Liraglutide Leads The Way To Cardiovascular Risk Reduction?
Earlier this week, Novo Nordisk, the maker of Victoza and Saxenda, announced top-line results from the LEADER trial, which investigated the cardiovascular safety of liraglutide 1.8mg over a period of up to 5 years in more than 9,000 adults with type 2 diabetes at high risk of major adverse cardiovascular events. The trial compared the addition of either liraglutide 1.8 mg or placebo to standard care and apparently met the primary endpoint of showing non-inferiority as well as demonstrating superiority, with a significant reduction in cardiovascular risk. According to the news release, liraglutide demonstrated superior reduction of major adverse cardiovascular events in the primary endpoint of the study (composite outcome of the first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke), a reduction that that was derived from all three components of the endpoint. The safety profile of liraglutide in LEADER was reported as, “generally consistent with previous liraglutide clinical studies”. While it is hard to fully interpret the study, the detailed results of which will be reported at the American Diabetes Conference in a few months, this may well be a landmark trial both for diabetes but also for obesity medications. Thus, although LEADER did not test the higher liraglutide 3 mg dose indicated for obesity, it is indeed reassuring that at least the liraglutide 1.8 mg dose indicated for diabetes, did not increase (and even decreased) the risk for cardiovascular complications. This is of importance, as readers may be well aware that the history of anti-obesity medications is plagued with drugs that raised safety concerns regarding cardiovascular events. Thus, while we await the full results of the LEADER trial, there appears hope for optimism that with liraglutide we may finally have a drug for the treatment of obesity that has a favourable cardiovascular safety profile. That would be a landmark indeed. @DrSharma Edmonton, AB Disclaimer: I have received honoraria as a consultant and speaker for Novo Nordisk
Obesity Management Update
A recent issue of The Lancet features a short review article on obesity management by George Bray and colleagues. The paper summarizes the general approach including behavioural (lifestyle), medical and surgical treatments. While the section on behavioural interventions focuses much on the experience of the Look AHEAD trial (of which several of the authors were co-investigators), it adds little to what is already known on this. As I often say, “lifestyle” treatments for obesity are no more important or effective in real life than “lifestyle” treatments for other chronic conditions including diabetes, hypertension or dyslipidemia – without medications, the vast majority of patients with these issues will be “uncontrolled”. Thus, the only real new change in obesity management is the increasing number of anti-obesity drugs available in the US (and hopefully soon elsewhere). The paper gives a nice review over the various medications that have been approved as well as several that are in development. As for obesity treatment with medication, the authors note, “Several guiding principles should be followed when prescribing drugs for weight loss.First, effective lifestyle support for weight loss should be provided during their use. These medications work to reinforce the patient’s attempts to change eating behaviours and produce an energy deficit. Second, the prescriber and patient should be familiar with the drug and its potential side-effects. Third, unless clinically meaningful weight loss occurs after 3 to 4 months, (generally defined as loss of more than 4–5% of total bodyweight in patients without diabetes; in patients with obesity and diabetes, loss of more than 3% of total bodyweight can be considered satisfactory) a new treatment plan should be implemented. No one medication is effective in every patient just as not every patient is appropriate for every medication.” All of the above is correct and could be said about using medications for any other chronic condition – medications for hypertension, diabetes, or dyslipidemia work best when combined with “lifestyle” interventions, both prescribers and patients need to be familiar with the drugs for these conditions and their potential side effects. Obviously, when patients do not respond to or tolerate these drugs, they should be discontinued. Also, for these indications, no one medication is effective for every patient and not every patient is appropriate for every medication. Thus, in summary, medical management of obesity is beginning to look pretty much the same as management of other chronic medical diseases – the only… Read More »
Belanorib: Good Weight Loss Efficacy But Troubling VTE Risk
Yesterday, Zafgen released data from its phase 2b trial of beloranib in patients with severe obesity complicated by type 2 diabetes. Zafgen recently announced that its phase 2b trial (ZAF-203) of the MetAP2 inhibitor beloranib in 152 patients with severe obesity complicated by type 2 diabetes. Accompanying an impressive 12.7 and 13.5% weight loss on 1.8 mg and 1.2 mg beloranib (vs 3.1% for placebo), respectively. Unfortunately, these results are marred by the ongoing concern over potential thrombogenic adverse effects. Thus of the nine serious adverse events identified in eight patients during the trial, one was a pulmonary embolism in the 1.2 mg treatment group. A subsequent screening process (following the FDA’s partial clinical hold on the trial) identified silent pulmonay emboli in two additional patients in the beloranib treatment arms. Currently Zafgen is working to better understand the potential mechanisms underlying the apparent thrombogenic risk as well as developing a risk-mitigation strategy (at least for studies in patients with Prader-Willi Syndrome) that would help resolve the complete clinical hold the FDA placed on the beloranib for now. Thus, the future remains uncertain for what would otherwise certainly be a big step forward to fill the continuing gap of more effective medical treatments for obesity. @DrSharma Gurgaon, Haryana Disclaimer: I have received consulting honoraria from Zafgen, the makers of belanorib
It Is Time Canadian Benefits Plans Begin Considering Obesity A Disease
The recent declaration by the Canadian Medical Association that obesity is a chronic disease not only sends a strong signal to medical doctors to take this issue seriously but also has important consequences for Canadian benefits plans. As international readers may not be aware, while the Canadian publicly funded health care system covers all in-hospital costs and visits to doctors, it does not generally cover cost for medications or consultations with dietitians, psychologists or other allied health professionals in the community. These healthcare costs can be covered by private benefits plans, often paid or co-payed for by employers (plan sponsors). Thus, while consultations in hospital based clinics or primary care units are generally covered, whether or not patients have coverage for medications and other treatments depends on whether or not they have benefit plans. Unfortunately, when it comes to obesity, Canadian drug benefits plans generally do not cover treatments, as these plans consider obesity a “lifestyle” problem rather than a disease (e.g. unlike type 2 diabetes, which although as much a “lifestyle” issue, is covered as a disease). Thus, it will be interesting to see how the declaration of obesity as a chronic disease by the Canadian Medical Association, will change how obesity treatments are covered by Canadian benefits plans. Now a white paper sponsored by Novo Nordisk, the maker of Saxenda, a GLP-1 analogue recently approved for obesity treatment in Canada, outlines why reclassifying obesity as a disease would be of advantage to Canadian employers (who usually decide what is covered in the plans they buy for their employees). The paper summarizes finding from a series of meetings with obesity experts, patients, plan sponsors, benefits providers and advisors, and calls for a rethinking of obesity as a medical condition that can benefit from individualised and ongoing management. While it is obvious why Novo Nordisk would have an interest in better coverage for its anti-obesity drug, it is important to note that the white paper outlines the benefits of treating obesity like every other chronic disease that go well beyond just coverage for obesity drugs – rather it argues how this shift in thinking will benefit all Canadians affected by obesity irrespective of what treatment they chose. The full white paper is available on the Benefits Canada website and can be downloaded here. @DrSharma Edmonton, AB
Promising Data For Setmelanotide For Genetic Obesity
One of the most common genetics variations related to obesity found in the general population involves the melanocortin-4 (MC4) receptor, which plays a key role in appetite regulation. Now Rhythm Pharmaceuticals released its first data on the use of their novel MC4-R agonist setmelanotide in patients with obesity and proven MC4-R defects. According to their press release, “In this pilot study, obese (BMI >/= 30kg/m2) patients with a heterozygous MC4R loss-of-function mutation were enrolled in a double-blind, placebo-controlled, randomized, parallel-group study for 4 weeks. Eight patients (six active, two placebo) received placebo or RM-493 at 0.01 mg/kg/day (~ 1 mg/day) by continuous subcutaneous infusion. Key endpoints were safety, weight loss, waist circumference, and caloric intake. Setmelanotide was well tolerated over 4 weeks, with no serious adverse events or discontinuations. The most common side effects were headache and skin tanning, with the latter believed to be due to off-target activity at the related melanocortin-1 receptor. Setmelanotide demonstrated strong trends for placebo-subtracted weight loss (2.62 kg; p=0.088); WC (5.1 cm; p=0.188) and daily caloric intake (351 kCal/day; p=not significant), without clinically important effects on heart rate or blood pressure.” Overall, the company has taken (the perhaps wise) option of focussing their development program on genetic forms of obesity. Currently they have an ongoing Phase 2 setmelanotide trial for the treatment of Prader-Willi syndrome and a second Phase 2 trial for the treatment of pro-opiomelanocortin (POMC) deficiency obesity, a very rare, life-threatening genetic disorder of the MC4 pathway associated with unrelenting appetite and obesity. Clearly, this will be a space to watch. @DrSharma Edmonton, AB
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