Liraglutide Effects on Upper Gastrointestinal Investigations: Implications Prior to Bariatric Surgery
With the considerable waits that patients in Canada often face prior to bariatric surgery, we generally recommend that patients, who have access to them, try anti-obesity medications while waiting. This not only prevents further wait gain, but also often helps them shed a significant amount of weight prior to surgery.
The GLP-1 analogue liraglutide is now approved for long-term obesity treatment and is generally well tolerated. Nevertheless, we now present a series of patients in Obesity Surgery, who were treated with liraglutide 3.0 mg whilst waiting for bariatric surgery, and showed significant upper GI dismotility that was reversible on discontinuation of liraglutide.
Although, investigations of upper GI motility are by no means part of routine assessment for bariatric surgery, tests may be ordered in patients who present with unclear upper GI symptoms, as the findings may guide the choice of surgical intervention.
In this paper, we present six cases in which patients treated with liraglutie 3.0 mg presented with varying degrees of esophageal and/or gastric dysmotility demonstrated using a variety of investigative procedures including formal gastric emptying scintiography as well as less specific esophageal manometry, and upper endoscopy.
In all cases normal motility was restored on discontinuation of liraglutide and all patients subsequently underwent or are continuing to wait for bariatric surgery.
Based on our observations we discuss that,
“Liraglutide is associated with decreased esophageal peristalsis and gastric emptying. These effects can result in abnormal upper GI investigations, leading to delays, increased testing, and questions of patient candidacy for surgery. If patients on liraglutide are noted to have abnormal esophageal manometry or gastric emptying studies, medication should be discontinued, with repeat studies done to look for reversibility. If this abnormal result is due to drug effect, this should not preclude patients from having bariatric surgery.”
Just how long liraglutide needs to be stopped prior to performing upper GI investigations remains unclear. Furthermore, as the dysmotility often appears to be symptomless and well-tolerated, we do not recommend routine ordering of motility tests in patients treated with liraglutide.
Disclaimer: I have served as a consultant and speaker for Novo Nordisk, the makers of liraglutide.
Readers will recall, that once-weekly injections of the novel long-acting GLP-1 analogue semaglutide was recently shown (in patients with type 2 diabetes) to result in a rather impressive weight loss.
Now, a phase II dose-finding study comparing various oral doses of semaglutide to subcutaneous injections in patients with type 2 diabetes was just published in JAMA.
The 26-week trial with 5-week follow-up included around 600 patients with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized to once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks.
Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, −0.7% to −1.9%) and subcutaneous semaglutide (−1.9%) and placebo (−0.3%);
Significant reductions were also seen in body weight with both oral (dosage-dependent range, −2.1 kg to −6.9 kg) and subcutaneous semaglutide (−6.4 kg) vs placebo (−1.2 kg)>
Adverse events (largely consisting of mild to moderate gastrointestinal events) were as expected and relatively comparable between the treatment arms.
Although this was a diabetes study, these findings clearly hold promise for the further development of an oral formulation of semaglutide for the obesity indication.
Disclaimer: I have served as a consultant for Novo Nordisk, the maker of semaglutide.
Readers may by now be familiar with the GLP-1 analogue liraglutide, which has now been approved at the 3 mg dose (Saxenda(R)) for long-term obesity treatment in a growing number of countries.
Now, Novo Nordisk, the maker of liraglutide, announced preliminary results from their long-acting GLP-1 analogue semaglutide, suggesting a rather remarkable ~14% weight loss in a one-year double-blind placebo controlled dose-finding study.
According to the company’s press release,
In the trial, 957 people with obesity were randomised to treatment with doses of semaglutide between 0.05 to 0.4 mg/day or placebo. Liraglutide 3.0 mg/day was included for comparison. Approximately 100 people were included in each active treatment arm in combination with diet and exercise. All people in the trial were treated for 52 weeks followed by a 7-week follow-up period.
From a mean baseline weight of around 111 kg and a body mass index of approximately 39 kg/m2, a weight loss up to 17.8 kg was observed after 52 weeks of treatment with semaglutide. This corresponded to an estimated 13.8% weight loss compared to the weight loss of 2.3% achieved by diet, exercise and placebo alone, with all treatment arms adjusted for people discontinuing treatment in the study. The results from the liraglutide 3.0 mg treatment arm were broadly in line with previously reported data.
Side effects were mainly reported as gastro-intestinal, as expected from this class of hormone analogues.
Clearly, if borne out by the final publication and confirmed in larger and longer studies, semaglutide may well prove to be even more effective than liraglutide.
It may be worth noting, that the ~14% weight loss reported in this trial comes very close to the mean ~15% weight loss seen with adjustable gastric banding, a bariatric surgical technique that is now increasingly seen as obsolete due to long-term complications and loss of effectiveness.
I’m guessing it’s now on to Phase 3 for this promising anti-obesity drug.
Disclaimer: I have received speaking and consulting honoraria from Novo Nordisk, the maker of liraglutide and semaglutide
Based on the failing access to obesity care for the overwhelming majority of the 6,000,000 Canadians living with obesity in our publicly funded healthcare systems, the 2017 Report Card on Access To Obesity Treatment For Adults, released the 5th Canadian Obesity Summit, has the following 7 recommendations for Canadian policy makers:
- Provincial and territorial governments, employers and the health insurance industry should officially adopt the position of the Canadian Medical Association that obesity is a chronic disease and orient their approach/resources accordingly.
- Provincial and territorial governments should recognize that weight bias and stigma are barriers to helping people with obesity and enshrine rights in provincial/territorial human rights codes, workplace regulations, healthcare systems and education.
- Employers should recognize and treat obesity as a chronic disease and provide coverage for evidence-based obesity programs and products for their employees through health benefit plans.
- Provincial and territorial governments should increase training for health professionals on obesity management.
- Provincial and territorial governments and health authorities should increase the availability of interdisciplinary teams and increase their capacity to provide evidence- based obesity management.
- Provincial and territorial governments should include anti-obesity medications, weight-management programs with meal replacement and other evidence-based products and programs in their provincial drug benefit plans.
- Existing Canadian Clinical practice Guidelines for the management and treatment of obesity in adults should be updated to reflect advances in obesity management and treatment in order to support the development of programs and policies of federal, provincial and territorial governments, employers and the health insurance industry.
If and when any of the stakeholders adopt these recommendations is anyone’s guess. However, I am certain that since the release of the Report Cards, the relevant governments and other stakeholders are probably taking a closer look at what obesity management resources are currently being provided within their jurisdictions.
Given that things can’t really get any worse, there is hope that eventually Canadians living with obesity will have the same access to healthcare for their chronic disease as Canadians living with any other illness.
Just imagine if the question in the title of this post was, “Why would anyone want access to prescription medications for diabetes?” (or heart disease? or lung disease? or arthritis? or, for that matter, cancer?)
Why would anyone even ask that question?
If there is one thing we know for sure about obesity, it is that it behaves just like every other chronic disease.
Once you have it (no matter how or why you got it) – it pretty much becomes a life-long problem. Our bodies are so efficient in defending our body fat, that no matter what diet or exercise program you go on, ultimately, the body wins out and puts the weight back on.
In those few instances where people claim to have “conquered” obesity, you can virtually bet on it, that they are still dealing with keeping the lost weight off every single day of their life – they are not cured, they are just treated! Their risk of putting the weight back on (recidivism) is virtually 100% – it’s usually just a matter of time.
Funnily enough, this is no different from people trying to control any other chronic disease with diet and exercise alone.
Take for e.g. diabetes. It is not that diet and exercise don’t work for diabetes, but the idea that most people can somehow control their diabetes with diet and exercise alone is simply not true. No matter what diet they go on or what exercise program they follow, sooner or later, their blood sugar levels go back up and the problems come back.
You could pretty much say the same for high blood pressure or cholesterol, or pretty much any other chronic health problem (that, in fact, is the very definition of “chronic”).
So why medications for obesity?
Because, like every other chronic disease, medications can help patients achieve long-term treatment goals (of course only as long as they stay on treatment).
Simply put, if the reason people virtually always regain their lost weight (no matter how hard they try to lose it) is simply because of their body’s ability to resist weight loss and promote weight regain, then medications that interfere with the body’s ability to resist weight loss and promote weight regain, will surely make it far more likely for them to not only lose the weight but also keep it off.
Now that we increasingly understand many of the body’s mechanisms to defend against weight loss and promote weight regain (and the body has a whole bag of tricks that you are up against), then pharmacologically blocking these mechanisms makes this a manageable (fair?) fight.
This is by no means easy. Interfering with human physiology always comes at a cost – which is why we need medications that are robustly tested for safety and efficacy (which is why we are here talking about prescription medications and not the nonsense you can buy over the counter in your local drug store or health supplement outlet).
There is of course no guarantee that any one medication will work for or be tolerated by everyone – again, no different from the medications for other chronic diseases (which is why we have so many of them for the same indication).
So who has access to prescription anti-obesity medications in Canada?
Short answer – almost no one.
Thus, in the 2017 Report Card on Access To Obesity Treatment For Adults, released last week at the 5th Canadian Obesity Summit, the less than 20% of Canadians living with obesity (and that is a very generous estimate) have access to the two prescriptions medications approved by Health Canada for long-term treatment of obesity.
Thus, as far a coverage for obesity medications in Canada is concerned,
Neither anti-obesity medication (Xenical® or saxenda®) are listed as a benefit on any provincial/territorial formulary and, therefore, they are not covered under any provincial public drug benefit (or pharmacare) programs.
There may be special-access programs in some provinces that adjudicate coverage for non-formulary medications based on individual case review; however, coverage for anti-obesity medications through these programs are not guaranteed and are, in fact, rare.
Anti-obesity medications are not covered in any federal public drug benefit programs.
Again one must ask, what will it take for governments, employers, and payers to stop discriminating against Canadians living with obesity in our healthcare system?
Disclaimer: I have received honoraria for speaking and consulting for companies that make anti-obesity medications