Medications That Can Cause Weight Gain

Medications that Can Cause Weight Gain

Derrick Cetin, D.O. Obesity Medicine Clinical Assistant Professor Dept. of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Bariatric and Metabolic Institute Digestive Disease Institute 9/15/18 Drug-Induced Weight Gain, Audience Should Know:

• A possible serious side effect of many commonly used drugs used for a variety of disease states • Leads to exacerbation of co-morbid conditions related to obesity due to associated weight gain • While some medications are more common than others to cause weight gain, not all individuals gain weight from every drug that has weight gain listed as a side effect • In many cases if possible, substitute an alternative medication to treat the same condition that is weight neutral or weight negative Case Study

55 year old Caucasian female referred by bariatric surgeon for medical evaluation of weight regain. S/P RYGB 2003 with 125 lbs weight loss. Regained her weight and now at highest post operative weight. Her current weight is 285 lbs with a BMI of 55 kg/m^2. Concerns that she has been noncompliant with her vitamin, mineral supplementation and dietary recommendations. She has not been able to exercise regularly due to a back injury. T2DM, HTN, and major depressive disorder.

Approach to Post Operative Bariatric Surgery Weight Regain

Post Operative Weight Regain

Behavioral Anatomical Physiological Psychosocial Approach to Post Operative Bariatric Surgery Weight Regain

Post Operative Weight Regain

Behavioral Anatomical Physiological Psychosocial Physiological Causes of Weight Gain

• Pregnancy • Menopause • Smoking cessation • Endocrine disease • Hypothyroidism • Cushing's disease • Adaptations: hypoleptinemia, energy efficiency, gut hormones (PYY) • Weight-gain promoting medications Classification of Drugs That May Lead to Weight Gain CNS drugs Endocrine agents Miscellaneous Atypical antipsychotics Glucocorticoids Beta Blockers eg. olanzapine eg. prednisone eg. metoprolol Anti-epileptics (AEDs) Hormonal contraceptives Anti-histamines eg. valproate eg. medroxyprogesterone eg. diphenhydramine Lithium Diabetes agents: Sleep aids eg. zolpidem Antidepressants: Ø Insulin HIV medications

Ø Selective Serotonin reuptake Ø Sulfonylureas Chemotherapies inhibitors (SSRIs) eg. glyburide eg. paroxitene

Ø Tricyclic agents Ø Thiazolidenediones Common Migraine Medications eg. nortriptyline eg. pioglitazone (prophylaxis) Ø Others Gynecological medications eg. venlafaxine, mirtazapine

Leslie, et al. QJM. 2007; 100: 395-404 Antipsychotics and Weight Gain May substantially increase body May somewhat increase body Variable/neutral effects on body weight: weight: weight: Clozaril (Clozapine) Saphris (Asenapine) Solidan (Amisulpride)

Zyprexa (Olanzapine) Thorazine (Chlorpromazine) Abilify (Aripiprazole)

Fanapt (Iioperidone) Haldol (Haloperidol)

Invega (Paliperidone) Latuda (Lurasidone)

Seroquel (Quetiapine) Geodon (Ziprasidone)

Resperidol (Resperidone)

Serdolect (Sertindole) Lithium

35 30 29 25 20 23 15 18

Incidence (%) 10 10 8.1 9 5 6 3.2 4 3 0

Quetiapine Aripiprazole Ziprasidone Risperidone Olanzapine

Abilify [package insert], Geodon [package insert]. Risperdal [package insert]., Seroquel [package insert]., Zyprexa [package insert] Courtesy of Dr. Caroline Apovian Mechanism(s) of Antipsychotic-Associated Weight Gain

• Review of the literature indicates that a group of factors are associated with weight gain rather than a single mechanism • Coupled with genetic profile, the risk for antipsychotic-induced weight gain is heterogeneous among individuals and specific agents • Targets for weight gain include receptor interactions involving serotonin, histamine, dopamine, adrenergic, cannabinoid, and muscarinic receptors

CNS Drugs. 2011 Dec 1; 25 (12): 1035-59 Relative Likelihood of Metabolic Disturbances with Atypical Antipsychotic Medications Medication Weight Gain Glucose Metabolism Dyslipidemia Metabolic Syndrome Abnormalities

Amisulpride Low Low Low ─ Aripiprazole Low Low Low Low Clozapine High High High High Melperone ─ ─ ─ ─ Olanzapine High HIgh High High Paliperidone ─ ─ ─ ─ Resperidone Medium Medium-to-low Low Medium Sulpiride ─ ─ ─ ─ Quetiapine Medium Medium-to-low High High Sertindole Low ─ ─ ─ Ziprasidone Low Low Low Low Zotepine Medium ─ ─ ─ Primary Care Diabetes. 2009; 3: 5-15. Current Diabetes Reports. 2010; 10: 209-216. Atypical Antipsychotic Medications are associated with weight gain

Potential Mechanism • 5 HT2c blockade • H1 affinity Clinical Practice Guidelines for the Use of Atypical Antipsychotic Medications

• Body weight at 4 week intervals and the quarterly • Fasting plasma glucose at baseline, 12 weeks, and annually • Lipid profile at baseline, 12 weeks, and every 5 years • Waist circumference at baseline and annually

Clinical Pharmacology & Therapeutics. 2011 Apr 11 Anti-epileptics (AEDs) and Weight Gain

• Valproate- weight reported in the range of 5-49 kg - weight gain usually observed in the first 3 months of treatment - women > men • Carbamazepine- weight gain to a lesser extent than valproate • Gabapentin- least weight gain of AEDs Mechanism of Anti-epileptics (AEDs) Associated Weight Gain

• Mechanisms by which AEDs cause weight gain are not fully understood and controversial • It is likely that the weight change may have some underlying genetic underpinning

Measurements of body weight before initiation of valproic acid therapy should be done as part of the monitoring of patients with epilepsy to detect changes before there are serious adverse consequences; an increase of 2 kg of body weight after 1 month of treatment should imply considerations to change antiepileptic drug therapy.

Obes Rev. 2011 May; 12(5): e 32-43 Antidepressant Medications and Weight Gain WEIGHT GAIN ASSOCIATE WITH USE Antidepressants/mood stabilizers: Amitriptyline tricyclic antidepressants Doxepin Imipramine Nortriptyline Mirtazapine

Antidepressants/mood stabilizers: Bipolar disorder Lithium

Antidepressants/mood stabilizers: SSRIs Fluoxetine? Sertaline ? SSRI use ≥ year or more cause weight gain of about 5 lbs Paroxetine SNRIs cause less long term weight gain Fluvoxamine

Antidepressants/mood stabilizers: MAO Inhibitors Phenylzine Tranylcypromine

J Clin Endocrinol Metab. 2015 Feb; 100(2):342-62 Why Weight Gain Happens with Antidepressants?

• Antidepressants work by interacting with muscarinic, acetylcholine, and the histamine receptors; when blocked have a proclivity toward weight gain • Tricyclic antidepressants block all these receptors, therefore reliably cause weight gain • Paroxetine (paxil) has more anticholinergic activity of all the SSRIs, therefore causes the most weight gain. • Mirtazapine (remeron) blocks the histamine receptor and is associated with significant weight gain Diabetes Medications Associated with Weight Gain

Drug Class/Type Common Name Brand Name (and Potential Related Weight Gain)

Insulin (weight gain differs with type Insulin lispro Humalog and regimen used) Insulin aspart Novolog Insulin glulisine Apidra

Thiazolidinediones (TZDs) pioglitazone Actos

Sulfonylureas (SUs) glypizide Glucotrol glyburide Diabeta glimepride Micronase chlorpropamide Glynase tolubutamide Amaryl Diabinese Diabetes Medications Associated with Weight Gain

Drug Class/Type Common Name Brand Name (and Potential Related Weight Gain)

Insulin (weight gain differs with type Insulin lispro Humalog and regimen used) Insulin aspart Novolog Insulin glulisine Apidra

Thiazolidinediones (TZDs) pioglitazone Actos Shift in fat distribution from visceral to subcutaneous adipose depots that is associated with improvements in hepatic and peripheral tissue sensitivity to insulin Sulfonylureas (SUs) glypizide Glucotrol glyburide Diabeta glimepride Micronase chlorpropamide Glynase tolubutamide Amaryl Diabinese Diabetes Medications Associated with Weight Gain

Drug Class/Type Common Name Brand Name (and Potential Related Weight Gain)

Insulin (weight gain differs with type Insulin lispro Humalog and regimen used) Insulin aspart Novolog Insulin glulisine Apidra

Thiazolidinediones (TZDs) pioglitazone Actos

Sulfonylureas (SUs) glypizide Glucotrol Drugs exert their hypoglycemic effects by glyburide Diabeta stimulating insulin secretion from the pancreatic beta-cell glimepride Micronase chlorpropamide Glynase tolubutamide Amaryl Diabinese Diabetes Medications and Weight Gain

• Sulfonylureas usually ≤ 5 kg gain during 3-12 months of treatment - increase weight by decreasing amount of glucose excreted in the urine, leads to storage of glucose as fat • Insulin promotes weight gain by causing the body to retain more calories • TZDs lead to weight gain from fluid retention and SQ fat deposition • Both insulin and sulfonyureas can cause weight gain as a result of hypoglycemia - promotes overeating to avoid hypoglycemia Insulin-Associated Weight Gain in Diabetes

Diabetes, Obesity and Metabolism. Volume 9, Issue 6, pages 799-812, 15 Dec 2006 Cardiovascular Medications and Weight Gain

• Some β-blockers - Propranolol - Atenolol - Metoprolol • Some α-blockers - Clonidine- mechanism of weight gain from reduced metabolic rate as a result of decreased sympathetic activity • Calcium blockers are weight neutral except for flunarizine (sibelium)

J Clin Endocrinol Metab. 2015 Feb; 100(2):342-62 Potential Mechanisms of β-Blocker- Associated Weight Gain

• Reduction in resting energy expenditure • Reduction in the thermic effect of food • Reduction in exercise tolerance • Increase in tiredness • Reduction in nonexercise thermogenesis • Inhibition of lipolysis • Exacerbation of insulin resistance

Sharma AM, et al. Hypertension. 2001; 37: 250-254 Antihistamines and Hypnotics and Weight Gain

• May increase body weight: - Diphenhydramine • May have limited effects on body weight: - Benzodiazepines - Melatonergic hypnotics - Trazadone

• 33-75% of patients with HIV infection receiving highly active antiretroviral therapy (HAART) develop a syndrome referred to as lipodystrophy • All Protease inhibitors (PI) and the Nucleoside Reverse Transcriptase Inhibitors (NRITs), ddi, D4t, AZT linked to lipodystrophy, risk is greater the longer the drug is used, and if older, Caucasian, or overweight/obese

• Characteristic body habitus associated with peripheral wasting of fat in the face, arms, legs and buttocks • Manifest as lipid redistribution to other areas: - increase in abdominal girth from accumulation of intra-abdominal fat - buffalo hump - enlargement of the breasts Lipodystrophy a Possible Side Effect of HIV Drugs

• May increase body weight: - Tamoxifen - Cyclophosphamide - Methotrexate - 5- fluorouracil - Aromatase inhibitors - Corticosteroids

ALTERNATIVES MEDICATIONS WEIGHT GAIN ASSOCIATED WITH USE (WEIGHT REDUCTING IN PARENTHESES)

Progestational steroids Barrier methods Oral contraceptives Hormonal contraceptives containing IUDs progestational steroids

Endometriosis Depot leuprolide acetate Surgical treatment treatment

J Clin Endocrinol Metab. 2015 Feb; 100(2):342-62

Cardiovascular Medications and Weight Gain

ALTERNATIVES MEDICATIONS WEIGHT GAIN ASSOCIATED WITH USE (WEIGHT REDUCTING IN PARENTHESES)

ACE inhibitors? Hypertension α-blocker? Calcium channel blockers ? medications β-blocker? Angiotensin-2 receptor antagonists

J Clin Endocrinol Metab. 2015 Feb; 100(2):342-62

Antipsychotic and Anticonvulsant Medications and Weight Gain

ALTERNATIVES MEDICATIONS WEIGHT GAIN ASSOCIATED WITH USE (WEIGHT REDUCTING IN PARENTHESES)*

Clozapine Risperidone Olanzapine Ziprasidone Antipsychotics Quetiapine Aripiprizole Haloperidol Perphenazine Quetiapine

Carbamazepine Lamotrigine? Anticonvulsants Gabapentin (Topiramate) Valproate (Zonisamide)

* Only phentermine/topiramate ER is FDA-approved for chronic weight management in patients with BMI 30+ kg/m2 or BMI 27-29.9 kg/m2 with one or more comorbidities J Clin Endocrinol Metab. 2015 Feb; 100(2):342-62 Metformin Prevents Antipsychotic Induced Weight Gain in Adolescents

Metformin 850 bid, in addition to program of diet and physical activity, prevented weight gain in adolescents gaining weight on antipsychotic agents

Klein DJ, et al Am J Psychiatry 2006; 163:2072–2079.

Diabetes Medications Associated with Weight Gain and Alternatives Drug Class/Type Common Name Brand Name Alternative Drugs (and Potential Related (Weight neutral or may promote weight- Weight Gain) loss) Insulin Insulin lispro Humalog Insulin aspart Novolog Insulin glulisine Apidra Thiazolidinediones (TZDs) pioglitazone Actos

Sulfonylureas glypizide Glucotrol glyburide Diabeta glimepride Micronase chlorpropamide Glynase tolubutamide Amaryl Diabinese Diabetes Medications Associated with Weight Gain and Alternatives Drug Class/Type Common Name Brand Name Alternative Drugs (and Potential Related (Weight neutral or may promote weight- Weight Gain) loss) Insulin Insulin lispro Humalog Insulin aspart Novolog Insulin glulisine Apidra Thiazolidinediones (TZDs) pioglitazone Actos

Sulfonylureas glypizide Glucotrol These drugs exert their glyburide Diabeta hypoglycemic effects by stimulating insulin secretion from the glimepride Micronase pancreatic beta-cell. chlorpropamide Glynase tolubutamide Amaryl Diabinese Diabetes Medications Associated with Weight Gain and Alternatives Drug Class/Type Common Name Brand Name Alternative Drugs (and Potential Related (Weight neutral or may promote weight- Weight Gain) loss) Insulin Insulin lispro Humalog Insulin aspart Novolog Insulin glulisine Apidra Thiazolidinediones (TZDs) pioglitazone Actos

Sulfonylureas glimepride Amaryl Diabetes Medications Associated with Weight Gain and Alternatives Drug Class/Type Common Name Brand Name Alternative Drugs (and Potential Related (Weight neutral or may promote weight- Weight Gain) loss) Insulin Insulin lispro Humalog metformin (Glucophage, Fortamet, Insulin aspart Novolog Glumetza, Riomet) Insulin glulisine Apidra SGLT 2 inhibitors linagliptin (Tradjenta) Thiazolidinediones (TZDs) pioglitazone Actos saxagliptin (Onglyza) sitagliptin (Januvia) exenatide (Byetta) liraglutide (Victoza) acarbose (Precose, Prandase) miglitol (Glyset) Pramlintide (Amylin) Sulfonylureas glimepride Amaryl Diabetes Medications Associated with Weight Gain and Alternatives Drug Class/Type Common Name Brand Name Alternative Drugs (and Potential Related (Weight neutral or may promote weight- Weight Gain) loss) Insulin Insulin lispro Humalog metformin (Glucophage, Fortamet, Insulin aspart Novolog Glumetza, Riomet) Insulin glulisine Apidra SGLT 2 inhibitors linagliptin (Tradjenta) Thiazolidinediones (TZDs) pioglitazone Actos saxagliptin (Onglyza) sitagliptin (Januvia) exenatide (Byetta) liraglutide (Victoza) acarbose (Precose, Prandase) miglitol (Glyset) Pramlintide (Amylin) metformin/pioglitazone (Actoplus Met) Sulfonylureas glypizide Glucotrol glipizide/metformin (Metaglip) glyburide Diabeta glyburide/metformin (Glucovance) glimepride Micronase glimepiride/metformin chlorpropamide Glynase tolubutamide Amaryl Diabinese Diabetes Medications Associated with Weight Gain and Alternatives Drug Class/Type Common Name Brand Name Alternative Drugs (and Potential Related (Weight neutral or may promote weight- Weight Gain) loss) Insulin Insulin lispro Humalog Insulin aspart Novolog Insulin glulisine Apidra Thiazolidinediones (TZDs) pioglitazone Actos

These combinations tend to have fewer side-effects and less weight gain:

metformin/pioglitazone (Actoplus Met) Sulfonylureas glypizide Glucotrol glipizide/metformin (Metaglip) glyburide Diabeta glyburide/metformin (Glucovance) glimepride Micronase glimepiride/metformin chlorpropamide Glynase tolubutamide Amaryl Diabinese Drugs That Cause Weight Gain and Some Alternatives

• Patients with obesity and T2DM requiring insulin therapy, suggest adding at least one of the following: metformin, pramlintide, or GLP-1 receptor agonists to mitigate associated weight gain due to insulin • The first-line insulin for this type of patient should be basal insulin (this is preferable to using either insulin alone or insulin with sulfonylurea) • Recommend the initial insulin therapy strategy consider a preferential trial of basal insulin prior to premixed insulins or combination insulin therapy

J Clin Endocrinol Metab. 2015 Feb; 100(2):342-62

Antipsychotic and Anticonvulsant Medications and Weight Gain

MEDICATIONS WEIGHT GAIN ASSOCIATED WITH USE ALTERNATIVES (WEIGHT REDUCTING IN PARENTHESES)*

Clozapine Risperidone Olanzapine Ziprasidone Antipsychotics Quetiapine Aripiprizole Haloperidol Perphenazine Quetiapine

Carbamazepine Lamotrigine? Anticonvulsants Gabapentin (Topiramate) Valproate (Zonisamide)

Antidepressant Medications and Weight Gain

MEDICATIONS WEIGHT GAIN ASSOCIATED WITH USE ALTERNATIVES (WEIGHT REDUCTING IN PARENTHESES)* Amytriptyline Doxepin Antidepressants/mood Imipramine (Bupropion) stabilizers: tricyclic Nortriptyline Nefazodone antidepressants Trimipramine Fluoxetine (short term) Mirtazapine Sertraline (< 1 yr) Lithium Lithium Fluoxetine? * Only naltrexone SR/ bupropion Antidepressants/mood Sertraline? SR combination is FDA-approved stabilizers: SSRIs Paroxetine for chronic weight management Fluvoxamine in patients with BMI 30+ kg/m2 or Antidepressants/mood BMI 27 <30 kg/m2 with one or Phenylzine stabilizers: MAOI more comorbidities Tranylcypromine

Bupropion is the only antidepressant associated with long-term weight loss, but only in nonsmokers, according to a new retrospective cohort study published in the Journal of Clinical Medicine, April 13, 2016 J Clin Endocrinol Metab. 2015 Feb; 100(2):342-62

Antidepressant Medications and Weight Gain MEDICATIONS WEIGHT GAIN ASSOCIATED WITH USE ALTERNATIVES (WEIGHT REDUCTING IN PARENTHESES)* Amytriptyline Doxepin Antidepressants/mood Imipramine (Bupropion) stabilizers: tricyclic Nortriptyline Nefazodone antidepressants Trimipramine Fluoxetine (short term) Mirtazapine Sertraline (< 1 yr) Lithium Lithium Fluoxetine? * Only naltrexone SR/ bupropion SR Antidepressants/mood Sertraline? combination is FDA-approved for stabilizers: SSRIs Paroxetine chronic weight management in Fluvoxamine patients with BMI 30+ kg/m2 or Antidepressants/mood BMI 27 <30 kg/m2 with one or Phenylzine stabilizers: MAOI more comorbidities Tranylcypromine

• May help treat complications of other concurrent drug treatments: - Antipsychotic-related weight gain - Human immunodeficiency virus (HIV) protease inhibitor-associated abnormalities ( i.e., HIV lipodystrophy) Conclusion

• Weight promoting medications are one of the many modifiable environmental & lifestyle factors to consider when evaluating a patient for weight gain • Drug-induced weight gain is a serious side effect of many commonly used medications leading to noncompliance with therapy and exacerbation of comorbid conditions related to obesity • If possible discontinue or change weight gain-promoting medications to an alternative that has a weight neutral or a weight negative effect • An exception, is if a medication is specifically indicated for an underlying condition, should be continued regardless of the effects on weight gain A Brighter Future For Patients

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