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Simply Suppressing Hedonism or Truly a Magic Bullet for Obesity?

Aaron_VinikAaron I. Vinik, MD, PhD, FCP, MACP
Eastern Virginia Medical School, Strelitz Diabetes and Neuroendocrine Center
Department of Medicine, Division of Endocrinology and Metabolism
Norfolk, Virginia USA

Topiramate is a structurally novel anti-epileptic drug effective in management of various types of epilepsy and prevention of migraine headaches. A sulfamate substituted derivative of d-fructose, it has several properties suggesting that its action in the CNS is legion.

It enhances gamma aminobutyric acid (GABA) activity by binding to non-benzodiazepine sites on GABA receptors, has negative effects on voltage-gated sodium channels and selectively blocks AMPA/kainate, glutamate receptors and has negative modulating effects on L-type high voltage-activated Ca++ channels. These multiple mechanism may contribute to its anticonvulsive, antinociceptive and neuroprotective properties and its ability to relieve pain1 an effect which persists for many months2. A clear side effect which emerged during the course of these studies on pain was the beneficial effects on weight, blood pressure and lipids. Earlier studies on the weight reduction indicated a unique ability of the drug to reduce appetite initially and then to alter metabolism in such a way that weight loss persisted despite the loss of reduction in appetite3. Most recently we (Boyd et al) reported that topiramate improves neurovascular function, epidermal nerve fiber morphology and metabolism in type 2 diabetes patients as well as causing a fall in weight, BMI, systolic and diastolic blood pressure, HbA1c 4 and improved quality of life5. Johnson and Johnson first studied the effects of Topiramate alone as a weight loss drug and an anti-metabolic syndrome drug but the side effects of memory loss, difficulty concentrating and suicidal ideation were thought to be a risk that outweighed the advantages!

In contrast the notion that one should lose weight by speeding up metabolism dates to the early 1930’s. Doctors prescribed a chemical called dinitrophenol which accelerated metabolism but also cause fever, swelling, and was deadly toxic to some people — it was the basis of the formation of the FDA which then banned the use of the compound. Undeterred industry developed amphetamines in the 50’s and 60’s which became popular to boost metabolism and suppress appetite but the risk was addiction and the increase heart rate and blood pressure. Nonetheless the amphetamine, phentermine, remains approved for short term weight loss over 12 weeks. In the 90s a further debacle in this arena was the introduction of a combination of phentermine and fenfluramine or phenfen. This was never FDA approved but more than 18 million prescriptions were written and then in 1997 up to one third of patients, taking the combination developed heart valve abnormalities and Wyeth was forced to withdraw the drug and paid 13 billion in settlements.

When first reviewed by the FDA, Vivus’ Qnexa pill, a combination of topiramate and phentermine was rejected by the FDA requiring more safety information. Recently, the FDA panel re-reviewed the available data and voted 20 to 2 in favor of approving the drug. The chairman of the FDA committee Ken Burman at Washington Hospital in DC said, "The potential benefits of the medicine seem to trump the side effects" but added a cautionary note "but in truth only time will tell." As a physician prescribing Topamax for migraine, addiction or habituation, epilepsy and neuropathic pain and having been involved in the clinical trials, I need to point out that the prescription and use of this drug is not easy. One needs to start with low doses and increase gradually over weekly intervals to allow tolerance with ample warning of its effects on cognition and memory. Similarly in patients with diabetes who have autonomic dysfunction and an increase in sympathetic/parasympathetic tone6,7 sensitivity to the adrenergic effects of phentermine may cause untoward effects on heart rate, palpitations and elevation in blood pressure. Furthermore, physicians need to be alerted to the need for careful withdrawal from anti-epileptic drugs which can result in seizures. Despite these caveats the drug Qnexa which is capable of causing more than a 10% weight loss should be a useful addition to the limited armamentarium we now have. Even 7% weight loss results in significant metabolic benefit as shown in the Look Ahead study8. Since the only FDA-approved drug, orlistat (marketed as Xenical), blocks the absorption of fat which causes steatorrhea, unacceptable to most patients, and the beneficial effects of the GLP-1 agonist Exenatide has untoward effects such as nausea and vomiting, the 75 million people with obesity and our children — one-third of whom born today are destined to become diabetic — will welcome and endorse a pill which will be perceived as obviating the need for defying nature’s proclivity to defending the body against starvation. Of course some will regard this as license to continue to abuse their bodies with fast foods with dense caloric content and the industry-promoted hedonistic pursuits of a nation that over-indulges.

References:

  1. Raskin J, Wang F, Wernicke J, Stroud C, Clemens J: Duloxetine does not affect glycemic control or lipid profiles in diabetic neuropathic pain patients (Abstract). Diabetes 52 : 2, 2004
  2. Donofrio,PD, Raskin,P, Rosenthal,NR, Hewitt,DJ, Jordan,DM, Xiang,J, Vinik,AI: Safety and effectiveness of topiramate for the management of painful diabetic peripheral neuropathy in an open-label extension study. Clin Ther 27:1420-1431, 2005
  3. Ben Menachem,E, Axelsen,M, Johanson,EH, Stagge,A, Smith,U: Predictors of weight loss in adults with topiramate-treated epilepsy. Obes Res 11:556-562, 2003
  4. Boyd,AL, Barlow,PM, Pittenger,GL, Simmons,KF, Vinik,AI: Topiramate improves neurovascular function, epidermal nerve fiber morphology, and metabolism in patients with type 2 diabetes mellitus. Diabetes Metab Syndr Obes 3:431-437, 2010
  5. Boyd A, Casellini C, Vinik E, Vinik A: Quality of Life and Objective Measures of Diabetic Neuropathy in a Prospective Placebo Controlled Trial of Ruboxistaurin and Topiramate. Journal of Diabetes Science and Technology 5: 2011
  6. Vinik,AI, Maser,RE, Ziegler,D: Neuropathy: The Crystal Ball for Cardiovascular Disease? Diabetes Care 33:1688-1690, 2010
  7. Vinik,AI, Maser,RE, Ziegler,D: Autonomic imbalance: prophet of doom or scope for hope? Diabet Med 28:643-651, 2011
  8. Wing,RR, Lang,W, Wadden,TA, Safford,M, Knowler,WC, Bertoni,AG, Hill,JO, Brancati,FL, Peters,A, Wagenknecht,L: Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care 34:1481-1486, 2011

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