for patients with poorly controlled diabetes and a BMI > 35”.

2)                  Surgery may also be appropriate for type 2 diabetic patients with a BMI of 30-35.  Further clinical trials with this patient population was deemed a priority to establish a fact-based foundation to base further recommendations for the less obese and/or non-obese type 2 patients.

Published studies examining the effect of bariatric surgery in severely obese type 2 diabetics have demonstrated remarkable efficacy in “curing” diabetes, or putting the disease in long-lasting remission (75-90% efficacy).   Normalization of glycemic control independent of weight loss has been reported by numerous investigators, as recently summarized in a meta-analysis by Dr. Abdulzahra Hussain and colleagues in the Canadian Journal of Surgery (Dec. 2009, Vol. 52, No. 6, pp E269-E275).

There has been a dramatic decrease in mortality resulting from bariatric surgery over the last decade as minimally invasive protocols have been improved, with the current mortality rate being about 0.5%.  This mortality rate compares favorably with that in the poorly controlled diabetic population over time. Many major pharmaceutical companies are investing heavily into research aimed at the ultimate goal of providing chemical or biological agents that could mimic the effects of bariatric surgery.  The key to pharmacological success lies in the ability to unravel the underlying biochemical mechanisms responsible, and then to produce drugs that can safely mimic the process.

Clearly further research is warranted to firmly establish safety and efficacy in the mildly obese type 2 diabetic population, and if warranted clinical studies should be extended to non-obese type 2 diabetics.  Until positive outcomes are achieved in research studies, it is premature to think that bariatric surgery is appropriate beyond the patient population defined in the DSS consensus statement.

A study published online Feb. 5 in The Lancet (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61998-X/fulltext) and superbly highlighted in the New York Times (http://www.nytimes.com/2010/02/05/business/05diabetes.html 2/5, B1, Singer) reports that “a novel computer algorithm that analyzed children’s glucose levels and recommended frequent adjustments in their insulin doses was better at preventing overnight hypoglycemia, which is dangerously low blood glucose, than a standard diabetes management system.”  None of the patients in the study who were treated using the computer-driven algorithm experienced hypoglycemia, whereas nine instances of hypoglycemia occurred out of nineteen patient nights amongst the children that were using the standard treatment.

The study authors utilized a glucose monitoring system that allowed “real time” assessment of blood glucose levels and combined this capability with an insulin pump in a “closed-loop” system that allowed more precise delivery of required insulin increments.  Both of these critical individual components are commercially available, and the success of this small study may spur a race by biomedical device companies to develop a fully automated and integrated system that theoretically would function as an “artificial pancreas.”  Study leader Dr Roman Hovorka said: “This is the first randomised study showing the potential benefit of the artificial pancreas system overnight using commercially-available sensors and pumps.”  The authors conservative interpretation of their results is that “Closed-loop systems could reduce risk of nocturnal hypoglycemia in children and adolescents with type 1 diabetes.”

Karen Addington, chief executive of the Juvenile Diabetes Research Foundation (JDRF), who co-funded the research said the study provided “proof of principle” of an artificial pancreas.  “We need to redouble our efforts to move the artificial pancreas from a concept in the clinic to a reality in the homes of children and adults with type 1 diabetes.” In fact according to the JDRF, their sponsored “Artificial Pancreas Project (http://www.artificialpancreasproject.com/) stands on the cusp of a breakthrough that represents the first step toward dramatically improving the lives of millions of people with type 1 diabetes: an artificial pancreas, an automated system to disperse insulin based on real-time changes in blood sugar levels.”  As part of the Artificial Pancreas Project, in January of this year the JDRF announced an $8 million partnership with Animas, a Johnson & Johnson company that manufactures insulin delivery and glucose management systems, to develop a first-generation artificial pancreas.  Hopefully, these research efforts will soon translate into real treatment options for patients with type 1 diabetes.

The Lancet study was funded by the Juvenile Diabetes Research Foundation, the European Foundation for Study of Diabetes and the Medical Research Council.

We all are familiar with the old axiom that ‘if it sounds too good to be true, then it most probably is’; well in this case the old axiom may be wrong and ‘one can have their breakfast and eat it too’.  In her new diet book entitled “The Big Breakfast Diet: Eat Big Before 9 a.m. and Lose Big For Life” (Workman Publishing), Dr. Daniela Jakubowicz, a clinical professor at Virginia Commonwealth University and the Hospital de Clinicas, Caracas Venezuela, promotes the idea that eating a larger than normal breakfast that is stuffed with high quality carbohydrates and protein, followed by a low-carbohydrate, low calorie diet the rest of the day reduces cravings for high-calorie food.  Over time, this appetite reduction results in a more markedly reduced sustained weight loss than would occur if one were to eat a very low-carbohydrate diet that is even lower in calories than the big-breakfast diet.  Many diet advocates have long stressed the importance of eating a good breakfast as part of an overall weight loss program, but this diet makes breakfast the key meal of the day. Read more…

Paula J. Caplan, a clinical and research psychologist at Harvard University wrote in a perspective article in the Boston Globe (01/24/10) that one commonly overlooked cause of obesity in many Americans is the use of second generation antipsychotic medications, which are strongly linked to weight gain and metabolic dysfunction. Its amazing that the link between these antipsychotic medications, such as the best selling drug, Zyprexa, remains little known despite the fact that it has been six years since the leading medical associations encompassing obesity, diabetes, endocrinology and psychiatry issued a joint statement proclaiming just such a link (Diabetes Care, Vol. 27, Number 2, Feb. 2004; 596-601). Read more…

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