Medications as Modifiable Contributors to Weight Gain

A Role for Clinical Preventive Medicine

Ingrid Kohlstadt, MD, MPH

Disclosures

March 24, 2010

Introduction

Obesity in the United States has grown by 48% in the past 15 years, offsetting the health gains achieved by a 20% reduction in smoking over the same time period.[1] Obesity is difficult to correct, suggesting an urgent role for prevention of every known risk factor. Although not often considered in the list of risk factors for obesity, the medications taken by many people may be contributing to the population's increasing girth.[2]

Unlike poor diet or lack of exercise, medications alone aren't a separate fast track for obesity. Rather, they undermine a person's efforts at lifestyle modification by raising the incline on the uphill struggle to stick to diet and exercise regimens.

Appetite Deregulation: A Food-Drug Interaction

Several classes of medications act centrally to alter the hypothalamic satiety and appetite centers, through mechanisms not yet fully elucidated. Medications can change the amount and type of food that a person selects. Such food-drug interactions are covered only modestly in the medical literature, suggesting that they may be underrecognized.[2]

Clinicians may hesitate to inform patients of the potential of medications to alter appetite. A patient may conclude erroneously that a drug caused weight gain, and therefore discount the importance of lifestyle modification. Clinicians may also be concerned about the lack of evidence of drug-induced weight gain, because most clinical trials last only 6-8 weeks, a timeframe that may be too short for patients to exhibit weight gain. Additionally, insufficient comparative effectiveness data are available to help clinicians select medications that won't affect a patient's appetite. Perhaps discussion of a medication's potential effect on appetite has simply fallen victim to the practical realities of shorter office visits.

On the other hand, reasons to discuss potential effects of a medication on appetite include:

  • Patients who are obese are more frequently prescribed appetite-increasing medications. Counseling on lifestyle modification or a specialist referral may be indicated on the basis of US Preventive Services Task Force recommendations.[3] Children and people with mental illness are 2 groups at increased risk.[4]

  • Informing patients of the possibility of appetite deregulation may prompt a joint decision to choose another medication, use a lower dose, or modify environmental factors.

  • Collective decision-making can improve adherence to a treatment plan.

  • Forewarned patients may be better able to recognize an increase in caloric intake and take preventive measures before weight gain occurs.

Medications that promote adipose accumulation cross numerous disease and therapeutic categories. Both public health and clinical intervention approaches are available to modify the effects of appetite and avoid weight gain.

Medications for Type 2 Diabetes Mellitus

Insulin increases appetite, whether it is exogenously administered or endogenously synthesized. An endogenous effect can occur when a diet high in refined carbohydrates (high-glycemic index foods) is ingested. These foods rapidly raise blood glucose, which, in turn, induces insulin production. When the blood glucose drops as rapidly as it rose, the lingering insulin stimulates appetite, leading to weight gain.

Exogenous insulin similarly stimulates appetite, and the tighter the glucose control, the greater the effect of insulin on appetite. Sulfonylureas increase appetite by stimulating insulin secretion. Another class of medications used to treat diabetes is the thiazolidinediones. Thiazolidinediones contribute to adiposity and cardiovascular disease by encouraging the division and differentiation of fat cells.[5] The potential exists for a combined weight gain effect from increased appetite and more fat cells to store the accompanying excess food intake.

One public health prevention strategy has been to raise the bar on clinical trials for antidiabetic drugs. New therapeutic agents not only need to demonstrate effects on hyperglycemia, but also long-term benefit or neutrality on cardiovascular disease and weight gain.

Clinical applications can be illustrated by our patient John. At age 55 years, John weighed 290 lb and was using insulin and a sulfonylurea to manage his diabetes. He felt hungry all of the time and too tired to exercise. In the process of a work-up for bariatric surgery, John was diagnosed with sleep apnea. From a discussion with his physician, a successful treatment plan without surgery emerged. John's sleep apnea would be corrected, and his insulin would be halved. John would be closely monitored on a reduced-calorie and high-fiber diet, take a biguanide instead of a sulfonylurea, and begin a cardiovascular fitness program.

Medications for Hypertension

Thiazide diuretics,[6] loop diuretics, calcium channel blockers, beta-blockers, and alpha-adrenergic blockers can promote weight gain, generally by increasing appetite. However, not every agent in each of these classes exerts a measurable effect on weight. The more centrally acting medications in a class tend to be the more obesogenic.

Beta-blockers may promote weight gain through 3 additional mechanisms. They reduce the cardiac response to exercise, so that patients expend fewer calories during exercise. Patients may exercise less because of fatigue. Patients taking beta-blockers may also select less healthful foods or overeat as a result of a medication-induced slump in mood.

The angiotensin-converting enzyme inhibitors and angiotensin receptor blockers used to treat hypertension appear to be weight neutral. Combining them with other agents allows lower doses of the appetite-stimulating medications to be used. Lifestyle modification is another effective option that tends to be underused in reducing a patient's medication requirement.

A public health success has been the availability of comparative effectiveness data to guide medication selection. Additionally, more can be done at the public health level to promote the lifestyle interventions of salt restriction, weight loss, stress reduction, exercise, and a diet rich in fruits and vegetables.

From a clinical perspective, it would be strategic to help patients avoid obesogenic medications, circumventing a vicious cycle of weight gain and hypertension.

Medications for Gastroesophageal Reflux

H2 blockers and proton-pump inhibitors, with one possible exception, did not precipitate weight gain in clinical trials and do not directly alter appetite. However, they may contribute to obesity indirectly via well-established biological mechanisms that are currently undergoing clinical study. Both public health and clinical benefits will be derived from testing hypotheses generated from the study of biological mechanisms.

Recent studies suggesting that dietary intake of acidic beverages, such as coffee and vinegar, improves glycemic control may prompt the question: "What are the effects of the converse -- raising gastric pH?" In many patients, gastroesophageal reflux disease (GERD) is the direct result of a poor diet. In these patients, medication may serve as a substitute for a healthful diet: smaller meals; avoidance of saturated fats; and eating more fruits and vegetables -- all habits that promote weight maintenance. The mealtime pH induced by medications for GERD reduces absorption of vitamin B12. This may lead to insufficiency for select individuals because a wide range exists between B12 sufficient to prevent anemia and B12 for optimal adherence to diet and exercise. Chromium is one of the minerals requiring a low pH for adequate absorption. Because chromium is in picomolar concentrations, it is not clinically measured, but suboptimal levels are associated with less favorable body composition across mammalian species and may contribute to appetite deregulation in humans.[7]

Antihistamines

Histamine potentiates leptin and its anorexigenic influence. Medications that block H1 or activate H3 receptors increase appetite by reducing leptin's central activity.[8] From a public health perspective, educating patients about the appetite-stimulating potential of antihistamines can help guide their selection of over-the-counter medications. Identifying the over-the-counter preparations that contain antihistamines among the active ingredients could also be helpful. Some over-the-counter drugs could interact with and even potentiate the obesogenic effects of a patient's prescription medications, but this has not been well studied.

Ella's case illustrates approaches that could be used to mitigate symptoms. It is hay-fever season and Ella's allergies are flaring up. Her physician phones in her yearly allergy prescription, and she finds fast relief. However, Ella's weight loss program is becoming increasingly difficult, to the point at which she is discouraged and doubting her self-discipline. Ella's prescription antihistamine medications are potentially contributing to her dieting difficulties.

If Ella had known that her prescription could make weight loss more challenging, she might have chosen to reduce her exposure to allergens and build up her body's natural defenses by staying well hydrated, thereby requiring less medication. She would have been more likely to view her weight control setbacks differently, in a way that is more conducive to long-term success.

Steroid Hormones

The corticosteroids have been known to increase appetite by their influence on glucose uptake.[2] They promote fat gain and reduce muscle mass, thereby exerting 2 unfavorable influences on body composition. A decrease in muscle mass lowers metabolic rate and required caloric intake, predisposing an individual to additional weight gain.

Sex steroids influence appetite, as demonstrated by the monthly fluctuation in hormone levels among women of childbearing age. During the luteal premenstrual phase, women take in 270 kcal more per day than during the preceding periovulatory phase.[9] Sex hormone imbalances, caused by disease, toxicity, or medication, exacerbate the normal variation in caloric intake. Therefore, hormonal contraceptives, agents that promote fertility, and medications to prevent prostate or breast cancer recurrence could be anticipated to increase appetite. The public health and clinical implications are many and are not discussed here.

Anticonvulsants

Historically, the medications used to treat epilepsy increase appetite. Some newer anticonvulsants can have the opposite effect; they are appetite stabilizing or even appetite suppressing. In theory, genetic tests that are being used to help find the most effective medication for a patient as well as the optimal dose can limit the exposure to obesogenic medications. The ketogenic diet, used to treat epilepsy since the 1920s, is appetite suppressing. Although its mode of action has yet to be elucidated, it was estimated to be effective in approximately half of pediatric patients in a large treatment center. A modified ketogenic diet may be effective, better tolerated, and provide a more balanced nutrient intake.[10]

Psychoactive Medications

Psychotherapeutic agents that act on neurotransmitters cannot be assumed to be appetite neutral, and some can induce profound increases in appetite and subsequent increases in adiposity. Any medication that alters serotonin or dopamine levels centrally will influence the hypothalamic appetite and satiety centers. The outcomes are appetite stimulation and failure to achieve satiety at a set caloric intake, both of which promote weight gain. The neuroactive metal lithium exerts its therapeutic effects centrally, where it also promotes accumulation of adipose through a yet to be elucidated mechanism. In summary, for many patients every therapeutic option is likely to increase appetite.

Patients with mental illness are at increased risk for metabolic syndrome.[4] An 8-state study revealed that people with mental illness across the United States have a 25-year shorter life expectancy.[11] Over half of the years lost were attributed to chronic diseases other than mental illness. Patients were dying from obesity-associated diseases, such as heart disease, diabetes, and cancer, 15 years earlier than the general population. The effects of obesity among those with mental illness may be profoundly life shortening.

The appetite-stimulating effects of atypical antipsychotics have been a topic of recent public health discussion, especially with respect to the use of these therapeutic agents in children. The pediatric indications for antipsychotics are schizophrenia (ages 13-17 years), bipolar disorder (ages 10-17 years), and irritability in autism (ages 5-16 years). Attention-deficit/hyperactivity disorder and aggressive behavior are not labeled indications for these drugs in any age group, primarily as a result of the metabolic and neurologic adverse effects that make the risk-benefit ratio consistently unfavorable.

Weight gain in children is especially concerning because it influences growth in ways not fully appreciated. Furthermore, 80% of obese children become obese adults. Studies conducted under the legislation of the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act demonstrated adverse metabolic effects among children. When the study results were reviewed by the US Food and Drug Administration's (FDA's) Pediatric Advisory Committee in December 2009, the committee voted unanimously to strengthen the labeling about pediatric weight gain on an atypical antipsychotic medication.

At the clinical level, appetite stimulation does not necessarily translate into weight gain, although it is extremely difficult to prevent. An illustration of this point stems from the early clinical trials of atypical antipsychotics. The appetite stimulation and obesogenic potential of these medications were not fully appreciated in the first trials because participants were institutionalized patients who were served fixed-portion meals. An increase in intake is required for the obesogenic effects to manifest as weight gain.

One clinical intervention is to select a medication with fewer metabolic effects. The Clinical Antipsychotic Trials for Intervention Effectiveness study, a comparative effectiveness trial for the treatment of schizophrenia in adults, demonstrated that medications differ in their adverse metabolic profiles.[12] This research has been combined with other data to extrapolate the findings to pediatrics.[13]

Monitoring for the adverse effects listed on the drug labeling facilitates early detection of adverse metabolic effects. Communication between the prescribing specialists and primary care providers, who are often the providers who identify and manage the metabolic drug effects, is especially important.

In summary, the treatment options for many patients with mental illness are limited to choosing the effective medication with the least unfavorable metabolic effects, optimizing their physical health so that a lower medication dose may be effective, restricting caloric intake, and promptly treating associated chronic physical diseases.

Summary

A complex system of brain and peripheral signals entwine to create appetite and satiety. At the hypothalamic nexus, the system is precisely regulated down to the kilocalorie. Select medications across disease entities and therapeutic classes disrupt equilibrium and increase appetite. An evolutionary advantage to the response of appetite stimulation may have existed at one time. However, in the modern era of high caloric intake with comparably low nutrient intake, the deck of cards appears to be stacked against weight maintenance.

In some patients the resulting adipose accumulation is significant. However, on a population basis the relative risk for weight gain from medications has not been well quantified. Even if the contribution of medications to obesity is small, the public health impact will be large because of the high prevalence of obesity.

A common mechanism for drug-induced weight gain is appetite deregulation, but an increase in appetite need not translate into excess caloric intake and deposition of body fat. Behavior and lifestyle management, such as the techniques offered in a specialized weight management center, may help maintain weight. These techniques include eating more slowly and monitoring and limiting caloric intake; staying well hydrated with noncaloric beverages; eating breakfast but not late-night snacks; choosing foods that meet the daily recommended intake of fiber, vegetables, and fruits; and avoiding foods that contain highly processed fats, sugar, and other refined carbohydrates.

Research is needed on how concurrent medications might interact to cause weight gain. Identifying medications that work synergistically to promote weight gain could help guide clinical practice.

Laboratory and genetic testing make it possible to further study how food and nutrients, such as fish, phytonutrient-rich foods, omega-3 fatty acids, and vitamin D (to list a few), can be combined with medications in weight management.[14] Methods to improve the uptake of healthful lifestyles can reduce both the need for medications and a medication's obesogenic potential. Such innovations will have a significant impact on public health.

Author Disclaimer

This article is the scientific work of the author. No endorsement by the US Food and Drug Administration (FDA) is intended or should be inferred.

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