July 30, 2012 4:40 pm
This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com
Bariatric surgery is not yet ready to be integrated into the standard treatment paradigm for type 2 diabetes, experts told BioPharm Insight.
A study published in The New England Journal of Medicine (NEJM) in April, conducted in obese patients with type 2 diabetes, found that medical therapy plus bariatric surgery worked in more patients than medical therapy alone.
Experts interviewed, however, cited the need for additional randomized, controlled trial (RCT) evidence specifically in the type 2 diabetes population. The authors of the NEJM paper did note that further study will be necessary to assess durability.
Current bariatric surgery procedures work by reducing calorie absorbtion. They include biliopancreatic diversion (BPD), Roux-en-Y gastric bypass, and Allergan’s (NYSE:AGN) LAP-BAND procedure, said Dr Xavier Pi-Sunyer, director, New York Obesity Research Center.
BPD makes the stomach smaller and connects it to the lower part of the small intestine. Roux-en-Y connects a small stomach pouch to the middle of the small intestine, and LAP-BAND is a device placed around the top of the stomach and does not involve changes to the stomach or re-routing intestines.
The BPD procedure is more common in Europe, said Dr Francesco Rubino, chief of gastrointestinal metabolic surgery, Weill Cornell Medical Center, New York.
Current evidence of surgery’s benefit
Touting the benefits of bariatric surgery, Rubino noted the magnitude of glycemic effect, or the modulation of blood insulin and glucose levels, observed with bariatric surgery is “unprecedented.” He noted blood glucose levels are in an appropriate range as early as two weeks post-operatively.
As obesity is largely still viewed as a cultural or behavioral issue, there is a stigma around bariatric surgery, said Rubino. Bariatric surgery is not yet ready to be integrated into regular practice because of this cultural barrier, he said.
The International Diabetes Federation now includes bariatric surgical procedures in its updated 2011 position statement for the treatments and preventions of type 2 diabetes in obese people, Rubino noted.
Pi-Sunyer said, however, there are only three RCTs, including the study in NEJM, comparing medical versus surgical therapy. He questioned building treatment guidelines specifically for the cure and/or remission of type 2 diabetes, regardless of weight, on the basis of three trials. He noted an additional study on the surgical treatment of type 2 diabetes added promising evidence, but it is not acceptable for creating guidelines, as there was no randomization or comparator in the study.
Further study is also required into effects on blood pressure, sleep apnea, heart disease, quality of life, mortality, adverse events (AEs) and cost of surgical therapy relative to medical therapy, said Pi-Sunyer. He conceded reasonably good analyses have been done on AEs and cost thus far.
Pi-Sunyer called for more data on the appropriate procedure to be performed, on what patient subgroups according to body mass index and perhaps genetic data, and where in a step-wise treatment protocol surgery can be performed.
Theories behind how surgery works
The mechanism for the observed reversal in diabetes is unresolved, and the durability of the surgical treatment is unresolved, said Pi-Sunyer. Remission does not appear to be due to weight loss alone, agreed Rubino.
Additionally, considering the amount of weight a patient needs to drop to see blood glucose levels drop sufficiently, weight loss drugs are unlikely to mimic the effects of bariatric surgery unless they exceed that threshold, he said.
Patients need to drop more than just a little weight to see improvements in HbA1c, added Pi-Sunyer. Typically, more than a 5%-10% decrease in body weight is required, though a decrease in calorie consumption usually improves glucose homeostasis - the balance of insulin and glucagon to maintain blood glucose - he added.
Weight loss drugs include Arena’s (NASDAQ: ARNA) Belviq, approved 27 June, and Vivus’ (NASDAQ:VVUS) Qsymia, approved 17 July. Orexigen (NASDAQ:OREX) has a late-stage experimental drug, Contrave.
An ideal goal of therapy would be to induce a shift in the body’s “set point,” – whereby weight loss continues even after food intake levels return to normal, said Bart Henderson, president and founder of private anti-obesity drug developer Rhythm. Gastric bypass is the only therapy proven to do that, he added.
Rhythm is developing a drug that targets melanocortin type 4 receptor (MC4R), as previous non-human studies suggested MC4R plays a role to some degree in the effects of bariatric surgery, Henderson noted.
AstraZeneca (LON:AZN) and Palatin Technologies (NYSEAMEX:PTN) reported 19 June a Phase I study of their MC4R partial agonist, AZD2820, was halted because of a serious AE, suspected to be an allergic reaction following the first dose. Henderson noted allergic reactions are generally compound-specific and not mechanism-based toxicities. This should not have implications for the MC4R mechanism, he added.
Impact of weight loss on diabetes
The effects of weight loss on diabetes and its co-morbidities is often underestimated, added Dr Louis Aronne, clinical professor of medicine, Weill Cornell, and director, Comprehensive Weight Control Program. His center is focused on taking a “weight-centric” approach to diabetes management with a preference for drugs associated with weight loss.
An intervention that causes weight loss will “be the right decision 95% of the time,” he said. While certain patients will see benefit from surgery, a majority of patients can benefit from any type of weight loss, added Dr Harold Lebovitz, professor of medicine, division of endocrinology and metabolism/diabetes, State University of New York, Brooklyn.
He also noted that a drug with a 0.2% mortality rate such as that associated with surgery “would never be approved.” Rubino conceded bariatric surgery is not currently performed on the most ideal type 2 diabetes candidates.
Management of diabetes is more than just lowering of blood glucose as measured by hemoglobin A1c (HbA1c), said Lebovitz. When patients already have complications, intensive HbA1c control is not sufficient, Lebovitz said, calling for additional focus on diabetes complications over the long term.
More than one-third of U.S. adults (35.7%) are obese, according to the Centers for Disease Control. The National Institute of Health estimates 18.8 million people in the US are diagnosed with diabetes and another 7.0 million are undiagnosed, with 90-95% of diabetes being type 2.
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