Evolving Combination Therapies Needed for Lifelong Weight Control

Obesity remains a fundamental clinical challenge to be aided by a range of new weight loss devices that promise to meet the varying needs of individual patients as spotlighted at Digestive Disease Week.

with Christopher C. Thompson, MD, MSc, Shelby Sullivan, MD, Reem Z. Sharaiha, MD, and J. Michael Gonzalez-Campoy, MD, PhD

Endocrinologists and primary care doctors need no reminder that obesity now affects nearly 40% of the US adult population—clear evidence that is reflected during the many patient visits occurring in every physician’s office on a daily basis.1 Despite the clinically supported benefits, only 1% of eligible patients opt to have bariatric surgery.1

Many more individuals who have a higher body mass index as well as others who may have type 2 diabetes or fall into the ''gray area'' where they are perhaps overweight and may not qualify for insurance reimbursement would benefit from effective weight management procedures. Still the resistance to gastric bypass surgery remains high, and the reasons are varied from thinking such surgery is too drastic to thinking that acquiescing is a sign of failure.

Fortunately, the introduction of a range of new, non-surgical weight control treatments is growing fast, as demonstrated by several devices and procedures that were featured during Digestive Disease Week 2019, a conference of gastroenterologists and other specialists, who came together to share clinical results featuring the latest advances in non-invasive procedures.2-4

These new weight loss devices are not expected to replace bariatric surgery, known to be the most efficacy method of achieving substantial weight loss. Rather, these innovative procedures are more likely to supplement lifestyle and pharmacotherapy or function as an adjunct for patients unwilling or unable to pursue gastric bypass surgery. Perhaps the widening array of weight loss methods will help reverse the ever-increasing rates of obesity and concomitant chronic diseases.

In addition to the novel procedures highlighted last week, there more minimally invasive weight control methods garnered attention at the conference including a new gastric balloon device for which approval is anticipated from the Food and Drug Administration soon.

The new weight loss interventions worthy of consideration are:

  • Endoscopic Sleeve Gastrectomy (ESG) with Overstitch
  • Fecal transplant capsules
  • Spatz3 adjustable intragastric balloon

Extending Use of the Endoscopic Sleeve Gastrectomy Out to Five Years

The endoscopic sleeve gastrectomy, is introduced in an outpatient endobariatric procedure,which resulted in significant total body weight loss,2 said Reem Z. Sharaiha, MD, MSc, associate professor of medicine at Weill Cornell Medicine and assistant attending physician at New York—Presbyterian Medical Center in New York City. Dr. Sharaiha presented results of a five-year follow-up trial using the ESG, which has beendeemed as effective as gastric sleeve surgery.2

This retrospective trial entailed reviewing the experience of 203 patients who were followed over five years, which is far longer than similar studies that provided results for only one to two years.2  The mean age of the cohort was 46 years with 67% of patients being female. The ESG is inserted durng an outpatient procedure that involves placing about 12 sutures in the stomach, changing its structure and leaving it looking like an accordion tube; the net result is in less absorption of calories.

With a baseline body mass index (BMI) of 39 kg/m2, at the one-year mark, overall weight loss was 18.1 kilograms (95% CI 15.820.5, P < 0.0001), with % total body weight loss (TBWL) of 15.2% (95% CI 13.5-16.8, P < 0.0001). Even more compelling, at the 5-year mark that an impressive 89% retention rate, weight loss was 18.7 kg (95% CI 10-27.3, P = 0.0003) with % TBWL of 14.5% (95% CI 8.2-20.9, P = 0.0002).

Of note at 60 months, 69% of patients had achieved a 10% or greater TBWL, which is considered the necessary minimum to convey a reduction in comorbid weight-related conditions such as type 2 diabetes and cardiovascular disease.  Another confirmed trend—weight loss achieved at 3-, 6- and 12- months were predictive of TBWL at 24 months, which appeared to be the interval at which the maximum weight loss was achieved by most patients,2 said Dr. Sharaiha.

Overall, the average maximum weight loss was 17.6 kg (95% CI 15.9-19.1, P < 0.00010), leading to a 6.1 kg/m2 decrease in BMI (95% CI 5.6-6.6, P < 0.0001) and 15.2% TBWL (95% CI 13.5-16.8, P < 0.0001), corresponding to a 5.2 kg/m2 decrease in BMI. After reaching a maximum post-ESG weight loss, patients tended to regain about 14% of their lost weight,2 he said.

Among the risks inherent in the use of ESG were pain and nausea, which while common resolved after a few days after the procedure was completed. Other possible complications, according to the Baylor College of Medicine researchers, were bleeding, gastric leaking, ulcers, and the development of gastroesophageal reflex disease (GERD).2 However, less than 1% of patients experienced any of these complaints, which is an improvement over all forms of bariatric surgery.

"The ideal candidate for ESG is a patient with an initial BMI of 30 to 40 kg/m2," Dr. Sharaiha told EndocrineWeb. The results reflected very sustainable weight loss—with an average total body weight loss of 15% at the five-year mark—accompanied by improvement in T2D, cardiovascular outcomes, and blood pressure.2 The research team intends to follow this cohort out to 20 years.

Fecal Matter Transplants Aim to Reinvigorate Gut Bacteria to Foster Weight Loss

Using capsules filled with fecal matter retrieved from a lean donor, this Harvard-based research team attempted to change the gut microbiota of patients with obesity to achieve weight loss.3 Jessica Allegretti, MD, lead author and director of the Fecal Microbiota Transplant Program at Brigham & Women's Hospital in Boston, Massachusetts, presented the results at DDW 2019.

In this pilot study of 22 patients,3 half of the group took the capsules containing fecal matter while the control group received placebo capsules during this 12-week study. In this parallel study of patients with a BMI of 35 kg/m2 or higher, the researchers randomized participants to receive 30 fecal transplant capsules followed by two doses of 12 capsules over the 12 weeks, or the same volume of placebo capsules. One single, healthy donor, with a BMI of 17, was used to donate the fecal samples.

Two biomarkers: glucagon-like peptide-1 (GLP-1) and leptin were measured and stool was collected at baseline and at 1-, 4-, 6-, 8- and 12-week periods in the post-treatment phase. The researchers assessed the data for a change in the area under the curve (AUC) for GLP-1 at 12 weeks compared to baseline; secondary endpoints were gut microbiome profiles and diversity as well as bile acid profiles.3 Measurements of BMI and waist circumference were evaluated at week 12.

Overall, no increase in GLP-1 was seen in either group. The change in leptin AUC showed an increase only in the placebo group; no changes in BMI were reported, according to Dr. Allegretti.

However, there were global signals of donor community engraftment and increased similarity in bacteria population in stool samples in patients in the treated arm but not the placebo group. No safety issues or side effects were noted.3

While the results fell short in achieving the primary objective of weight loss, it's too soon to abandon this research,3 Christopher C. Thompson, MD, MSc, director of endoscopy at Brigham & Women's Hospital and associate professor of medicine at Harvard Medical School in Boston, Massachusetts, and a study investigator, told EndocrineWeb. "This was very, very early results, but the data are compelling and suggest that we are changing the microbiome," he said, so there is good reason to pursue this line of study.

Intragastric Balloons—A Competition Environment with More Options

With three FDA-approved intragastric balloons on the market—Obalon, Orbera and ReShape, the companies have been advancing the differences in their respective devices such as efficacy of weight loss.

In one of the most beneficial types of research, a team from Washington University in St. Louis, Missouri and the University of Colorado in Denver conducted a head-to-head assessment of the three intragastric balloons as well as ESG and Aspire Assist, an aspiration treatment,4 and presented their results at DDW 2019.5

The retrospective cohort study encompassed 94 patients who received one of the therapies between October 2015 and April 2018. The primary endpoint was percent total body weight loss (% TBWL) and percent excess body weight loss (% EBWL) at six months after undergoing implantation of one of the devices in patients who completed more than 20 weeks. They looked at safety endpoints, such as ER visits, intolerance, GI bleeding.4

The treatments were comparable in terms of efficacy and safety,4 achieving a percent TBWL (P < 0.519) as follows:

  • 12% for aspiration
  • 12.4% for Obalon
  • 9.9% for Orbera
  • 10.9% for ReShape
  • 4.6 for ESG

Endpoints for EBWL for each procedure (P <  0.072) was:

  • 25.7% for aspiration
  • 56.7% for Obalon
  • 29.8% for Orbera
  • 37.4% for ReShape  
  • 47.9% for ESG

The researchers acknowledged that results of this single center study indicated that the five treatments under review were comparable in terms of efficacy—that is the percent total body weight loss and the percent excess body weight loss at 6 months—were comparable with no device among these five offering significantly improved outcomes.5 The five devices proved similar in terms of safety, with no serious adverse events reported for any of the devices studied,5 according to Dr. Sullivan.

Therapeutic Twist Introduced in Application of Spatz Balloon Enhanced Weight Loss

The next innovation in the minimally invasive, endoscopic weight control device sector is likely the Spatz adjustable balloon, currently under review by the FDA. In the clinical trial, increasing the balloon volume after the fourth month triggered a second round of weight loss.6

Of all the devices and procedures presented at DDW 2019, the greatest buzz centered around this adjustable balloon that is meant to be left in place for up to a year. The device is meant for those with a BMI of 27 kg/m2 or higher who had not had a prior weight loss surgery, and expressed a willingness to make advised lifestyle changes.6

In following 13 females with a mean BMI of 34.9%, researchers found the percent total body weight loss continued at 3-, 5- and 8 months, (6.9% vs. 8.% vs. 10.7%, P <0.005).6 The adjustability feature, said Shelby Sullivan, MD, associate professor of medicine and director of the Gastroenterology Metabolic and Bariatric Program at the University of Colorado School of Medicine, Aurora, helped remedy weight loss plateaus,7 which is a common problem for many individuals attempting weight loss.

Rethinking Outcomes and Goals to Focus Efforts on Benefits Beyond Weight Loss

While the 2013 obesity guidelines issued by the American Heart Association, American College of Cardiology, and the Obesity Society often refer to a 5% weight loss as being linked with health benefits such as a reduction in hemoglobin A1C and fasting glucose,7 the goal of any weight loss procedure should be higher, said Dr. Sullivan.

While the obesity guidelines do infer that more is better: "I argue that if you really want to make an impact on mortality [and other outcomes], achieving and sustaining weight loss of at least 10% of baseline BMI should be the norm,” he said.

As emerging and many of the newer therapies continue to be studied, combination treatment will become much more common, said Dr. Thompson. For instance, if the fecal capsule study bears out, it could be used by gastric balloon patients to improve their outcomes, he told EndocrineWeb.

Instituting Combination Therapy is the Future of Weight Management

Any procedure to support weight loss is welcome, said J. Michael Gonzalez-Campoy, MD, PhD, FACE, medical director and CEO of the Minnesota Center for Obesity, Metabolism and Endocrinology in Eagan.

"Any procedure for weight loss is welcome. However, for most patients who have adiposopathy, overweight or obesity, it will take a combination of therapies—to include better nutrition, physical activity, pharmacotherapy, non-invasive procedures, and surgical procedures, to achieve successful treatment. Which combinations are used will be patient-dependent, and will require individualized care," Dr. Gonzalez-Campoy told EndocrineWeb.

The other important caveat, he stressed, is to remind your patients that "regardless of the approach, adiposopathy is a  life-long disease, so the approach to weight management will be for life." And that means that ''what may be effective for an individual patient may change over time. These newer therapies are likely to provide better options for implementation of 'precision medicine,''' he said.

As such, tailoring the weight management approach to the patient should be based on the success rates for a given treatment as well as individual patient characteristics.

Dr. Sullivan consults for UCI Medical, Obalon, Elira, Aspire Bariatrics and Spatz and has stock warrants in Elira Therapeutics. Drs. Sharaiha, Thompson and Gonzalez-Campoy had no financial conflicts.

Continue Reading:
Classifying Patients with Obesity to Predict Bariatric Surgery Outcomes
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