A Better Way
8/3/10

William M. Blackshear, Jr., M.D., F.A.C.S.
Diplomate, American Board of Bariatric Medicine
Diplomate, American Board of Surgery . Vascular Surgery/General Surgery

Avandia is in the news again. The recent nonbinding vote by an FDA advisory panel to retain the former blockbuster diabetes drug as an option for Type 2 diabetics will in all likelihood be adopted by the FDA in the near future, albeit with significant new usage restrictions and additional safety warnings. Manufacturer GlaxoSmithKline PLC has reacted by booking an additional $2.4 billion charge applied to legal costs. This brings the total charges allocated by Glaxo for this purpose to almost $6 billion, much of which will go toward defending and settling some 11,000 Avandia-related suits, with more surely on the way.

Predictably, these events will spawn a wave of new solicitations from plaintiff’s attorneys alleging that Glaxo concealed adverse results and “knew or should have known” of Avandia’s potential to cause untoward effects. Never one to be left out of the limelight, Congress is also jumping on the bandwagon with calls from Rep. DeLauro and Sens. Grassley and Baucus to withdraw Avandia from the market and to reform the FDA’s post market surveillance protocols. Meanwhile, Avandia’s sales have fallen over 50% from their 2006 high of $2.3 billion – a decrease which Glaxo may judge to be too great to support the continued sale of a drug with ongoing litigation costs.

When released in 1999, Avandia and its sister glitazone, Takeda Pharmaceutical’s Actos, were hailed as major advances in the treatment of Type 2 diabetes. By increasing cellular sensitivity to insulin, blood sugar control was enhanced and insulin resistance reduced. Each drug had successfully navigated the FDA’s rigorous pathway to final market approval – a three phase process of successive clinical trials involving increasing numbers of subjects to determine safety and efficacy and detect adverse effects. This process often takes up to twelve years at a cost of several hundred million dollars. Once approved, a drug is released to the open market and, especially in the case of a drug like Avandia which treats a common medical disorder, is used by a vastly greater number of patients than those in the FDA pre-market trials.

However, this massive expansion in use has a dark side. As the numbers of patient-years with these medications increased, disturbing new reports of adverse effects emerged. An increased risk of bone fractures, congestive heart failure, liver toxicity, anemia, peripheral edema and vision problems from macular edema was noted with both Avandia and Actos. When it was determined that Avandia might increase the risk of myocardial infarction, the circus was on.

It’s an all too familiar story. A heralded new medication representing a major therapeutic advance felled by reports trumpeting alarming findings of detrimental side effects that were not detected in pre-market trials. 2004’s Bextra and Vioxx debacle comes immediately to mind. These potent Cox-2 inhibitors, which relieved pain and inflammation for millions of arthritis patients, were withdrawn when an increase in vascular complications was noted after widespread use. The resultant massive publicity storm and a deluge of lawsuits were fatal for both drugs and significantly curbed usage of their sister Cox-2, Celebrex, and other non-steroidal anti-inflammatory medications (NSAID’s).

In each of these cases the manufacturers were accused, often on flimsy evidence, of deliberately concealing reports of complications or, worse, knowingly bringing harmful drugs to the open market in a display of naked greed in order to recoup their considerable developmental costs. Billions of dollars in judgments and settlements attest to the heavy burden pharmaceutical companies must assume when unexpected adverse reactions torpedo a product from which great returns were anticipated – a burden eventually passed on to patients.

The glitazones and NSAID’s are not the only medications to experience these post market blues. Many other widely used therapeutic agents – drugs and devices alike – treating a broad spectrum of chronic diseases have seen their use questioned and often curtailed after reports of potential adverse effects following market release, including:

Lantus insulin for diabetes – cancer
Foradil, Serevent, Symbicort for asthma and chronic lung disease – asthma related death
Singulair for asthma – suididal thinking/depression
Prozac, Zoloft (and other SSRI’s) for depression – suicidal thinking/violent actions
Seroquel, Risperdal, Zyprexa, Clozaril for psychosis – sudden cardiac failure and death
Baycol (and other statins) for elevated blood lipids – muscle and liver damage
Bisphosphonates for osteoporosis – atrial fibrillation
Nexium/Prilosec/Prevacid/Protonix for GE reflux and heartburn – fractures, colitis, inhibit anticoagulant activity of Plavix
Infuse Bone Graft for bone growth in spine surgery – airway blockage, nerve damage, bleeding
Menaflex device for knee cartilage repair – safety and efficacy concerns

These post market shockers should not be surprising to any student of basic statistics. They are an inevitable consequence of a statistical phenomenon knowing as sampling error. Simply stated, the larger a study’s sample (patient) size, the better its ability to detect small differences in events with a low occurrence rate. Phase 1 and 2 FDA premarket trials typically involve 50-300 patients. Even the larger Phase 3 trials rarely exceed 3,000 subjects. Little surprise that when the patient base expands to millions, differences are noted which were not apparent in the much smaller FDA trial studies. Sampling error can be decreased by increasing the size of the study population, but changing the FDA premarket trial protocols is hardly a viable option since it would markedly increase developmental costs and in all likelihood discourage new drug development. The underlying problem is not greedy, capitalistic drug companies with little regard for patients. It’s a statistical fact of life which will always be with us.

All of the chronic diseases listed above share one common feature. Each is strongly associated with obesity. Over 70% of Type 2 diabetics are overweight or obese, and excess body fat is implicated as a causative factor in patients with chronic lung disease, cancer, arthritis, lumbar disc disease, cardiovascular disease, memory disorders, depression, hyperlipidemia and hypertension. How can patient and doctor navigate the confusing array of post market study statistics, rife with conflicting findings and recommendations from experts, to develop a reasonable approach to managing these chronic diseases?

Clearly there will always be patients whose risk-benefit analysis justifies use of potent, yet potentially harmful, medication. However, instead of electing drug therapy which may have adverse effects, whenever possible a better way to first manage many chronic diseases might be to control patient related factors which either cause or exacerbate the disorder. Foremost on this list is excess body fat. With fully one third of the US population obese and another third overweight (National Center for Health Statistics – 2006), the obesity epidemic is clearly a major contributing factor in the marked escalation of medical costs over the past decade. The Centers for Disease Control and Prevention has estimated the 2008 medical costs of treating obesity related diseases to be in excess of $147 billion and these numbers don’t even include the considerable costs of lost productivity. Estimates of 500,000 US deaths annually from obesity related diseases are probably conservative and far exceed the reduction in all cause mortality projected to result from universal health care. A large dose of nature’s best medicine – prevention – by reducing weight would be a better initial approach to chronic disease.

Does obesity control really work? You bet it does! Numerous reports in the medical literature, particularly those from centers performing weight loss surgery on the morbidly obese, attest to dramatic improvement, and even cure, in virtually every obesity-related chronic disease following significant weight loss in both adults and teens. The author’s own experience with a medical weight loss program chronicles similar improvements in arthritic symptoms, hypertension, diabetes and hyperlipidemia, with many patients reducing or eliminating medication upon which they had been dependent, often for years.

Clearly there will always be a place for medication in the treatment of chronic disease. Weight loss is not a cure-all for everyone. The experience with weight reduction programs, however, strongly suggests that instead of routinely resorting to medication as the initial therapeutic intervention in patients with many chronic diseases, a better way to first deal with these conditions might well be to objectively evaluate patients for excess body fat and, in those who are significantly overweight, first employ a trial of supervised weight reduction with specific target weights or, better, body fat percentages assigned. There are many different methods to lose weight, medical and surgical, and each works for some patients. Taking individual responsibility for one’s health rather than first resorting to therapies with an inherent risk of long term adverse effects is surely worth a shot. Both direct and indirect costs of medical care will decrease as fewer patients undertake costly therapy, thus reducing potential litigation from unexpected adverse outcomes.

Last year in the Wall Street Journal the CEO of Safeway, Inc., described how their health care plan rewarding employees’ healthy behavior quickly capped burgeoning health care costs in their self-insured plan. Safeway’s experience also suggests that by first looking to the individual to take personal responsibility for their own health remarkable dividends to employee and employer alike will result. Controlling patient related conditions, like obesity, seems a better way to initially attempt management of chronic diseases caused or exacerbated by excess body fat. And, it’s a better way to minimize the health and financial impact of unanticipated outcomes from new drugs and therapies…

A better way for individuals to bring their own health care costs under control…

A better way to reassert personal control over health.

Dr. Bill Blackshear practices bariatric medicine and vascular surgery in St. Petersburg, Florida. He is President and Managing Member of Prescription Health Network LLC, a closely held Florida company marketing Prescription Weight Loss Clinic® ranchises and is Board Certified in Bariatric Medicine and both Vascular Surgery and General Surgery.