Medications that Can Cause Weight Gain · - weight gain usually observed in the first 3 months of treatment - women > men • Carbamazepine- weight gain to a lesser extent than valproate

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 UniversityBariatric and Metabolic Institute

Digestive Disease Institute9/15/18

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

Anatomical PhysiologicalBehavioral

Psychosocial

Approach to Post Operative Bariatric Surgery Weight Regain

Post Operative Weight Regain

Anatomical Physiological BehavioralPsychosocial

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

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

CNS drugs Endocrine agents MiscellaneousAtypical antipsychotics

eg. olanzapineGlucocorticoids

eg. prednisoneBeta Blockers

eg. metoprolol

Anti-epileptics (AEDs)eg. valproate

Hormonal contraceptiveseg. medroxyprogesterone

Anti-histamineseg. diphenhydramine

Lithium Diabetes agents: Sleep aidseg. zolpidem

Antidepressants: Ø Insulin HIV medications

Ø Selective Serotonin reuptake inhibitors (SSRIs)eg. paroxitene

Ø Sulfonylureaseg. glyburide

Chemotherapies

Ø Tricyclic agentseg. nortriptyline

Ø Thiazolidenedioneseg. pioglitazone

Common Migraine Medications (prophylaxis)

Ø Otherseg. venlafaxine, mirtazapine

Gynecological medications

Leslie, et al. QJM. 2007; 100: 395-404

Classification of Drugs That May Lead to Weight Gain

May substantially increase body weight:

May somewhat increase body weight:

Variable/neutral effects on body 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

Antipsychotics and Weight Gain

Obesity Algorithm®. ©2015-2016 Obesity Medicine Association.

Abilify [package insert], Geodon [package insert]. Risperdal [package insert]., Seroquel [package insert]., Zyprexa [package insert]Courtesy of Dr. Caroline Apovian

Significant Weight Gain (³7%) with Antipsychotic Medications

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15

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25

30

35

Aripipraz

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Ziprasidone

Risperi

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Quetiap

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Olanza

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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 MedicationsMedication Weight Gain Glucose Metabolism

AbnormalitiesDyslipidemia Metabolic Syndrome

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: tricyclic antidepressants

AmitriptylineDoxepinImipramineNortriptylineMirtazapine

Antidepressants/mood stabilizers: Bipolar disorder Lithium

Antidepressants/mood stabilizers: SSRIs Fluoxetine?Sertaline ?ParoxetineFluvoxamine

Antidepressants/mood stabilizers: MAO Inhibitors PhenylzineTranylcypromine

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

SSRI use ≥ year or more cause weight gain of about 5 lbsSNRIs cause less long term weight gain

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

Drug Class/Type(and Potential Related Weight Gain)

Common Name Brand Name

Insulin (weight gain differs with type and regimen used)

Insulin lisproInsulin aspartInsulin glulisine

HumalogNovologApidra

Thiazolidinediones (TZDs) pioglitazone Actos

Sulfonylureas (SUs) glypizideglyburideglimepridechlorpropamidetolubutamide

GlucotrolDiabetaMicronaseGlynaseAmarylDiabinese

Diabetes Medications Associated with Weight Gain






Thiazolidinediones (TZDs)Shift in fat distribution from visceral to subcutaneous adipose depots that is associated with improvements in hepatic and peripheral tissue sensitivity to insulin

pioglitazone Actos

Sulfonylureas (SUs) glypizideglyburideglimepridechlorpropamidetolubutamide









Sulfonylureas (SUs)Drugs exert their hypoglycemic effects by stimulating insulin secretion from the pancreatic beta-cell

glypizideglyburideglimepridechlorpropamidetolubutamide



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)


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


Human Immunodeficiency Virus (HIV) Medications and Weight Gain

• 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

Obesity Algorithm®. ©2015-2016 Obesity Medicine Association

Lipodystrophy a Possible Side Effect of HIV Drugs

• 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

• 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

Chemotherapies and Weight

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


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

Oral contraceptivesProgestational steroids Hormonal contraceptives containing progestational steroids

Barrier methods IUDs

Endometriosistreatment

Depot leuprolide acetate Surgical treatment

Gynecologic Medications and Weight Gain


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

Hypertension medications

α-blocker? β-blocker?

ACE inhibitors? Calcium channel blockers ?Angiotensin-2 receptor antagonists

Cardiovascular Medications and Weight Gain


MEDICATIONS WEIGHT GAIN ASSOCIATED WITH USEALTERNATIVES

(WEIGHT REDUCTING IN PARENTHESES)*

Antipsychotics

Clozapine Risperidone Olanzapine Quetiapine Haloperidol Perphenazine Quetiapine

Ziprasidone Aripiprizole

AnticonvulsantsCarbamazepine Gabapentin Valproate

Lamotrigine? (Topiramate) (Zonisamide)

Antipsychotic and Anticonvulsant Medications and Weight Gain


* 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

Metformin Prevents Antipsychotic Induced Weight Gain in Adolescents

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

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



Insulin Insulin lisproInsulin aspartInsulin glulisine



Sulfonylureas glypizideglyburideglimepridechlorpropamidetolubutamide


Diabetes Medications Associated with Weight Gain and AlternativesAlternative Drugs(Weight neutral or may promote weight-loss)






SulfonylureasThese drugs exert their hypoglycemic effects by stimulating insulin secretion from the pancreatic beta-cell.

glypizideglyburideglimepridechlorpropamidetolubutamide








Sulfonylureas glimepride Amaryl









metformin (Glucophage, Fortamet, Glumetza, Riomet)








metformin (Glucophage, Fortamet, Glumetza, Riomet)SGLT 2 inhibitors







Diabetes Medications Associated with Weight Gain and Alternatives

Alternative Drugs(Weight neutral or may promote weight-loss)

metformin (Glucophage, Fortamet, Glumetza, Riomet)SGLT 2 inhibitorslinagliptin (Tradjenta)saxagliptin (Onglyza)sitagliptin (Januvia)








metformin (Glucophage, Fortamet, Glumetza, Riomet)SGLT 2 inhibitorslinagliptin (Tradjenta)saxagliptin (Onglyza)sitagliptin (Januvia)exenatide (Byetta)liraglutide (Victoza)








metformin (Glucophage, Fortamet, Glumetza, Riomet)SGLT 2 inhibitorslinagliptin (Tradjenta)saxagliptin (Onglyza)sitagliptin (Januvia)exenatide (Byetta)liraglutide (Victoza)acarbose (Precose, Prandase)








metformin (Glucophage, Fortamet, Glumetza, Riomet)SGLT 2 inhibitorslinagliptin (Tradjenta)saxagliptin (Onglyza)sitagliptin (Januvia)exenatide (Byetta)liraglutide (Victoza)acarbose (Precose, Prandase)miglitol (Glyset)








metformin (Glucophage, Fortamet, Glumetza, Riomet)SGLT 2 inhibitorslinagliptin (Tradjenta)saxagliptin (Onglyza)sitagliptin (Januvia)exenatide (Byetta)liraglutide (Victoza)acarbose (Precose, Prandase)miglitol (Glyset)Pramlintide (Amylin)









metformin (Glucophage, Fortamet, Glumetza, Riomet)SGLT 2 inhibitorslinagliptin (Tradjenta)saxagliptin (Onglyza)sitagliptin (Januvia)exenatide (Byetta)liraglutide (Victoza)acarbose (Precose, Prandase)miglitol (Glyset)Pramlintide (Amylin)metformin/pioglitazone (Actoplus Met)glipizide/metformin (Metaglip)glyburide/metformin (Glucovance)glimepiride/metformin









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

metformin/pioglitazone (Actoplus Met)glipizide/metformin (Metaglip)glyburide/metformin (Glucovance)glimepiride/metformin

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


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

Antipsychotics

Clozapine Risperidone Olanzapine Quetiapine Haloperidol Perphenazine Quetiapine

Ziprasidone Aripiprizole

AnticonvulsantsCarbamazepine Gabapentin Valproate

Lamotrigine? (Topiramate) (Zonisamide)

Antipsychotic and Anticonvulsant Medications and Weight Gain


* 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

Antidepressant Medications and Weight GainMEDICATIONS WEIGHT GAIN ASSOCIATED WITH USE ALTERNATIVES


Antidepressants/mood stabilizers: tricyclicantidepressants

Amytriptyline Doxepin Imipramine Nortriptyline Trimipramine Mirtazapine

(Bupropion) Nefazodone Fluoxetine (short term) Sertraline (< 1 yr)

* Only naltrexone SR/ bupropion SR combination is FDA-approved for chronic weight management in patients with BMI 30+ kg/m2 or BMI 27 <30 kg/m2 with one or more comorbidities

Lithium Lithium

Antidepressants/mood stabilizers: SSRIs

Fluoxetine? Sertraline? Paroxetine Fluvoxamine

Antidepressants/mood stabilizers: MAOI Phenylzine

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

Antidepressant Medications and Weight GainMEDICATIONS WEIGHT GAIN ASSOCIATED WITH USE ALTERNATIVES


Antidepressants/mood stabilizers: tricyclicantidepressants

Amytriptyline Doxepin Imipramine Nortriptyline Trimipramine Mirtazapine

(Bupropion) Nefazodone Fluoxetine (short term) Sertraline (< 1 yr)

* Only naltrexone SR/ bupropion SR combination is FDA-approved for chronic weight management in patients with BMI 30+ kg/m2 or BMI 27 <30 kg/m2 with one or more comorbidities

Lithium Lithium

Antidepressants/mood stabilizers: SSRIs

Fluoxetine? Sertraline? Paroxetine Fluvoxamine

Antidepressants/mood stabilizers: MAOI Phenylzine

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

Metformin

• 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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Contact: [email protected]

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Documents

Medications that Can Cause Weight Gain · - weight gain usually observed in the first 3 months of treatment - women > men • Carbamazepine- weight gain to a lesser extent than valproate