Obesity is a growing global health concern, contributing to a rise in metabolic disorders. While various medications exist to address these conditions, some can inadvertently lead to weight gain, further complicating patient health. This article examines the potential roles of metformin and fluoxetine, two drugs with reported weight-loss effects, in managing weight, particularly in specific populations.
Metformin and Weight Loss: An Overview
Metformin, a widely used first-line treatment for type 2 diabetes, has demonstrated weight-loss effects in adults with obesity, even without diabetes. Kevin M. Pantalone, DO, ECNU, FACE, and Marcio L. Yes, support the evidence that the magnitude of metformin-induced weight loss is modest but clinically significant. Metformin is achievable at low cost with an agent that has proven long-term safety, few serious adverse effects, and well-documented favorable non-glycemic effects. To date, metformin is the only pharmacologic weight-loss intervention to demonstrate long-term effects. Metformin should be seriously considered as an off-label initial therapy and as an adjunct to antiobesity medications approved by the US Food and Drug Administration for the management of obesity, particularly in the presence of specific concomitant conditions.
Supporting Evidence for Metformin's Weight Loss Effects
The Diabetes Prevention Program (DPP) trial and its long-term follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS), provide the main evidence for weight loss with metformin in people without type 2 diabetes. The DPP, a 3-arm randomized controlled trial, compared the effects of intensive lifestyle intervention, metformin 1,700 mg/day, and placebo in 3,234 participants with prediabetes. The primary outcome measure was prevention or delayed onset of type 2 diabetes, with weight loss reported as a secondary outcome. During the initial 2.8-year follow-up, the metformin group experienced an average weight loss of 2.1 kg, compared with 5.6 kg in the lifestyle intervention group, and 0.1 kg in the placebo group.
Unlike the weight loss experienced in the intensive lifestyle intervention group, weight loss in the metformin group was maintained throughout the DPP and DPPOS follow-up periods (N = 2,766 participants). Those on metformin had an average 2.5-kg weight loss over time, while the lifestyle intervention group progressively regained weight, with a final average weight loss of 2.0 kg after 10 years of follow-up. Approximately 30% of participants randomized to metformin lost more than 5% of their body weight in the first year, and a post hoc analysis demonstrated that their mean weight loss relative to baseline was 6.2% after 15 years of follow-up, compared with 3.7% in the lifestyle intervention arm. Adherence and weight loss during the first year of treatment with metformin were relevant predictors of long-term weight-loss maintenance.
The Biguanides and Prevention of the Risks in Obesity trial evaluated weight loss with metformin as a primary outcome in patients without diabetes, with 324 participants with abdominal obesity (inclusion criterion was waist-to-hip ratio, not BMI) and no diabetes. Participants were randomized to receive metformin 1,700 mg/day or placebo. After 12 months of treatment, metformin had a significantly better effect on weight (mean −2 kg, 95% confidence interval [CI] −3.0 to −1.1, vs placebo −0.8 kg, 95% CI −1.6 to 0.1, P < .06).
Read also: Berberine and Metformin
A real-world study assessed the efficacy of metformin for weight loss in 154 patients with obesity and no diabetes compared with 45 control participants. The mean weight loss in the metformin group was 5.8 kg (± 7.0), whereas controls gained 0.8 kg (± 3.5 kg) on average (P < 0.0001). Both absolute and relative weight loss increased with higher degrees of insulin resistance, as measured by the Matsuda index and HOMA index.
A meta-analysis that included 21 trials and 1,004 participants analyzed the effect of metformin on BMI in different populations and found that in patients with obesity, BMI was reduced by 1.3 units (weighted mean difference [WMD] 1.31; 95% CI −2.07 to −0.54). A subanalysis found that metformin had the most pronounced effect in the population with BMI greater than 35 kg/m2 (WMD −1.12; 95% CI −1.84 to −0.39), at doses higher than 1,500 mg/day (WMD −1.01; 95% CI −1.29 to −0.73) for at least 6 months (WMD −1.09; 95% CI −1.71 to −0.47).
Timeframe for Weight Loss with Metformin
Evidence regarding the timeframe in which weight loss might be expected to occur is inconsistent. Commonly, however, in trials with longer follow-up periods, weight loss generally starts after 4 weeks of treatment with metformin and occurs mainly during the first 6 to 12 months of continuing metformin therapy.
Metformin in Specific Populations
Metformin has shown particular effectiveness in preventing or delaying diabetes in subgroups of participants with higher BMI (≥ 35), younger age (< 60), and higher baseline fasting blood glucose and hemoglobin A1c, and in women with a history of gestational diabetes. This particular effect has been shown to be durable after 15 years of follow-up. In these populations, the role of metformin goes beyond its weight loss effects, and its use should be encouraged with the dual goal of promoting weight loss and preventing or delaying the onset of type 2 diabetes.
Patients Treated with Antipsychotic Drugs
Most antipsychotic drugs are associated with weight gain. It has been reported that 75% of patients receiving antipsychotic agents increased their baseline weight by more than 7%. Atypical antipsychotics have greater potential for inducing weight gain, and among them, clozapine and olanzapine are the agents most associated with weight gain, followed by risperidone and quetiapine. These are also the agents for which the literature on metformin’s weight-attenuating and weight-loss effects is more abundant. However, there does not appear to be an antipsychotic drug-specific beneficial effect of metformin, and it is rather the magnitude of weight gain that drives metformin efficacy.
Read also: Comprehensive Study: Metformin and Phentermine/Topiramate
Several trials have demonstrated beneficial effects of metformin in reversing or preventing weight gain associated with antipsychotic drug therapy. A meta-analysis including 12 studies and 743 participants confirmed that metformin is effective in treatment of weight gain associated with these agents. The mean weight loss was 3.27 kg (95% CI −4.66 to −1.89; Z = 4.64; P < .001), and metformin resulted in significant reduction in BMI (−1.13; 95% CI −1.61 to −0.66) compared with placebo.
Weight gain can be associated with other medications, including some anticonvulsants, antidepressants, and systemic glucocorticoids, but evidence regarding the utility of metformin in those groups of patients is lacking.
Polycystic Ovary Syndrome
In women with polycystic ovary syndrome, metformin therapy has been shown to increase ovulation, menstrual frequency, fertility, and rates of live birth. A meta-analysis comparing orlistat with metformin in women with polycystic ovary syndrome found that both had similar favorable effects on BMI, with a mean decrease in BMI of 3.4 to 4.55 with metformin, and 4.48 to 5.7 with orlistat (difference −0.65%, 95% CI −2.03 to 0.73).
Potential Mechanisms of Action for Metformin's Weight Loss Effects
Some evidence suggests that the mechanisms underlying metformin’s effects on body weight are much broader than its insulin-sensitizing effects. These include:
- Appetite suppression through increased secretion of glucagon-like peptide 1 and peptide YY, and increased hypothalamic leptin sensitivity
- Alteration of the gut microbiome
- Induced expression and secretion of growth-differentiating factor 15, which reduces food intake, body mass, fasting insulin, and glucose intolerance.
There is sufficient evidence to suggest no differences between immediate-release and extended-release formulations in terms of their weight-loss properties or the secretion of substances that potentially underlie this effect.
Read also: Health Benefits of Metformin
Safety and Side Effects of Metformin
When metformin is used and prescribed appropriately, serious adverse events are extremely rare. The most common side effects are gastrointestinal-diarrhea, nausea, flatulence, vomiting, and abdominal discomfort. These are less frequent with postprandial use and with extended-release than immediate-release formulations. Given the lack of prospective data on the effect of metformin on weight loss, it is unclear whether weight loss is associated with gastrointestinal side effects. Since the magnitude of weight loss during the DPP (and its maintenance during the DPPOS) was directly related to adherence to metformin therapy, such an association seems unlikely.
The main contraindication associated with metformin is severe renal impairment, defined as an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2. Recommendations for metformin use based on eGFR include:
- eGFR less than 45 mL/min/1.73 m2: refrain from starting metformin
- eGFR 45 to 60 mL/min/1.73 m2: prescribe a maximum total daily dose of 1,500 mg (or 1,700 mg if prescribing an immediate-release formulation)
- eGFR 30 to 45 mL/min/1.73 m2 and already on metformin therapy: adjust to a maximum daily dose of 1,000 mg.
Chronic metformin use has been associated with a decrease in serum vitamin B12 levels without clinical manifestations. Reported in approximately 7% of patients, it is attributed to interference with vitamin B12 absorption. It is rarely associated with anemia and appears to be reversible with discontinuation of metformin or with vitamin B12 supplementation, or both.
Cost of Metformin
Metformin is widely available, with an average price of about $10 for a 90-day supply. There are no studies of the cost-effectiveness of metformin as a weight-loss intervention. However, cost-effectiveness analysis of metformin as a diabetes prevention strategy in the DPP concluded that, compared with placebo, it was “extremely cost-effective (that is, improved outcomes at a low incremental cost) or even cost-saving (improved outcomes and reduced total costs).”
Fluoxetine and Weight Loss: A Serotonergic Approach
Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) typically prescribed for depression, obsessive-compulsive disorder, and bulimia, has also been investigated for its potential weight-loss effects. Fluoxetine is believed to impact weight control by changing an individual's appetite.
Fluoxetine's Mechanism of Action in Weight Loss
Fluoxetine favors the hunger inhibition signals produced by the neuropeptide “Y” in the paraventricular hypothalamic nucleus, operating on appetite, altering food selection, and leading to a reduction in food intake.
Evidence from Clinical Trials
A comprehensive review of studies examined the administration of fluoxetine for adults (>18 years) with overweight (body mass index [BMI] 25-29.9 kg/m2) or obesity (BMI ≥30 kg/m2) according to the WHO's criteria compared with placebo, other anti-obesity agents, non-pharmacological therapy, and no treatment. Trials in which participants presented with diabetes mellitus, polycystic ovary syndrome, eating disorders, schizophrenia, HIV infection, cancer, and pregnancy were excluded.
The review identified 19 trials with 2,216 participants with a mean age of 30-51 years, a wide variety of comparisons according to fluoxetine doses (10, 20, 40, and 60 mg once a day), and time of administration (from 3 days to 12 months).
Ten trials compared fluoxetine with placebo. A weight loss of −2.5 kg (95% CI −3.8 to −1.2; p = 0.0001; 7 trials) was identified in 819 participants who received fluoxetine 60 mg/day, while for the adults who received fluoxetine 40 mg/day, the weight loss was −3.97 kg (95% CI −8.8 to 0.8; p = 0.10; 2 trials, 182 participants), and for individuals who received fluoxetine 20 mg/day, the weight loss was −1.5 kg (95% CI −3.5 to 0.5; p = 0.15; 3 trials, 279 participants). Overall, across all fluoxetine dosages and durations of treatment, the weight loss was −2.7 kg (95% CI −4 to −1.4; p = 0.0001; 10 trials, 956 participants; low-certainty evidence in favour of fluoxetine).
Three trials compared fluoxetine with placebo for BMI reduction. It was identified that 19 participants who received fluoxetine 60 mg/day showed a BMI reduction of −3.3 kg/m2 (95% CI −7.3 to 0.7; p = 0.10; 1 trial) and who received fluoxetine 40 mg/day showed −2.8 kg/m2 (95% CI −8.7 to 3.1; p = 0.35; 1 trial, 18 participants). On the other hand, an increase in BMI of 0.2 kg/m2 was observed in one trial in 60 individuals who received fluoxetine 20 mg/day. However, overall, a BMI reduction across all fluoxetine doses compared with the placebo that was −1.1 kg/m2 (95% CI −3.7 to 1.4; 3 trials; 97 participants; very-low-certainty evidence).
Adverse Events Associated with Fluoxetine
Nine trials reported adverse events in the comparison of fluoxetine with placebo. An increase in the risk to develop at least one adverse event with RR 1.16 (95% CI 0.93-1.44; p = 0.18; 7 trials) was observed in 1,134 participants who received fluoxetine 60 mg/day; same findings were identified in 262 adults who received fluoxetine 40 mg/day (RR 1.07; 95% CI 0.93-1.24; p = 0.32; 1 trial), fluoxetine 20 mg/day (RR 1.10; 95% CI 0.92-1.31; p = 0.30; 1 trial, 592 participants), and fluoxetine 10 mg/day (RR 0.96; 95% CI 0.82-1.12; p = 0.59; 1 trial, 262 participants) without significant subgroup differences. However, pooling the trials showed an increase in the risk of experiencing at least one adverse event in the fluoxetine groups, compared with the placebo with an RR of 1.18 (95% CI 0.99-1.42; p = 0.07; 9 trials, 1,253 participants; low-certainty evidence).
Fluoxetine Compared to Other Treatments
Two trials compared fluoxetine with five types of anti-obesity agents (sibutramine, metformin, diethylpropion, fenproporex, and mazindol), and one trial compared with no treatment. It was identified that participants who received fluoxetine 60 mg/day showed a BMI reduction from −0.5 kg/m2 (95% CI −0.6 to −0.3; p = 0.0001, 60 adults) to −2.2 kg/m2 (95% CI −8.4 to 4; p = 0.48; 1 trial, 17 adults) compared to no treatment and metformin, respectively; however, on the other hand, an increase of BMI was also observed in participants who received fluoxetine 20 mg/day from 2 kg/m2 (95% CI 0.9-3.1; p = 0.0001; 1 trial, 62 adults) to 2.9 kg/m2 (95% CI 1.8-4; p = 0.0001; 1 trial 61 participants) compared to sibutramine, diethylpropion, fenproporex, and mazindol.
Three trials reported the development of adverse events comparing fluoxetine with six anti-obesity agents, and one trial compared with no treatment. Overall, an increase in the risk to develop at least one adverse event from an RR of 1.05 (95% CI 0.68-1.65; p = 0.82; 1 trial, 60 participants) to an RR of 1.58 (95% CI 0.91-2.77; p = 0.11; 1 trial) in participants who received fluoxetine at any dose was observed; however, the meta-analysis could not be performed due to the heterogeneity between the trials.
Limitations and Considerations for Fluoxetine Use
The review identified a great variety of doses and durations of treatment in the intervention groups, many different groups of comparators, and variation in the diagnostic criteria and characteristics of the grade of obesity in the participants, which limited comparability and increased the heterogeneity between trials. In most trials, the risk of selection bias was unclear because their reports did not mention in detail the methods of random sequence generation and concealment of allocation. Blinding of outcome assessment was unclear in almost all trials.
Fluoxetine: A Potential Strategy for Weight Loss?
Although the indication for fluoxetine is for the treatment of obsessive behaviors, depression, and anxiety crises, it could be considered as another strategy for weight loss in adults with this condition since it may produce a modest weight loss as a side effect compared to the annoying adverse effects of the administration of pancreatic lipase inhibitors such as the presence of steatorrhea, flatulence, and deficits in the absorption of vitamins A, D, E, and beta-carotene or those developed by the use of GLP-1 analogues and MC4R agonists, which in addition to injection site reactions and their high cost, also favor the appearance of headache, hypoglycemia, nausea, vomiting, and diarrhea.
Adverse Effects of Fluoxetine
Low-certainty evidence suggests that off-label fluoxetine may produce a modest weight loss compared with placebo at any dose, especially when given at a dose of 60 mg/day. However, there is low-certainty evidence of a small increase in the risk for specific adverse events, such as dizziness, drowsiness, fatigue, insomnia, and nausea following fluoxetine consumption.
Combination Therapy: Metformin and Fluoxetine
A study explored the effects of combination therapy with fluoxetine and metformin for weight reduction in obese women. Obese and overweight patients referred to obesity clinics were first put under a diet and behavior therapy education program before being invited to this study. The patients who accepted drug therapy were put in the case group. Those who did not accept drug therapy were put in the control group. Fluoxetine, 20 mg daily, and metformin, 500 mg three times daily, were prescribed to the participants. Weight and body mass index (BMI) changes within case and control groups were analyzed by paired t-tests and between groups by t-testing.
In a 6.68-month period, a 7.89 kg decrease in weight (9.32%) and a 3.43 U decrease in BMI (10.14%) were observed in participants of the case group that was statistically significant (P<0.0001). The participants of the control group were followed for a mean period of 8.12 months. In this period, the participants of the control group showed a 0.48 kg decrease in weight (0.52%) and a 0.11 U decrease in BMI (0.42%). This was not significant.
Considerations for Pharmaceutical Treatment and Medication-Induced Weight Changes
Improving clinical indicators and patient’s health is paramount when selecting pharmaceutical treatment options and there are several factors that need to be taken into consideration. Given that weight gain is a commonly reported side effect for many medications, clinicians should strive to prescribe medication(s) with more favorable weight-related outcomes whenever clinically possible. In order for fluctuations in weight to be monitored, baseline weight measurements should be taken prior to initiating a pharmaceutical treatment. A weight gain of >2.0 kg within a month, in the absence of health and lifestyle changes suggests that intervention may be necessary.
Prior to making changes to medication, changes to dietary and physical activity may be able to counteract the weight gaining effects of medications. Indeed, research has suggested that individuals taking psychiatric medications that are associated with weight gain can still lose a clinically significant amount of weight by participating in a lifestyle intervention without the need to alter their medication. If lifestyle changes alone do not result in the desired amount of weight loss, changes to medication should be considered. Where possible, changes to the dose or delivery of the medication should be attempted prior to medication substitution. When it is not feasible, clinicians should consider substituting medications. Once the decision has been made to change medications, clinicians should be cognizant to switch only one medication at a time, so that the effects on weight and medical efficacy can be appropriately evaluated. A protocol highlighting clear instructions should be created for the patient to minimize the potential of withdrawal symptoms.
Medications Associated with Weight Change
Several classes of medications are known to be associated with weight changes, including:
- Antipsychotics and Mood Stabilizers: Medications for schizophrenia are known to result in significant weight gain. Clozapine- and olanzapine-treated patients can gain on average 4.5-16.2 and 3.6-10.2 kg, respectively. Lithium is commonly prescribed for the treatment of bipolar disorder and has been associated with lesser, yet relevant weight gain (1.1-9.9 kg). Additionally, valproic acid, a second-line treatment option for bipolar disorder, is also associated with significant gain in weight (0.7-6.9 kg), albeit slightly lesser than reported with lithium.
- Antidepressants: Antidepressants consistently have a lower weight gain potential when compared to antipsychotics. However, antidepressants may carry a greater weight gain burden globally as they are prescribed more frequently than antipsychotics. There are five classes of antidepressants - tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors and atypicals. TCAs have been prescribed since the 1950s and are reported to elicit the greatest weight gain among antidepressants. Amitriptyline and nortriptyline appear to be associated with the greatest amount of weight gain for these types of antidepressants. Studies consistently report that of the MAOIs, phenelzine elicits the greatest amount of weight gain. Conversely, tranylcypromine appears to have a more favorable weight change profile and is associated with lesser to no weight changes in users. Citalopram is associated with the greatest amount of weight gain and fluvoxamine with the greatest amount of weight loss for SSRIs. Atypical antidepressants are newer medications with distinct mechanisms from other classes of antidepressants. Mirtazapine is a used atypical antidepressant which is associated with a mean weight gain of 0.4-2.4 kg, while bupropion is associated with mean losses of 0.4 to 2.4 kg and is commonly used as a substitute for some SSRIs.
- Antihyperglycemics: There is a high prevalence of comorbid obesity and diabetes, with over 80% of patients who have type 2 diabetes also having obesity. Metformin is a first-line treatment option for type 2 diabetes and is associated with favorable weight outcomes. Alternative treatment options for patients with type 2 diabetes include thiazolidinediones. These medications carry a lower risk of hypoglycemia than other antihyperglycemic medications as they lower the blood sugar by making the body more sensitive to insulin rather than by increasing the production. However, thiazolidinediones are associated with the most weight gain of antihyperglycemics, second only to insulin. Insulin secretagogues are another alternative treatment option for diabetes. Sulfonylurea drugs such as chlorpropamide and tolbutamide are associated with weight gains of 2.6-5.3 and 1.6-2.8 kg, respectively. Other insulin secretagogues, such as meglitinides, are associated a lower risk of hypoglycemia and may be a more weight-favorable alternative than sulfonylurea drugs. Inhibitors of dipeptidyl peptidate-4 (DPP-4) are essentially weight neutral and include alogliptin, sitagliptin, saxagliptin and linagliptin. Recently, there have been two new classes of diabetes medications that have made it to the market: glucagon-like peptide-1 (GLP-1) agonists and sodium-glucose co-transporter 2 (SGLT-2) inhibitors with promising weight reduction properties. Weight gain is a well-known side effect of insulin and can range from 0.4 to 4.8 kg.
- Antihypertensives: Gaining weight is associated with increases in both systolic and diastolic blood pressure, dietary changes and weight management are typical first-line treatments for hypertension, and as such, medications which are associated with weight gain should be avoided. Of the commonly prescribed angiotensin-converting enzyme inhibitors, enalapril and perindopril are associated with the greatest amount of weight loss. Beta-blockers are typically associated with weight gain for the first few months of treatment, followed by a plateau. Of the commonly prescribed beta-blockers, atenolol, propranolol and metoprolol are associated with the highest weight gain. Conversely, timolol and acebutolol appear to be weight neutral and may even have some weight loss properties. For alpha-blockers, weight gain is not a commonly reported side effect. Of the most commonly used angiotensin II receptor blockers, telmisartan and losartan are associated with the greatest amount of weight loss. Olmesartan and irbesartan are associated with weight neutral effects and valsartan is primarily weight neutral, but can be associated with modest weight gains.
- Corticosteroids: Corticosteroids including cortisone and other glucocorticosteroids can be used for the treatment of conditions such as asthma, dermatological or inflammatory disorders and rheumatic or autoimmune diseases. The short-term use of corticosteroids has not been shown to be associated with significant changes in body weight. Conversely, literature on the long-term usage (≥3 months) of corticosteroids suggests the opposite, with prednisone, prednisolone and cortisone being associated with significant weight gains.