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The association between weight-promoting medication use and weight gain in postmenopausal women: findings from the Women's Health Initiative

Stanford, Fatima Cody MD, MPH, MPA1; Cena, Hellas MD2,3; Biino, Ginevra PhD4; Umoren, Olivia BS5; Jimenez, Monik ScD6; Freeman, Marlene P. MD5; Shadyab, Aladdin H. PhD7; Wild, Robert A. MD, MPH, PhD8; Womack, Catherine R. MD9; Banack, Hailey R. PhD10; Manson, JoAnn E. MD, DrPH6,11

Author Information
doi: 10.1097/GME.0000000000001589

Abstract

Obesity, a serious chronic disease, is a global epidemic that affects both youth and adults, and it is associated with myriad co-morbidities including type 2 diabetes mellitus, cardiovascular disease, and cancer.1 In the United States, obesity has increased steadily over the last three decades. Women have a higher prevalence of obesity at 41.1% compared to 37.9% for men.2 Racial and ethnic minorities, especially non-Hispanic Black women, have disproportionately high levels of obesity.3 Premenopausal women tend to have a gynoid fat distribution (ie distribution in hip, buttock, and thigh region), whereas postmenopausal women have increased amounts of android fat deposits (ie abdominal region).4,5 Central adiposity is associated with metabolic disorders and an increased risk of type 2 diabetes, cardiovascular disease, and other chronic diseases.6

As the risk of comorbid conditions increases with obesity, medication use is more prevalent.7 Many of the medications prescribed to treat obesity-related co-morbidities such as hypertension, type 2 diabetes, and depression, have been linked to weight gain.2,8,9 Second-generation antidepressants, second-generation antipsychotics, second-generation antihistamines, neuropathic agents, and beta-blockers may also be associated with weight gain.7,10-18 In particular, antidepressant use (the third most frequently prescribed medication class) has increased by roughly 400% from 1988 to 1994 through 2005-2008.13 Previous studies indicate that antipsychotics and antidepressants are associated with weight gain and obesity, particularly among women and some racial/ethnic minority groups.19 In large cohorts in the Netherlands, Canada, and the United Kingdom, studies have demonstrated that these medications have been associated with clinically significant weight gain.20-23 Yet large studies investigating weight gain in United States cohorts are largely lacking which is of particular importance due to differences in the prevalence and gender distribution of obesity compared to other Western countries. It is important to note the United States has significantly higher obesity rates than the aforementioned developed countries (United States [39.8%],24 United Kingdom [27.8%],25 Canada [26.8%],26 and the Netherlands [18.8%]27), and it is unclear why this higher degree of excess weight is more commonplace and whether weight-promoting medications may play a role in this notable difference. Furthermore, women have a higher likelihood of having obesity in the United States, whereas men have higher obesity rates in Canada and the United Kingdom.2,24-26 Finally, postmenopausal women are of significant interest as those who have obesity and normal weight central obesity are at increased risk for conditions such as invasive breast cancer,28 sleep disturbances,29 type 2 diabetes,30 as well as mortality.31 The association between use of weight-promoting medications and the weight status of postmenopausal women within the WHI cohort, the largest international cohort of postmenopausal women, has not been examined previously.

The current analysis evaluates a large subcohort within the Women's Health Initiative observational study (WHI-OS). The objective was to analyze the use of drugs suspected to promote weight gain in relation to changes in body mass index (BMI) and waist circumference (WC) in postmenopausal women. Information on the association between putative weight-promoting prescription medications and change in body weight may help to inform clinical decision-making and spur the development of strategies to avert or minimize these adverse outcomes.

COHORT DESCRIPTION

Methods

The Women's Health Initiative observational study investigated the major causes of morbidity and mortality in postmenopausal women. Details of the study have been reported elsewhere.32 A total of 93,676 eligible women aged 50-79 years at baseline were administered several epidemiologic questionnaires and underwent physical examinations. The current analysis focused on weight change that occurred during the first 3 years from baseline (1993-1998) to the 3 year follow-up visit. Anthropometric measurements were conducted by trained clinic staff, at baseline and year 3. Weight was obtained to the nearest 0.1 kilogram (kg) and height to the nearest 0.1 centimeter (cm) to calculate BMI. WC was obtained at the natural waist or narrowest part of the torso to the nearest 0.1 cm. About 18% of the sample did not have anthropometric measurements (BMI and WC) at year 3 and were excluded; 76,252 postmenopausal women were evaluated for BMI change and 76,579 for WC change, respectively. Those who were excluded were of similar age and more likely to be white and less educated.

Medication use was assessed by a medication inventory based on pill bottles brought to the baseline and 3-year clinic visits. Medication exposure was defined as follows: 1) those not taking putative weight-promoting medications either at baseline or at year 3 (reference group); 2) those taking at least one of these putative weight-promoting medications either at baseline or year 3 (intermittent users); and 3) those taking the weight-promoting medications at both baseline and year 3 (persistent users). Also the total number of weight-promoting drugs was taken into account (see below).

The protocol and consent forms were approved by the institutional review board at each of the 40 sites throughout the US. All participants provided written informed consent before participation.

Statistical analysis

Baseline characteristics were summarized in the whole sample, by medication use, by race/ethnicity (Non-Hispanic White, African-Americans, Hispanic, Asian/Pacific Islander, and Native Americans), by WC (<88 cm or > 88 cm) and, by BMI class (Underweight (BMI < 18.5 kg/m2), Normal weight (BMI 18.5-24.9 kg/m2), Overweight (BMI 25-29.9 kg/m2), Class 1 obesity- Mild (BMI 30-34.9 kg/m2), Class II obesity – Moderate (BMI 35-39.9 kg/m2) and, Class III obesity - Severe (BMI ≥ 40 kg/m2).

Candidate weight-promoting drugs intake were described as frequencies (proportions) in the whole sample, by weight status and by ethnicity. Generalized linear models evaluated if intermittent or persistent use of weight-promoting drugs is associated with increased BMI and WC during a 3-year follow up. For each medication class (antidepressants, antipsychotics, beta-blockers, insulin, and glucocorticosteroids), and for the drugs that were most likely to be commonly prescribed in combinations and more frequently observed in the data, when more than one medication was taken, simple models assessed both BMI and WC change during the 3-year follow-up, stratifying by baseline BMI categories. Since association between weight-promoting drugs and increased BMI and WC might be confounded by other factors, multiple models were set up to take into account such confounding. Potential confounders have been selected among those variables that are independently associated with both the exposure and weight gain, supported by evidence obtained through literature.6,33,34 Baseline health conditions as diabetes, hypertension, and hypercholesterolemia as well as age, education, physical activity, sleep medications, smoking, and diet were evaluated as they are well-known risk factors for weight gain, but it is largely unknown how these factors interact with weight-promoting medications. The research strategy for identifying these factors was based on the knowledge of the field and expertise criteria were involved for evaluating the confounders.

The independent association of the potential mediators, namely the intake of putative weight-promoting medications, with weight gain (BMI and WC) was assessed using multivariate linear regression models. Those models included the following covariates: baseline health conditions as diabetes, hypertension and hypercholesterolemia; age (50-59, 60-69, 70-79); education (less than high school or GED, High school or GED, some college, college or higher); physical activity (total MET hours per week); smoking (never smoker, past smoker, current smoker); sleeping habits (use of sleep medication or not) and sleep duration (less than 4 hours, 4-7 hours, 8-9 hours, more than10 hours); dietary habits (healthy eating index [HEI]-2005 index score) of the postmenopausal women.

RESULTS

Table 1 shows baseline characteristics of women (N = 76,252) in the whole sample and by medication use, as Supplemental Table 1, http://links.lww.com/MENO/A608 shows them stratified by race/ethnicity. Although most of the women in the cohort were non-Hispanic White (n = 64,750), most of the major racial/ethnic groups in the United States including American Indian/Alaskan Native, Asian/Pacific Islander, African-American, and Hispanic were represented. Although a large majority of the cohort (n = 67,583, 88.6%) were not taking any putative weight-promoting medications, 11.4% (n = 8,669), were taking such medications. Weight, BMI, and WC was higher in patients who were prescribed weight-promoting medications, and there was a continuous rise in these values with the number of weight-promoting medications prescribed. As the number of weight-promoting medications increased, there were fewer individuals in the highest quartile for physical activity, but the HEI score did not seem to differ by number of weight-promoting medications. Those on weight-promoting medications had a higher likelihood of having insulin-dependent diabetes mellitus, treated hypertension, and high cholesterol.

TABLE 1
TABLE 1:
Distribution of baseline characteristics in whole study sample and by weight-promoting drugs

Table 1 demonstrates that 57.8% (44,060/76,252) of the WHI cohort had overweight or obesity at baseline. Supplemental Table 2, http://links.lww.com/MENO/A609 shows that those with overweight and obesity had lower levels of physical activity (MET-hours/wk) and lower diet quality (lower HEI scores). Women with overweight or obesity also had a higher prevalence of diabetes, hypertension, and high cholesterol requiring medication. By weight status, there was no significant difference in smoking, sleep medication use, or number of hours of sleep.

Women with overweight or obesity were more likely to be prescribed antidepressants, beta-blockers, insulin, and/or glucocorticosteroids (Supplemental Table 3, http://links.lww.com/MENO/A610). We assessed frequent combinations of weight-promoting medications in the cohort, and antidepressants and beta-blockers were found to be most frequently prescribed in combination (Supplemental Table 4, http://links.lww.com/MENO/A611). Non-Hispanic white women were most likely to be prescribed antidepressants and beta-blockers, whereas African-Americans were more likely to be on insulin and glucocorticosteroids (Supplemental Table 5, http://links.lww.com/MENO/A612).

Regardless of medications prescribed, on average all women in the sample gained 0.3 kg over the 3 years. Women taking at least one weight-promoting medication had a greater increase in BMI than those taking none of these medications (0.37 vs 0.27 kg/m2, respectively, P = 0.0045) and WC (1.10 cm vs 0.89 cm, respectively, P = 0.0077) over the course of 3 years. Both BMI and WC increased with the number of weight- promoting medications (Fig. 1).

FIG. 1
FIG. 1:
BMI and WC increase over 3 years with increasing number of weight-promoting medications.

In Table 2, we present medications associated with BMI changes at 3 years by medication groups and stratifying by BMI classes. In each model, the specific drug taken, which represents the exposure, is defined as a categorical variable with three levels: nonuser, intermittent user, and persistent user. We observed that the effect of taking a particular drug led to weight variation that increased or decreased with the intensity of its use and with the severity of BMI class. As such, the regression coefficient is thus interpretable as a trend effect. Those who took either antidepressants or insulin were most likely to have a significant increase in BMI whereas patients on glucocorticosteroids lost weight over the same time course. Overall, women on antidepressants had a 0.14 BMI unit increase over 3 years, whereas women with class I (mild) obesity showed 0.25 BMI unit increase. In those taking a combination of antidepressants and beta-blockers versus nonusers, a 0.25 BMI unit increase was observed, whereas in women with overweight, a 0.39 BMI unit increase was reported. Overall, women on OTC insulin had 0.21 BMI unit increase over 3 years of follow up, whereas those with normal weight status, overweight, class II (moderate) obesity, and Class III (severe) obesity had an increase in BMI of 0.39, 0.32, 036, 1.87, respectively. Overall beta-blockers in combination with glucocorticosteroids, were associated with 0.40 BMI unit decrease, whereas in women with overweight and obesity the decrease was, respectively, 0.7 and 1.51 BMI units.

TABLE 2
TABLE 2:
Medications associated to BMI changes at 3 years follow-up

Differences in BMI stratified by race/ethnicity are shown in Supplemental Table 6, http://links.lww.com/MENO/A613. Non-Hispanic white women were more likely to have an increase in BMI than other groups for all medications except antidepressants which were associated with a higher BMI increase in the Hispanic group.

Overall, women on antidepressants had 0.47 cm WC increase at 3 years follow-up, whereas with class I (mild) obesity showed 0.63 cm WC increase. Overall, women on OTC insulin had 0.4 cm WC increase over 3 years of follow-up, whereas those with normal weight and Class III (severe) obesity increased, respectively, by 0.96 and 1.24 cm. In those taking a combination of antidepressants and beta-blockers versus nonusers a 0.51 cm WC increase was observed, whereas in women with overweight and class I (mild) obesity 0.78 and 1.11 cm WC increase was seen, respectively (Table 3).

TABLE 3
TABLE 3:
Medications associated to WC (cm) changes at 3 years follow-up

Differences in WC stratified by race/ethnicity are shown in Supplemental Table 7, http://links.lww.com/MENO/A614. Women of Hispanic origin were more likely to have an increase in WC than other groups when taking antidepressants. Similarly, Asian/Pacific Islanders were most likely to have an increase in WC if they were taking insulin. African-American women showed the highest increase in WC if taking antipsychotics. In Non-Hispanic white women, there was a greater increase in WC than other groups when taking beta-blockers. Antidepressant and antipsychotic combinations were most likely to be associated with an increase in WC, especially in African-American women. Hispanic women were most likely to have weight gain when taking a combination of antidepressants and glucocorticosteroids.

Even after adjusting for baseline health conditions and other covariates (physical activity, smoking, sleep medications, diet), participants who were on antidepressants had a higher likelihood of an increase in BMI or WC, and also the associations with other drugs remained unchanged (Tables 4 and 5 and Supplemental Tables 8, http://links.lww.com/MENO/A615 and 9, http://links.lww.com/MENO/A616). The higher the number of putative weight-promoting medications, the greater the increase in BMI, adjusting for other covariates (Fig. 1).

TABLE 4
TABLE 4:
Multiple regression models investigating factors associated to BMI changes
TABLE 5
TABLE 5:
Multiple regression models investigating factors associated to WC changes

DISCUSSION

Use of several classes of putative weight-promoting medications was associated with an increase in BMI and WC over 3 years among postmenopausal women in the WHI cohort. The primary classes of medications associated with weight gain were antidepressants, antihypertensives, and insulin.35 Study participants who took either antidepressants or those with diabetes who took insulin were most likely to have greater increases in BMI. It is important to note that these statistically significant BMI and WC changes are likely to demonstrate clinical significance. There has been a steady increase in BMI and WC over time in developed and developing countries throughout the world, but the role of putative weight-promoting medications in this epidemic is largely overlooked. In the clinical setting, health care providers may address diet quality and/or physical activity, but there is rarely a focus on whether a patient's previous or current medications have led to weight gain. As such, strategies to mitigate medication induced weight gain are not incorporated into clinical care.

Despite adjusting for factors usually known to be associated with BMI and WC, such as physical activity, diet quality, sleep duration, smoking status, several putative weight-promoting medications were associated with weight gain over 3 years. The data highlight that, when weight-promoting medications are prescribed, it may be helpful to encourage regular physical activity, adequate sleep, and attention to diet quality.36-38 Yet, it is important to note that even with positive lifestyle interventions, medications may still lead to weight change. Antidepressants have a well-documented history of numerous side effects, particularly weight gain.39,40 Older generation antidepressants like tricyclics have been shown to cause an increase in BMI and WC. In a study by Berken and colleagues,41 low doses of the tricyclics amitriptyline, nortriptyline, and imipramine were correlated with weight gain of up to 2 lbs. per month. Newer antidepressants, namely citalopram, escitalopram, sertraline, paroxetine, venlafaxine, duloxetine, and mirtazapine have also been associated with significant increases in body weight.18 There has been a 400% rise in prescriptions for antidepressants since 1988 with a concomitant rise in adult and pediatric obesity since 1980, and it has been postulated that the increase in antidepressants is a contributor to the obesity epidemic. The hypothalamic-pituitary-adrenal axis is activated in stress, dysregulated in obesity and metabolic syndrome, and it shares a common pathophysiologic pathway with major depressive disorder9; how antidepressants modify these pathways and exacerbate weight gain is largely unknown. When a patient has a predisposition to weight gain and would benefit from an antidepressant, bupropion is an agent that has been more likely to demonstrate weight loss than weight gain,42 and it is also currently prescribed in combination with naltrexone as an Food and Drug Administration-approved weight loss medication in the US.43

Medication-related weight gain may affect patient medication compliance with these medications.44 Patients taking antihypertensive drugs may experience weight gain through multiple pathways, including direct obesogenic effects of medications or other mechanisms. For example, beta-blockers may reduce total energy expenditure by 5% to 10%, which corresponds to a reduction of 100 to 200 kcal/d in utilized energy,45,46 and fatigue and reduced exercise tolerance may exacerbate the weight gain. Randomized, controlled studies in patients with or at increased risk for cardiovascular disease have also found a correlation between beta-blocker use and risk of diabetes mellitus. In patients with abdominal obesity, the use of beta-blockers impaired fasting glucose and increased triglycerides, which may contribute to the risk of cardiovascular disease.6,47 If beta-blockers are an essential medication for a patient, the patient would likely have less weight gain on carvedilol when compared to other medications in this class.48

Type of medication, dosage, and race/ethnicity may have important interrelationships. In our study, non-Hispanic white women were most likely to be prescribed antidepressants and beta-blockers. African-Americans were more likely to have diabetes and be on insulin and/or glucocorticosteroids. Previous studies have shown that African-Americans, in addition to Native American, Pacific Islander, and Hispanic patients, are more likely to have weight gain when taking weight-promoting medications.49 Excess adiposity, particularly in type 2 diabetes is associated with insulin resistance, which promotes dyslipidemia and beta-cell dysfunction, further exacerbating insulin resistance and weight gain. To mitigate the likelihood of weight gain, other medications within the medication classes studied that are less likely to promote weight gain should be considered. In the United Kingdom Prospective Diabetes Study, patients in the insulin-treated intensive intervention cohort gained an average of 6.5 kg. Within that group, weight gain was even higher in patients who were more than 120% of their ideal body weight at baseline.14 In addition to the aforementioned health issues, medications might influence food preferences (towards high-energy dense foods), and lead to increased sugary beverage consumption due to dry mouth, increased hunger and/or delayed satiety with concomitant increased food intake, down regulation of body fat stores, fatigue (resulting in decreased exercise tolerance and lower physical activity levels), and reductions in resting metabolic rate and diet-induced thermogenesis. Weight gain associated with insulin treatment is almost exclusively due to an increase in fat mass consequent to decreased 24-hour energy expenditure50 and the same has been observed during glucocorticosteroid therapy40 with a typical increase in truncal fat stores. Many of the medications associated with weight gain are prescribed for chronic conditions and are often taken in combination.

We found some racial differences in these relationships. With antidepressants and antipsychotics in combination, African-American women were most likely to have an increase in WC. Hispanic women were most likely to have weight gain on a combination of antidepressants and glucocorticosteroids. However, these findings should be interpreted cautiously due to multiple comparisons and they may be due to chance. Individual susceptibility and genetic predisposition to weight gain may be contributory.51 Options to mitigate the weight gain may include proactive lifestyle modifications, reduction in dose, change to another agent, or discontinuation of the medication altogether. If alternative medications are not an option, lifestyle factors such as diet quality, physical activity level, and sleep quality and duration warrant emphasis.

This study has important strengths and limitations. The strengths include prospective follow-up of a large cohort, inclusion of a racially and ethnically diverse sample, use of medication inventories, and measured weights and WC at baseline and 3 years. However, limitations also warrant consideration. We have limited information regarding the indications for the prescription of some of the medications studied, and the underlying health condition may confound the results. Some disorders, such as major depressive disorder, are associated with higher rates of obesity, and depression severity might increase the risk of overweight and obesity. Although antidepressant use may contribute to overweight/obesity, it cannot be ruled out that participants using antidepressants have a more severe form of depression than those not using antidepressants. However, information about depression was not collected routinely in the cohort. Similarly, concomitant treatment with other psychotropics such as antipsychotics could exacerbate weight gain but may also signal a more severe form of illness or different diagnoses altogether, such as bipolar disorder or a psychotic disorder. Without controlling for the specific diagnosis and its severity, it is not possible to directly attribute risk to the medication alone. Finally, there does appear to be an increased risk of obesity with psychiatric disorders themselves, and this is complicated/compounded by many of the medications.

CONCLUSIONS

Many medications prescribed for hypertension, diabetes, depression, and/or mental conditions are associated with unintentional weight gain. Postmenopausal women, a group with a high prevalence of overweight and/or obesity, are already at risk for an increase in BMI and WC over time. Racial and ethnic minority women, groups with a higher weight status at baseline, also may be particularly susceptible to weight gain associated with the use of prescription medications. Before patients are prescribed weight-promoting medications, clinicians should be vigilant about whether the medication is necessary, whether alternative agents are available, and utilize only the lowest dose necessary to achieve the desired effect. Information about weight-promoting medications may help to inform clinical decision-making and support increased attention to lifestyle modifications and other strategies to mitigate these side effects.

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Keywords:

Obesity; Weight gain; Weight-promoting medications; Antidepressants; Psychotropic weight gain; Beta-blockers; Antihistamines; Sleep agents; Insulin; SteroidsAntiWeight-promoting

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