Higher-Dose Liraglutide Creates New Options to Fight Obesity, but Payment Remains a Challenge

Obesity specialists hailed the December 23, 2014,¹ approval of high-dose liraglutide for weight management as a valuable addition to their meager arsenal. Not only is it just the fth prescription drug cleared for long-term use in that capacity,² it also has a completely different mechanism of action from any of the others, so it may help patients who get little benefit from other therapies.

Dosing and usage are perfectly straightforward in obese patients who are otherwise healthy. There is only 1 approved dose—3-mg daily injections—and there is only 1 approved usage—monotherapy. The only real decision is with the sequence of treatment—whether before or after other approved medications. In obese patients who also suffer from type 2 diabetes mellitus (T2DM), however, the options multiply. Physicians can prescribe liraglutide at the 1.2- or 1.8-mg/d dosages previously approved for control of glycated hemoglobin (A1C), or at the new 3-mg/d dosage, and they can use combine liraglutide at any of those dosages with dozens of other medications.

Trials have yet to definitively establish the best strategy for mixing these endless options to maximize weight loss and keep A1C levels in check. There may not even be a “best” strategy beyond experimenting to see what works for each patient. There are, however, considerations that may help physicians experiment intelligently. “Regulators, researchers, and physicians are all beginning to take obesity more seriously, but there is still a tendency to look at it as a secondary problem compared to the ‘serious’ conditions that are often associated with it,” said Louis J. Aronne, MD, the Sanford I. Weill Professor of Metabolic Research at Weill-Cornell Medical College and director of the school’s Comprehensive Weight Control Center, in an interview with Evidence-Based Diabetes Management.

“We need to take obesity as seriously as any other condition and treat it as aggressively, because the more we learn about obesity, the more we realize how much it contributes to so many other problems. We are going to look back in 10 or 20 years and just kick ourselves for delaying medication until BMI 35 or more instead of attacking it with all we had at BMI 27,” he said, referring to thresholds for body mass index (BMI) at which different treatments, including surgery, may be indicated.

There is, unfortunately, an obstacle that prevents physicians today from heeding Aronne’s advice and using anti-obesity medications early and often: insurance coverage. Medicare never pays for them. Medicaid rarely pays for them. Private insurance programs sometimes pay for them, but only sometimes.3 Most patients, moreover, cannot or will not purchase their own medications, because all the anti-obesity drugs approved for long-term use are only available in expensive branded versions. The 3-mg strength of liraglutide, for example, is expected to sell for about $900 a month.⁴

Prices like that, combined with lingering memories about the dangers of older diet drugs, have made long-term anti-obesity medications a niche product in a nation with nearly 80 million obese people. Indeed, a pair of medications approved with much fanfare in 2012, phentermine-topiramate (Qsymia) and lorcaserin (Belviq), each struggled to produce rst-year sales of $30 million.⁵ Physicians and researchers who specialize in obesity have been lobbying payers to change their practices, pointing not only to the American Medical Association’s 2013 decision to recognize obesity as a disease⁶ but also to estimates that obesity-related problems produce $190 billion in healthcare costs per year.⁷

Widespread payer coverage may well be a precondition for widespread use of anti-obesity medications, particularly if the key to real efficacy turns out to be using therapies in combination, a strategy that has proved the most effective way to manage everything from hypertension to cancer. As things stand, however, the 3-mg dose of liraglutide is an option that physicians can use only on the minority of patients who either have insurance that will pay or overstuffed wallets.

Obese diabetic patients who fall into one of those 2 categories are likely to lose considerable amounts of weight with the 3-mg liraglutide dose, which Novo Nordisk markets as Saxenda to separate it from the lower-dose options that treat diabetes under the Victoza brand. A phase 3a trial of the 3-mg version found that diabetic patients who began with an average BMI of 37 typically lost 5.9% of body weight after 56 weeks of use.⁸ Notably, those results were for patients who were new to liraglutide. The typical weight reduction in patients who move to the 3-mg dose after years of using the formula at lower doses is uncertain. Such patients were excluded from the trial.

Of course, now that liraglutide is approved at the 3-mg dose, physicians can experiment for themselves and see what effect the move up from lower doses tends to have on patient weight and blood sugar. That said, physicians who want to maximize weight loss while keeping diabetes in check have many options to try. Strategies endorsed by the Endocrine Society and the American.

Association of Clinical Endocrinologists (AACE) would be to stick with the 1.8-mg dose of liraglutide as a treatment for A1C, perhaps in combination with another treatment class that promotes weight loss, and then to add a different anti-obesity medication on top of that. This regimen would effectively create a combination anti-obesity treatment. ^9,10

Studies show that the individual components of such a strategy can each signicantly impact patient weight. A trial that compared the sodium-glucose cotransporters type 2 inhibitor canagliozin (Invokana) with sitagliptin (Januvia), for example, found that patients who added the former nto combination therapy with metformin and sulfonylurea lost an average of 2.5 kg (5.5 lb), while those who added the latter into the same therapy gained a small amount.¹¹

A trial that compared combining either liraglutide or sitagliptin with metformin found that patients who added the 1.8-mg dose of liraglutide lost an average of 3.68 kg (8.11 lb) in the next year while those who added sitagliptin lost an average of 1.16 kg (2.55 lb).¹² The trial of 3-mg liraglutide, moreover, found that diabetic patients who used the 1.8-mg dose lost an average of 4.6% of their body weight in 56 weeks.⁸ And trials of other anti-obesity medications approved for long-term use found that the average patient typically loses more than 5% of body weight.¹³

The question, of course, is whether combining such treatments will produce the sum of their individual effects, produce somewhat less (because of duplication or interaction), or produce somewhat more (because of synergy). Trials have yet to provide denfinitive answers about any of the countless possible combinations, but the general success of combination therapy against cancer, diabetes, and hypertension gives obesity researchers good reason to hope that benefits will prove additive or even synergistic for regimens that combine medications from unique classes.

If the effects of different medication types tend to add up or enhance one another, the potential benets are clearly signicant. A 250-lb patient who received the average benets listed above from each of those 3 treatments would lose signicantly more than 10% of his or her original body weight, which would constitute a major benefit.

“A 10% reduction in body weight greatly improves nearly every aspect of an obese patient’s life, even if it leaves the patient in the obese category. That degree of weight loss will increase energy and decrease cholesterol, blood pressure, and blood sugar. It will help patients move better and sleep better and be more productive. It’s a huge deal,” said Caroline Apovian, MD, professor at the Boston University School of Medicine and director of the Nutrition and Weight Management Center at Boston Medical Center, in an interview.

Apovian believes that physicians should try to maximize weight loss among overweight patient with diabetes, and that the best strategy for doing so involves combinations of anti-obesity drugs and weight-reducing diabetes medications. Indeed, she is the lead author of new Endocrine Society guidelines that explicitly recommend the combination strategy (and the avoidance, wherever possible, of diabetes medications that promote weight gain).⁹ Guidelines from AACE likewise suggest a combination of medications that reduce weight.¹⁰

“Ideally, you want to get aggressive about weight management before patients develop diabetes. The Diabetes Prevention Program found that a 7% reduction in body weight reduced diabetes risk by 58%,” said Apovian. “But even in people who already have diabetes, a loss of just 5% of body weight is signicant. The Framingham Study showed that it can reduce the risk of cardiovascular disease by 20% and reduce the need for medications that treat hypertension, diabetes, and lipids.”

Medications tend to have a much more variable impact on patient weight than they have on A1C levels, which makes it hard to predict how much patients will lose on individual medications. In the trial of liraglutide 3 mg, for example, the trial in which the average weight loss was 5.9% of body weight, 22% of all patients lost more than 10% of their original body weight, but 50% lost less than 5%.¹⁴ Results from the trials of diabetes medications tend to reveal a similar pattern. A modest average loss arises from a combination of substantial weight loss in some patients and virtually no weight loss in others. Finding a program that produces substantial declines for any particular patient often requires a fair amount of experimentation. It can also depend greatly upon patient behavior.

Some medications can certainly produce signicant weight loss without any help from improved diet or increased exercise. Reductions reported in trials that test medications against conditions other than obesity demonstrate this clearly, because patients in such trials often lose signicant amounts of weight despite receiving no instructions regarding diet or exercise. Still, patients often lose far more weight if they eat better and exercise more when they start taking a weight-reducing drug. While it’s true that the simple act of eating better and exercising more does produce weight loss by itself, patients who start such efforts when they begin taking a weight-reducing medication often see far more additional benet than their lifestyle changes would predict. Some weight-reducing medications, moreover, may only work in combination with diet and exercise, either because such activities trigger their effect or because their effect is making it easier to patients to stick with lifestyle changes.

“We know that initial weight loss is predictive of long-term success and that more weight loss produces more health benets, so we try to maximize the weight lost on each serious attempt,” said Donna H. Ryan, MD, an obesity drug researcher who is a professor emerita at Pennington Biomedical Research Center in Baton Rouge, Louisiana, told EBDM. “To do this, we use multiple approaches together. When patients are motivated to undertake the behaviors necessary to produce weight loss, we negotiate the most intensity in diet and exercise that patients can achieve, and we add in medications to amplify the weight loss response. After about 6 months, when weight loss plateaus, we pivot to a maintenance strategy, and continuing meds is an important part of that strategy. We believe that one of the most important aspects of these medications is that, as long as they are continued, weight loss is sustained. If we stop them, weight regain begins.”

REFERENCES

1. FDA approves weight management drug Saxenda [press release]. Silver Spring, MD: FDA Newsroom; December 23, 2014. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427913.htm.

2. Common weight-loss drugs. Mayo Clinic website. http://www.mayoclinic.org/healthy-living/weight-loss/in-depth/weight-loss-drugs/art-20044832?pg=2. Published October 14, 2014. Accessed February 17, 2015.

3. Andrews M. Many insurers do not cover drugs approved to help people lose weight. Kaiser Health News website. http://kaiserhealthnews.org/news/many-insurers-do-not-cover-drugs-approved-to-help-people-lose-weight/. Published January 6, 2015. Accessed February 17, 2015.

4. Novo Nordisk to promote drug to treat obesity in the United States. Reuters website. http://www.reuters.com/article/2014/12/29/novo-nordisk-obesity-fda-idUSL6N0UD0MB20141229. Published December 29, 2014. Accessed February 17, 2015.

5. Williams S. Have anti-obesity drug prospects finally gone belly up? the Motley Fool website. http://www.fool.com/investing/gen-eral/2014/03/04/have-anti-obesity-drug-pros-pects-finally-gone-bell.aspx. Published March 4, 2014. Accessed February 17, 2015.

6. Pollack A. AMA recognizes obesity as a disease. The New York Times website. http://www.nytimes.com/2013/06/19/business/ama-recognizes-obesity-as-a-disease.html. Published June 18, 2013. Accessed February 17, 2015.

7. Cawley J, Meyerhoefer C. The medical care costs of obesity: an instrumental variables approach. J Health Econ. 2012;31(1):219-230.

8. Phase 3a liraglutide 3 mg trial demonstrated significant weight loss and improved cardiovascular risk factors in adults with obesity and type 2 diabetes compared with placebo [press release]. Chicago, IL and Bagsværd, Denmark: Novo Nordisk Corporate Communica-tions; June 21, 2014. http://novonordisk.com/include/asp/exe_news_attachment.asp?sAttachmentGUID=D869D535-6BD9-432A-84FF-DE4A6E5AFE8E.

9. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an Endocrine Society Clinical Practice Guideline [published online January 15, 2015]. J ClinEndocrin Metab. doi:http://dx.doi.org/10.1210/jc.2014-3415.

10. Gonzalez-Campoy JM, St Jeor ST, Castorino K, et al. Clinical practice guidelines for healthy eating for the prevention and treatment of metabolic and endocrine diseases in adults: cosponsored by the American Association of Clinical Endocrinologists/the American College of Endocrinology and the Obesity Society. Endocr Pract. 2013;(suppl 3):1-82.

11. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sylfonylurea. Diabetes Care. 2013;36(9):2508-2515.

12. Pratley R, Nauck M, Bailey T, et al. One year of liraglutide treatment offers sustained and more effective glycemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomized, parallel-group, open-label trial. Int J Clin Pract. 2011;65(4):397-407. 13. Colman E. Food and Drug Administration’s obesity drug guidance document: a short history. Circulation. 2012;125:2156-2164.

14. Company announcement: people with type 2 diabetes achieve 6% weight loss with liraglutide 3 mg in phase 3a obesity trial [press release]. Bagsværd, Denmark: Novo Nordisk Corporate Communications; March 18, 2013. http://www.novonordisk.com/include/asp/exe_news_at-tachment.asp?sAttachmentGUID=872441e7-92cb-4a08-9bd7-ef262e9c797b.

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