Managing Obesity Through Pharmacology

Review

“Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guideline” Apovian, et. al. J Clin Endocrinol Metab, February 2015, 100(2):342—362

Study Methods

This evidence-based guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system by consensus of members of the Endocrine Society, European Society of Endocrinology and Obesity Society.

Using an evidence based approach, a consensus panel of experts were convened to offer guideance on the medical management of obesity. They performed a systematic review of the literature and analyzed weight changes associated with 54 medications. Studies included were RCTs, retrospective and meta-analyses. Cost was not considered in these recommendations.

Results & Outcomes

This expert panel begins this medication review with the admonition to: “recommend that diet, exercise, and behavioral modification be included in all obesity management approaches for body mass index (BMI)_25 kg/m2” and then offers advice on when to use more aggressive treatment: “ and that other tools such as pharmacotherapy (BMI _ 27 kg/m2 with comorbidity or BMI over 30 kg/m2) and bariatric surgery (BMI _ 35 kg/m2 with comorbidity or BMI over 40 kg/m2) be used as adjuncts to behavioral modification.”

With this as a guiding principle, they reviewed the efficacy of a variety of on and off label medications, the data of which is summarized below.

Obesity

Orlistat: Weight loss of 2.9-3.4 kg at 1 year; considered minimally effective, and limited by side effects (flatulence, oily spotting, fecal urgency)

Phentermine/topiramate ER: Weight loss of 6.6-8.6 kg at 52 weeks; most effective,but costly; side effects include insomnia, dry mouth, constipation, dizziness

Phentermine: Weight loss of 3.6 kg at 2-24 weeks; approved in 1960’s and considered safe but only short term data available on efficacy; side effects include headache and CHD

Lorcaserin: Weight loss of 3.6 kg at 12 months; mildly effective; side effects include headache, nausea, dry mouth; should be used with CAUTION with SSRI’s, SNRI’s, triptans, buproprion.

Naltrexone/bupropion: Weight loss of 4.8% at 52 weeks; considered effective but expensive; use with caution in those with hypertension, eating disorders and drug and alcohol withdrawal.

The expert panel recommends to only use medications that are approved for weight loss. In patients with co-morbidites where medications may benefit both diseases, they recognize the following medications as potentially useful. Below is a listing of the impact on obesity of certain medications per disease state.

Type 2 Diabetes mellitus:

GLP-1 agonist, Liraglutide, weight loss of 2 kg.

Pramlintide, amylin analog, weight loss of 2.7 kg.

SGLT-2 inhibitors had 2% weight loss at 12 weeks.

Metformin had weight loss of 1-3 kg.

Insulin had 10 kg weight gain in 3-6 months with basal insulin 1.9 kg gain in 1 year.

Adding metformin, amylin analogs or DPP-4 inhibitors to insulin mitigates gain.

Glimepiride and Pioglitazone had 1 and 3 kg gains respectively.

Hypertention:

β-blockers associated with gain of 1.19 kg with carvedilol and nebivolol having the least.

ACE inhibitors/ARBs were weight neutral.

Antidepressants:

Of SSRIs, Paroxetine is associated with weight gain but others are weight neutral. TCAs are associated with weight gain. Mirtazapine is associated with 1.5 kg gain. Data on SNRIs are lacking. Bupropion had weight loss of 1.3 kg.

Antipsychotics:

>7% weight gain in 30% on Olanzapine, 16% Quetiapine, 14% Risperidone, 12% Perphenazine, 7% Ziprasidone. In youth, gain was 3.8-16.2 kg with Olanzapine, 0.9-9.5 kg with Clozapine, 1.9-7.2 kg with Risperidone, 2.3-6.1 kg with Quetiapine and 0-4.4 kg with Aripiprazole.

Antiepileptic drugs:

Felbamate, Topiramate (loss over 5 kg for use > 16 weeks- Obes Rev. 2011 May;12(5):e338-47), Zonisamide are associated with weight loss.

Gabapentin, Pregabalin, Valproic acid, Vigabatrin, Carbamazepine had weight gain.

Lamotrigine, Levetiracetam, Phenytoin are weight neutral.

Oral Contraceptives:

Weight neutral, but trials exclude obese women.

HIV:

Antiretrovirals associated with increased visceral adipose tissue, and gain of 8.6 kg.

Chronic inflammatory disease:

Glucocorticoids associated with 1.7 kg gain at 1 year compared to sulfasalazine.

Conclusion:

This clinical practice guideline summarizes data regarding pharmacologic treatment of obesity and effects on weight of medications used to treat hypertension, T2DM, depression, psychosis, seizures, HIV and chronic inflammatory disease in obese patients. They recommend choosing medications with favorable weight profiles when possible and monitoring weight and lipid profiles when weight gain is expected.

In patients with T2DM, anti-diabetic medications that promote weight loss should be used in addition to metformin especially in patients requiring insulin as this mitigates weight gain.

For hypertension, ACE inhibitors, ARBs and CCBs should be first-line in obese hypertensive patients when appropriate.

In depression, Bupropion is the only antidepressant consistently associated with weight loss. Of atypical antipsychotics, Aripiprazone and Ziprasidone are associated with the least weight gain. None are weight neutral. For anti-seizure medication, Felbamate, Topiramate and Zonisamide are associated with weight loss.

Patients taking HIV medications should be monitored for weight gain, and signs of insulin resistance.

Off-label use of medications approved for other disease states is not recommended for weight loss.

Commentary:

Weight loss is difficult for patients to accomplish with behavioral modification alone. Medications can enhance weight loss and may improve adherence to behavioral change. Weight loss effects of medications are sustained as long as medication is taken but most patients regain weight after discontinuation.

The challenges of helping patients lose weight remain far greater than the ability to lower a Total Cholesterol or Hemoglobin A1C number. Yet, for most diseases, it is the weight loss that is most critical to improving morbidity and mortality. This paper is an outstanding review of the pathophysiology of obesity, with graphics that should be as important to any medical education a the Krebs cycle. It includes the theory behind how to address obesity, and offers both the relative benefits of appropriate use of medication to treat obesity, as well as the risks and benefits from other medications.

There has been a long prejudice against using medication for the treatment of Obesity, yet there is rather fast acceptance for the role of bariatric surgery. This is likely related to the past complications associated with fenfluramine, a drug combined with phentermine that produced beneficial weight loss, but may have induced heart valve disease. Additionally, the medications traditionally used for weight loss have had worrisome side effects, like elevations of blood pressure, and possibly dependence. While these are theoretically true risks, this must be balanced with the severe risks of obesity, which continues to be the leading cause of disease and disability and premature death in the western world.

This European panel clarifies many details about these medications and their use. They conclude with a rationale for us to use medications for weight loss appropriately, and when to consider surgery. Paramount is the understanding that Obesity kills, and limiting our treatment to “diet and exercise” alone will doom the vast majority to many risks, and premature death. Likewise, only addressing laboratory data (eg. using insulin in type 2 diabetes to lower an A1C) only placates our anxiety and misdirects patient’s attention form the cause of their illness.

Learn to use these medications as first line as part of a comprehensive diet and exercise program. Most commonly, for your obese type 2 diabetes, those with hyperlipidemia, and obese patients osteoarthritis of the knees; our past approach of addressing the symptoms or lab outcomes has increased morbidity and turned our focus from true patient outcomes.