Drug-Induced Weight Gain

Introduction

A variety of prescription medications have been associated with weight gain. These drugs differ in their propensity to increase body weight. The mechanism responsible for medication-induced weight gain has not been carefully studied for most of these agents but may be related to an increase in energy intake (e.g., antipsychotics and steroid hormones), a decrease in energy expenditure (e.g., β-adrenergic receptor blockers), a decrease in energy loss (e.g., decreased glycosuria from diabetes therapy), or a combination of these factors. This chapter will review weight gain associated with several classes of prescription medications, including antidiabetics, antihypertensives, anticonvulsants, steroid hormones and contraceptives, antidepressives and antipsychotics and antihistamines.

Treatment Selection to Prevent Drug-Induced Weight Gain

Drug-induced weight gain is a preventable cause of obesity, and can be avoided by selecting alternative treatments that promote weight neutrality or even weight loss. The desired level of clinical efficacy for a chosen therapy should be balanced against side effects, including the likelihood of weight gain. Clinicians should use a shared decision-making model - an approach where clinicians and patients take treatment decisions jointly, on the basis of best available evidence - to inform patients about the available treatment options and to agree on a treatment plan. Clinicians should also communicate effectively with the patient’s other healthcare providers, and not discontinue any vital medications without consulting the other prescribing providers first. In cases where there are no acceptable therapeutic alternatives, the minimal dose required to produce clinical efficacy may prevent or minimize drug-induced weight gain.

The patient’s initial weight status, the presence of risk factors for cardiovascular (CV) disease, diabetes and other obesity-related health complications, as well as the benefits of pharmacologic therapies warrant careful consideration when prescribing a first-line therapy or change in medication. The expected length of treatment is also a factor, as some medications may be associated with weight loss in the short-term (<1 year), but with weight gain in the long-term (>1 year) and vice versa.

Patients should be informed of potential drug-induced weight gain and educated on weight management techniques, such as proper nutrition, physical exercise and behavioral modification. Individual patient risk profiles can also be assessed. For appropriate medication selection, physicians should consider the weight gain potential of various drugs.

Table 7-1 provides a partial list of drugs and drug classes that contain medications associated with weight gain, weight neutrality and weight loss.

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Antidiabetic Medications

Many patients with type 2 diabetes (T2D) have overweight or obesity, both of which are associated with increased patient risk of CV events and mortality. Unfortunately, weight gain is often associated with many diabetes therapies. Patients can gain as much as 10 kg after initiating treatment with insulin, sulfonylureas other insulin secretagogues and the thiazolidinediones (TZDs). The causes of this weight gain are not fully understood but are thought to be due to drug-induced changes in the body’s metabolic control, which result in a state of positive energy balance, eventually leading to weight gain. Weight gain is of particular concern in patients with diabetes, because of the rise in insulin resistance associated with excess weight and obesity. Taking into consideration weight gain as well as other side effects of antidiabetic medication, the American Association of Clinical Endocrinologists (AACE) / American College of Endocrinology (ACE) Diabetes Management Algorithm recommends metformin, glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RAs) and SGLT2 (sodium glucose cotransporter 2) inhibitors as the preferred therapies for T2D treatment. All three have been associated with weight-loss in patients with T2D.

The most commonly used oral agent for the treatment of T2D is metformin. Metformin promotes weight loss by multiple mechanisms, including reducing hepatic glucose production and intestinal absorption of glucose, while improving insulin sensitivity. Due to the inconsistent effects of metformin on weight loss, the Food and Drug Administration (FDA) has not approved it as a treatment for obesity and it is currently used off-label for weight loss by many providers. The 2016 AACE/ACE Guidelines for the treatment of patients with obesity do recommend the use of metformin in select patients with obesity who are diagnosed with prediabetes and insulin-resistance and who do not respond to anti-obesity medications and lifestyle treatments.

Similarly, dipeptidyl peptidase 4 (DPP-4) inhibitors are considered to be a weight-neutral class and are ranked fourth in the hierarchy of recommended usage in the treatment algorithm for T2D. DPP-4 inhibitors exert slightly less pronounced blood glucose reductions than metformin but have better gastrointestinal (GI) tolerability. They lower plasma glucose by enhancing insulin release and reducing glucagon secretion. DPP-4 inhibitors in combination with metformin have been shown to be safe and effective for patients with T2D. A study comparing a DPP-4 inhibitor and metformin with pioglitazone in patients with T2D showed that the DPP-4 inhibitor/metformin treatment combination resulted in weight loss (-1.4 kg) while pioglitazone led to weight gain (3.0 kg).

Newer classes of drugs now exist that target pathways which actually promote weight loss, including the injectable GLP-1 RAs exenatide, dulaglutide, liraglutide 1.8 mg daily, semaglutide 1.0 and 2.0 mg weekly, tirzepatide (5.0-15.0 mg weekly) and oral semaglutide. The majority are subcutaneous injections which act by mimicking the GI incretin hormone glucagon-like peptide-1 (GLP-1), which is normally released in response to food intake. GLP-1 RAs enhance glucose-dependent insulin secretion, suppress glucagon and slow gastric emptying. GLP-1 RAs also improve glycemic control, decrease food intake and enhance satiety. A recent study has demonstrated a 7% reduction in mean body weight following treatment of patients with both T2D and a BMI ≥27 with 1.0 mg of semaglutide—a dose approved for T2D. The newly-approved 2.0 mg weekly dose of subcutaneous semaglutide produces even greater weight loss than the 1.0 mg weekly dose. Head-to-head comparison trials have demonstrated that subcutaneous semaglutide is superior to exenatide and dulaglutide for weight loss, while oral semaglutide 14 mg once daily is superior to subcutaneous liraglutide 1.8 mg daily. Tirzepatide, the newest GLP-1 RA to receive FDA approval for the treatment of T2D (May 2022), showed 11-13% weight loss from baseline in clinical trials of patients with T2D. It also demonstrated superiority to semaglutide 1.0 mg once weekly at all three once-weekly doses (5.0 mg, 10.0 mg and 15.0 mg) with respect to weight loss in a head-to-head comparison trial of patients with T2D. In a study of patients with obesity but without T2D, tirzepatide demonstrated a pharmacologically unprecedented 20.9% weight loss from baseline at the 15.0 mg once-weekly dose. However, unlike subcutaneous liraglutide and semaglutide, which in addition to being approved for T2D have also been approved by the FDA for treatment of obesity at the 3.0 mg once daily and 2.4 mg once weekly dose (respectively), tirzepatide has not yet received FDA approval for the treatment of obesity.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are another new class of drug for the treatment of patients with T2D. SGLT2 inhibitors reduce glucose reabsorption by the kidneys, resulting in increased urinary glucose excretion. Due to subsequent caloric loss, treatment with SGLT2 inhibitors may result in weight loss in addition to reduced hyperglycemia. Studies of SGLT2 inhibitors in patients with T2D have shown patient weight reductions from baseline of up to 4.7 kg.

The most common classes of drugs which can promote weight gain include insulin therapy, sulfonylureas and thiazolidinediones (TZDs). The weight gain observed with insulin therapy appears to be greater than the weight gain associated with oral hypoglycemic agents, although it is difficult to compare, as patients who require insulin therapy generally have more severe diabetes and may experience more drastic changes in energy conservation. The amount of weight gain associated with insulin therapy is associated with the daily insulin dose and mean plasma insulin level. Weight gain–associated with sulfonylurea medications, another class of antidiabetic drugs, is related to the resulting increased insulin secretion. TZDs are another class of commonly used oral antihyperglycemic agents, which are often associated with weight gain. These compounds, including rosiglitazone and pioglitazone, lower glucose concentrations by increasing peripheral insulin sensitivity. Pioglitazone is currently recommended as the preferred TZD for treatment of T2D.

The Clinical Guidelines Subcommittee (CGS) of The Endocrine Society recommends weight-losing and weight-neutral medications as first- and second-line agents in the management of T2D. Specific antidiabetic medications that are associated with weight gain, weight neutrality and weight loss are outlined in Table 7-1.

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Antihypertensive Medications

β-blockers have long been used for the treatment of hypertension and have been shown to be efficacious at decreasing CV morbidity and mortality. However, in certain populations, such as in patients with diabetes and hypertension, therapy with traditional β-blockers has been associated with adverse effects on lipid and insulin balance, leading to weight gain. Increased body weight is a particular clinical problem in the vast majority of hypertensive patients. Treatment with β-blockers can decrease the metabolic rate by as much as 10%. An analysis of eight randomized controlled hypertension trials showed that changes in body weight was higher in those that received β-blockers, with a median difference of 1.2 kg between the β-blocker group and the control group.

However, not all β-blockers are associated with weight gain. Selective β-blockers with a vasodilating component such as carvedilol and nebivolol appear to have less weight gain potential and less of an impact on glucose and lipid metabolism. Unlike metoprolol tartrate, carvedilol was not found in comparison studies to be associated with significant weight gain in patients with hypertension.

Treatments for hypertension that are not associated with weight gain or insulin resistance include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB) and calcium channel blockers (CCBs). Angiotensin is overexpressed in obesity, directly contributing to obesity-related hypertension, providing support for the use of ACE inhibitors. CCBs are also effective in the treatment of obesity-related hypertension and have not been associated with weight gain or adverse changes in lipids.

The Clinical Guidelines Subcommittee (CGS) of The Endocrine Society recommends the use of ACE inhibitors, ARBs and CCBs rather than β-adrenergic blockers as first-line therapy for hypertension in patients with T2D and obesity. Specific antihypertensive drugs that are associated with weight gain, weight neutrality and weight loss are outlined in Table 7-1.

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Anticonvulsant Medications

Pharmacologic treatment for epilepsy may be associated with substantial weight changes that may increase morbidity and impair adherence to the treatment regimen. Anti-epileptic drugs (AEDs) known to cause weight gain include valproic acid, carbamazepine and gabapentin. Valproic acid has been shown to cause weight gain in both adults and children. A study of long-term weight gain in adult epileptic patients on valproic acid therapy showed marked weight gain (>10% of baseline weight) in 47% of patients. Carbamazepine has also been associated with weight gain, although not as significant as valproic acid or gabapentin, and is sometimes classified as a weight-neutral AED. By contrast, topiramate is associated with weight loss during the first year of treatment, particularly in patients with overweight or obesity. This makes topiramate an attractive alternative anticonvulsant in this patient population.

In clinical practice, it is critical to weigh patients regularly and AED selection should be based on each patient’s profile without sacrificing therapeutic efficacy. The first step in treatment is to weigh all patients at each visit, calculate BMI and react to weight changes. In some patients, waist circumference may be an independent measure of health risk. The CGS of The Endocrine Society recommends considering weight gain potential in choosing an AED for any given patient. Specific AEDs that are associated with weight gain, weight neutrality and weight loss are outlined in Table 7-1.

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Contraceptives, Hormones and Steroids

Weight gain is a complaint of some women using oral, injectable and transdermal contraceptives and may cause discontinuation of treatment. Specifically, the use of the progestins depo-medroxyprogesterone acetate and megestrol acetate has been associated with weight gain. Megestrol acetate has been prescribed to induce weight gain in wasting illnesses, such as acquired immunodeficiency syndrome (AIDS) and cancer. Studies have found that women who used depo-medroxyprogesterone continuously for 1 or 2 years experienced more average weight gain than those who did not.

Specifically, weight gain after 1 year of use may range from 0.63-8.04 kg and increase further with ongoing use. Although not every patient will gain weight, predicting which patients will experience substantial weight gain is not simple. Le and colleagues found that women who experience >5% weight gain increase within 6 months of depot medroxyprogesterone acetate (DMPA) use puts them at high risk for continued weight gain.

Still, the research on oral contraceptives and weight gain is conflicting. Some studies show significant increases in body weight, total cholesterol and triglycerides in patients before and after contraceptive use, while others emphasize the lack of concrete changes in weight gain over menstrual cycles. In 2011, the Cochrane Review conducted a meta-analysis of 49 trials of contraceptives and determined that the current data are not sufficient to establish an effect of oral contraceptives on weight. In women with a BMI >27 with comorbidities or >30, the CGS of The Endocrine Society recommends using barrier methods or non-hormonal IUDs before contraceptives that may be associated with weight gain. Specific contraceptives that are associated with weight gain, weight neutrality and weight loss are outlined in Table 7-1.

In menopausal women taking hormone replacement therapy (HRT), drug-induced weight gain may contribute to the poor patient compliance and greater CV disease risk. It is difficult to quantify the specific impact of HRT on body weight and fat distribution because menopause itself is associated with changes in body composition, energy metabolism and physical activity. Weight gain has not been consistently observed as a side effect of HRT but rather varies considerably, not only with respect to weight change but also changes in fat distribution.

Long-term anti-inflammatory treatment of asthma with systemic corticosteroids frequently leads to fluid retention and weight gain. Even inhaled corticosteroids, which act locally and are rapidly processed by the body, are associated with weight gain. A recent retrospective cohort study demonstrated that pregnant women with overweight or obesity were more at risk for asthma than women with normal weight, and that women who gained ≥20 kg had a 2.7-fold increased odds of asthma compared with those who maintained their weight. Weight gain has also been widely reported with use of steroids to treat rheumatoid arthritis (RA). Other RA treatment options are available that do not cause weight gain. For example, leflunomide, a disease-modifying antirheumatic drug (DMARDs), has been associated with weight loss following a 6 month treatment course. The CGS of The Endocrine Society recommends the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and DMARDs where possible.

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Antipsychotic and Antidepressive Medications

Weight gain is a common adverse effect of psychotropic drugs such as antipsychotics, antidepressants, mood stabilizers and anxiolytics. Antidepressants vary considerably with respect to their long-term weight gain potential, often depending on the length of therapy. Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) have been associated with significant weight gain. Several reports suggest that weight gain with TCAs ranged from 0.57 kg (1.27 lb) to nearly 1.4 kg (3.1 lb) per month of treatment. Newer drugs, such as selective serotonin reuptake inhibitors (SSRIs) are now the preferred treatment for patients with depression. However, it must be noted that some SSRIs have been associated with weight loss during short-term treatment, but weight gain during long-term treatment. Therefore, when choosing an antidepressant treatment, the duration of therapy is especially important.

The CGS of The Endocrine Society recommends carefully weighing patient response and desired clinical efficacy with the potential of the antidepressant to cause weight gain. For example, while the SSRI paroxetine is associated with weight gain, bupropion is a weight neutral antidepressant. Although bupropion does not have the same efficacy or side-effect profile as SSRIs, it may be of benefit in those with depression. However, bupropion therapy is associated with an elevated risk of anxiety and may worsen some forms of depression. Specific antidepressants that are associated with weight gain, weight neutrality and weight loss are outlined in Table 7-1.

Many antipsychotic agents have weight gain as a side effect, which may impede patient compliance and exacerbate existing health issues in already overweight patients. Different types of antipsychotic medications have different effects on histamine receptors, anticholinergic effects and serotonin antagonistic response. A study investigating the effectiveness of five antipsychotic medications found that a weight gain of >7% from baseline occurred in 30% of those taking olanzapine, 16% for quetiapine, 14% for risperidone, 12% for perphenazine and 7% of those taking ziprasidone.

Since most antipsychotics are associated with weight gain, the CGS of The Endocrine Society recommends considering more weight neutral alternatives such as ziprasidone and aripiprazole when clinically indicated. These drugs have been shown in clinical studies to cause less weight gain than other antipsychotics.

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Other Medications That May Induce Weight Gain

Potent antihistamines may contribute to weight gain. Histamine is a neurotransmitter released by the posterior hypothalamus. Intravascular administration of histamine reduced food intake in animal studies, whereas histamine antagonism stimulates food intake. Commonly-prescribed allergy medications, such as the H₁-receptor antihistamines cetirizine, fexofenadine and desloratadine, stimulate appetite and may cause weight gain. Although it is not known whether the weight gain potential of sedating vs nonsedating antihistamines differ, it appears that it is proportional to the potency of the antihistamine. A recent study demonstrated that the chances of being overweight were increased in patients who were prescribed antihistamines. Antihistamine users were also shown to have significantly higher weight, waist circumference and insulin concentration than non-users. The CGS of The Endocrine Society recommends the use of milder, less centrally acting antihistamines, when possible.

Treatments for human immunodeficiency virus (HIV) include administration of antiretroviral therapy and protease inhibitors. Although effective for suppressing HIV viral activity, such treatments are associated with changes in the deposition of fat tissue in the body. One study of 10 HIV patients treated with protease inhibitor-containing regimens found that patients gained an average of 19 lb. after a period of 6 months.