ObesityWeek 2018:

Sustained Weight Loss Viable with Diet/Drug Combination Therapy

With Judy Loper, PhD, RDN, and J. Michael Gonzalez-Campoy, MD, PhD

Patients with obesity have achieved significant, even dramatic weight loss when adhering to a very low calorie diet (VLCD), particularly a physician-directed liquid protein diet.1-4 However, the problem has always been that weight loss is usually the easier aspect of weight management; it is the long-term maintenance of weight once lost that continues to elude most individuals with overweight or obesity.4

Now, there is evidence,5 recommending a weight control approach in which patients have been prescribed a very low calorie diet for weight loss followed by a more moderate low-calorie diet plus long-term phentermine; this two-step weight control plan achieved sustained weight loss—so long as they continued to adhere to the therapeutic plan.

Patients still struggle to keeping lost weight off.

Supporting Weight Maintenance after Weight Loss

"We were trying to look at weight maintenance since we can get the weight off," said Judy F. Loper, PhD, RDN, FTOS, director of the Central Ohio Nutrition Center, Inc, in Columbus, who presented the research at the ObesityWeek 2018, in Nashville, Tennessee.5

"We felt that we needed another tool to help patients, besides clinical support, and behavior change," she told EndocrineWeb, leading her team to take a closer look at the efficacy of phentermine as an adjunct to a low calorie diet to sustain lost weight.5

Phentermine—considered a schedule IV drug—a classification given to medications deemed as having the potential for abuse—was approved by the Food and Drug Administration for the treatment of obesity in 1959, and remains the most widely used prescription therapeutic agent for weight loss, 

“Phentermine is generic, and therefore affordable, safe and effective, making it a very appealing choice,” said J. Michael Gonzalez-Campoy, MD, PhD, FACE, medical director and Chief Executive Officer of the Minnesota Center for Obesity, Metabolism and Endocrinology, who reviewed the findings for EndocrineWeb and was not involved in the trial.

Any lingering concerns about phentermine becoming habit-forming, tolerance-building, or addictive have been abandoned,6 he said.

Low Calorie Diet Plus Phentermine to Halt Weight Regain

For this study,5 the researchers enrolled 523 individuals with obesity of which 96 were men.5 For the first phase: weight loss, individuals were given the option of following a VLCD with either Optifast shakes (800 calories) or a food-based restricted calorie plan for a minimum of eight weeks.

“The mean weight loss in patients during the VLCD phase was 14.6%, which was medically significant,” said Dr. Loper. The mean body mass index (BMI) dropped from 48.6 kg/m2 was 39.2 kg/m2; at baseline, the average age was 48.6. Their mean body weight at baseline was 242 pounds; at the end of the very low calorie diet, it was 206.9. 5

Once transitioned to Phase 2, participants were placed on an individually designed, low calorie diet calculated to provide 1,000 to 1,200 calories of solid foods plus phentermine at a dose of 18.75 mg to 37.5 mg daily; the phentermine was titrated up, as needed, in response to complaints of hunger.

Those continuing on in the study were followed for up to five years during which they were asked to return for follow-up visits with a physician and a registered dietitian/nutritionist every 2-4 weeks. At these visits, they attended group classes on behavior change, exercise, and nutrition as well as having their body weight parameters checked.5

"The mean overall weight loss at year one was 15.2%," Dr. Loper told EndocrineWeb. At year 2, 12.5%; year 3, 9%; year 4, 7.9%, and year 5, 7.2%.5 "The phentermine definitely helped."  

"We had minimal side effects," she said. There were a few reported complaints that included: elevated blood pressure, racing heart/palpations, dry mouth, sleep disturbances, and mild agitation.5

Dr. Loper acknowledged that the high dropout rate was problematic. At the end of year two, 73% of the participants had left the study.5 In year three, only 59 patients remained (baseline weight of 212 lb and 193.2 lb at the end of the year and at the end of year four, there were just 34 participants remaining; baseline weight 202.3 lbs; ending of the fourth year at 186.4 lbs. At year five, just 24 remained in the program. These individuals had an initial weight of 210.2 lb and an ending weight of 195.2 lb, for a retained weight loss of 7.2%.5

Further work definitely is necessary to address the poor retention rate, Dr. Loper said.

For Long-Term Weight Control, Look to Diet Plus Medication

"This is an interesting report that also highlights the recidivism common in the management of chronic diseases, and obesity in particular," said Dr. Gonzalez-Campoy. ''Patient education is imperative if we are to improve adherence to a program that steps through interventions (eg, weight loss to weight maintenance) for individual patients; the program must always involve an emphasis on healthy lifestyle strategies," he said, reinforcing this aspect of the Loper study.

The research adds to the sparse literature on the use of pharmacotherapy to maintain the weight loss following very low calorie diet periods, he said.

In addition, the study highlights several points that clinicians should appreciate when working to encourage weight control with patients, Dr. Gonzalez-Campoy told EndocrineWeb.

These include:

  • Very low calorie diet approaches offer an effective way to induce significant weight loss for selected patients who must then be transitioned back to a whole food meal plan, typically also restricted in calories.
  • As weight loss occurs, ''there are very powerful compensatory mechanisms that get activated, which may make further weight loss more difficult. These compensatory mechanisms result in more hunger, less satiety, and a decrease in the basal metabolic rate. Then comes the plateau and weight regain over time.” At this point, he said, patients often feel that the weight loss program is no longer effective or they have become resistant to it. So patients are better prepared, clinicians should communicate to patients about these likely deterrences.
  • For the most favorable results, the same approach often used to treat diabetes, hypertension, asthma, and depression should be employed to tackle obesity, he said. "In the management of chronic diseases, we transition from monotherapy to combination therapy. Therefore, after lifestyle changes that focus on improved dietary strategies and increased physical activity, we add pharmacotherapy, which we titrate up, anticipating a plateau." This process continues, sometimes adding up to four agents.
  • Any weight control plan for obesity or overweight must involve a progression, he said. "Each intervention has a finite effect and we must add to what is in place to overcome the biological compensation to each step of the weight loss [process]."

The Role of Phentermine in Long-Term Weight Management

"We understand that the perceived loss of its therapeutic effect is due, in reality, to the activation of compensatory mechanisms that are engrained in our pathophysiology to preserve stored calories in care of starvation," said Dr. Gonzalez-Campoy.

Still, there is a role for phentermine as a first line pharmacotherapy for overweight or obesity, he said. He recommends it, particularly when patients reach their plateau in weight loss after bariatric surgery. "Clinicians should then be ready to add to phentermine for ongoing weight loss."

One snag, according to Dr. Loper, is that phentermine alone is meant for short-term use, generally indicated for up to 12 weeks. For example, in Ohio, outside a research setting, patients given 12 weeks of phentermine must then go off it and wait six months before they are able to receive another course.7

This discrepancy arises from the historical nature in which phentermine was approved, which occurred in 1959, at which time obesity was not viewed as a chronic disease, as it is now.

Dr. Gonzalez-Campoy addressed these challenges. "Schedule IV drugs require an office visit at least every six months," Therefore, it is possible to write a 90-day prescription for phentermine with one refill, or 30 days with 5 refills, (notwithstanding state regulations like in Ohio).

Short-term use, for which phentermine has been approved for obesity, is interpreted as three months, he said, "It is used off-label for longer periods, which is appropriate."

Meeting Patient Needs Given Outdated Regulations  

Obsolete regulations, for example, such as in Ohio should be rescinded, Dr. Gonzalez-Campoy said. In the meantime, one possible, but costlier, workaround to the phentermine restriction is Qysmia. As of 2018, ''phentermine is approved by the FDA for long-term treatment of obesity in the combination medication Qysmia combined with topiramate," he said.

However, costs may make prescribing this new combined medication an issue. Out of pocket for the combination can be about $400, he says. Some online companies offer it for less, in the mid $250 range. That compares to only about $8 a month for generic phentermine, he says.

When costs are an issue, which for most patients is most of the time, this would translate to allowing for only intermittent pharmacotherapy for a chronic disease, he said. Another major obstacle, a lack of insurance coverage for medications for obesity, also persists.

Neither Dr. Loper or Dr. Gonzalez-Campoy have any financial conflicts of interest.

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