Side Effect Solutions: How to Avoid Medication-induced Weight Gain

Dr. Knudsen is an assistant professorof pharmacy practice at MidwesternUniversity College of Pharmacy—Glendale, Glendale, Arizona.

Every day the general public isbombarded with commercialsadvertising products or medicationsfor weight loss, as well as direct-to-consumer advertisements cataloginglong lists of side effects that includeweight gain.

Data from 2 National Health and NutritionExamination surveys by theCenters for Disease Control andPrevention's National Center for HealthStatistics show that, among adults aged20 to 74 years, the prevalence of obesityincreased from 15% (in the 1976-1980survey) to 32.9% (in the 2003-2004survey).¹

Pharmacists often encounter patientsattributing recent or long-term weightgain to their medication(s) or patientswanting to know if a new medicationwill cause weight gain. Sifting througheach medication can be a dauntingtask—one that is equaled by determiningif weight gain is caused by medication,lifestyle, or just plain edema.

When the source of the problem isedema associated with heart failure,and it is treated with diuretics, potassiumreplacement may be needed; as aresult, patients may increase dietaryconsumption of potassium-rich food,which can lead to weight gain.² Patientsshould be encouraged to keep a weightdiary and report sudden weight increasesto their physician. This can preventthem from developing a largebuildup of fluid weight and further cardiacproblems before seeking medicaltreatment. Patients also should beadvised that prescription potassium replacementshould suffice during diuretictreatment; consuming potassiumand calorie-rich foods is unnecessary.

Medications associated with weightgain include antipsychotics, antidepressants,and anticonvulsants. For patientstaking antipsychotics, for example,medication-induced weight gainhas been cited as a contributor todecreased quality of life and nonadherenceto their drug regimen.³

Atypical Antipsychotics

Of the 2 antipsychotic medicationclasses, the use of certain atypicalantipsychotics has produced evidencesupporting the risk of weight gain. Thisweight gain may have a relationshipwith the documented risk of developingdiabetes during atypical antipsychotictreatment. The risk of weightgain mirrors the risk of developing diabetesfor these agents. Atypical antipsychoticsinclude aripiprazole (Abilify),clozapine (Clozaril), olanzapine (Zyprexa),paliperidone (Invega), quetiapine (Seroquel),risperidone (Risperdal), andziprasidone (Geodon). Aripiprazole andziprasidone are associated with theleast amount of weight gain and arelisted as weight-neutral in some medicalliterature.⁴

Patients experiencing atypicalantipsychotic-induced weight gain canuse calorie reduction and dietary educationprograms, as well as pharmacologictreatment.⁴ Orlistat 60 mg (alli),orlistat 120 mg (Xenical), and sibutramine(Meridia) are available agents,but, currently, little literature existsregarding how they affect atypicalantipsychotic-induced weight gain.

Another option is switching between antipsychoticagents.⁴ Switching between antipsychotics, however, is notas easy as switching between statins. The risks and benefitsmust be seriously considered, and patients must be monitoredclosely during and after the transition period. Patientscan respond to antipsychotics differently depending on theagent, and little guidance is available for equivalent dosingbetween the agents. An American Diabetes Association consensustask force recommends changing agents if a patientgains more than 5% of baseline body weight after treatmentinitiation.⁵

Antidepressants

Although more medical literature exists regarding weightgain and antipsychotic medications, antidepressants also areassociated with weight gain. Tricyclic antidepressants (TCAs)are known for their anticholinergic side effects; however,weight gain can be an unfortunate side effect as well. TCAsblock histamine and serotonin receptors and peripheralalpha receptors. The blocking of these 3 receptors leads toincreased carbohydrate cravings, decreased physical activity,and increased appetite. TCAs also cause decreased basalmetabolic rates.⁶ The combination of these effects can lead toweight gain.

Mirtazapine (Remeron), an alpha-2 antagonist antidepressant,joins TCAs on the list of medications commonly causingweight gain. Of the several classes of antidepressants,selective serotonin reuptake inhibitors (SSRIs), including fluoxetine,citalopram, sertraline, paroxetine, fluvoxamine, andescitalopram,⁷ have a low association with weight gainbecause they do not have the receptor blockade like TCAs;therefore, if weight becomes an issue, switching a patient toan SSRI for depression treatment maybe a good choice.⁷ When switching apatient between antidepressants, however,proper titration and patient counselingare very important.

Anticonvulsants

Anticonvulsants, such as carbamazepine,gabapentin, lamotrigine,lithium, and valproic acid, can produceweight gain. Approximately one fifth ofpatients gain ≥22 lb while on lithiumtreatment. This could be due to fluidretention or decreased metabolic ratefrom hypothyroidism, both commonwith lithium.⁸ Frequent and close monitoringof these parameters can helpavoid weight gain.

Increased appetite and weight gainoccur in approximately 50% of patientson long-term valproate therapy.⁹Weight gain may be related to changesin metabolic rates and not to excessivefood intake; excessive weight gain mayresult in obesity-induced hyperinsulinemiaand insulin resistance.⁹ Carbamazepinecauses weight gain less frequentlythan valproate.¹⁰

Diabetic Medications

Among the other most common pharmacotherapiesassociated with weightgain are diabetic medications, such asinsulin and thiazolidinediones. An average3% to 9% increase in weight can bea consequence of insulin therapy.¹¹

Weight gain is predominantly from increasedtruncal fat and tends to be relatedto daily dose and plasma insulin levels.Less weight gain, when comparedwith more traditional insulin strategies,is achieved when patientsare converted to insulin byusing a bedtime injection ofan intermediate- or long-actinginsulin and using oralagents primarily for controlduring the day.¹¹

Thiazolidinediones (rosiglitazoneand pioglitazone)can cause weight gainthrough both fluid retention and fataccumulation.¹² Thiazolidinedionesstimulate appetite and fat-cell differentiation.A weight gain of 3.3 to 8.8 lb isnot unusual and seems to be doserelated.¹³ In addition, these agents carrya black-box warning regarding theincreased risk of new or worsening congestiveheart failure.¹⁴ The prescribinginformation states, "observe patientscarefully for signs and symptoms ofheart failure including excessive, rapidweight gain, dyspnea, and/or edema."¹⁴

Appropriate medical nutrition therapyand healthy lifestyle education arecritical to minimize weight gain associatedwith insulin therapy.

Smoking-cessation Products

Weight gain during smoking cessationhas been a deterrent to patientswishing to quit or being successful intheir attempts.¹⁵ Patientshoping to find a medicationthat assists with smokingcessation and causes weightloss or be weight-neutral willbe disappointed to learn thatsustained-release bupropion(Zyban) and nicotine-replacementtherapies—in particularnicotine gum—havebeen shown to delay, but not prevent,weight gain.¹⁶ Pharmacists must educatepatients about lifestyle modificationsand choices during smoking cessationto decrease the risk of weightgain.

Oral Contraceptives

Women taking oral contraceptives(OCs) have thought that these productscan be the cause of weight gain. Manyof the newer OCs advertise their abilityto prevent weight gain. Drospirenone(Angeliq) has antimineralocorticoid orantialdosterone activities, which mayresult in less weight gain, when comparedwith OCs containing levonorgestrel.¹⁷ A 2003 review of the datadid not find evidence supporting acausal association between combinationOCs or combination skin patchesand weight gain.¹⁸

Counseling Is Key

Pharmacists should expect questionsfrom patients experiencing weightgain while taking a particular medicationand counsel them on the possiblecontributing factors, including lifestyleand edema, in addition to potentialside effects of the medication itself.

References

• Centers for Disease Control and Prevention. Overweight and Obesity. www.cdc.gov/nccdphp/dnpa/obesity/index.htm. Accessed October 30, 2007.
• DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill; 2005:971.
• Nasrallah, HA. Pharmacoeconomic implications of adverse effects during antipsychotic drug therapy. Am J Health Syst Pharm. 2002;59(Suppl 8):S16-S21.
• Guthrie, SK. Clinical issues associated with maintenance treatment of patients with schizophrenia. Am J Health Syst Pharm. 2002;59(Suppl 5):S19-S24.
• American Diabetes Association. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27:596-601.
• Tom WC et al. Drugs Associated with Weight Gain. Pharmacist's Letter. March 2007. www.pharmacistsletter.com.
• DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill; 2005:1242.
• DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill; 2005:1278.
• DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill; 2005:1280.
• DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill; 2005:1276.
• Stoneking, K. Initiating basal insulin therapy in patients with type 2 diabetes mellitus. Am J Health Syst Pharm. 2005;62:510-518.
• DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill; 2005:1352.
• Young, D. Experts: Rosiglitazone needs stronger warnings. Panel backs diabetes drug. Am J Health Syst Pharm. 2007;64:1780.
• Avandia prescribing information. us.gsk.com/products/assets/us_avandia.pdf.
• Garwood CL, Potts LA. Emerging pharmacotherapies for smoking cessation. Am J Health Syst Pharm. 2007;64:1693-1698.
• DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill; 2005:1201.
• DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill; 2005:1450.
• Gallo MF, Grimes DA, Schulz KF, Helmerhorst FM. Combination contraceptives: effects on weight. Cochrane Database Syst Review. 2003(2);CD003987.