COMBINATION OF PHENTERMINE/TOPIRAMATE ER AND LIRAGLUTIDE 3MG FOR INTENSIVE THERAPY OF SEVERE OBESITY & T2DM A CASE SERIES AND BRIEF REVIEW

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1 AACE Clinical Case Reports Rapid Electronic Articles in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Case Report ACCR COMBINATION OF PHENTERMINE/TOPIRAMATE ER AND LIRAGLUTIDE 3MG FOR INTENSIVE THERAPY OF SEVERE OBESITY & T2DM A CASE SERIES AND BRIEF REVIEW Harris M. Baloch, MD 1 ; Karl Nadolsky, DO 2 From: 1 Walter Reed National Military Medical Center; 2 Spectrum Health Medical Group Running title: Severe obesity - Combination treatment Corresponding address: Harris M. Baloch, MD Walter Reed National Military Medical Center 8901 Wisconsin Avenue Bethesda, MD Building 19, Floor 5 Harris.m.baloch.mil@mail.mil

2 Keywords Obesity Pharmacology Type 2 Diabetes Disclosure Authors declared no conflicts of interest. The views expressed are those of the authors and do not reflect the official policy of the Department of the Army, Navy, the Department of Defense or the United States Government.

3 Abstract Introduction: Patients with obesity and type 2 diabetes (T2DM) have severe obesity warranting intensive treatment. The medical treatment of obesity can use multiple medications which target different pathways. At present, these medications are used independently for the treatment of obesity and there are scant data for using phentermine/topiramate (phen/top) and liraglutide combination. Methods: Here we present interventional data and outcome of three obese, diabetic patients treated with these medications. Results: Patient A: Achieved net weight loss of 25.6% over a 30 month period on phen/top and liraglutide. This weight loss correlated with improvement in triglyceride (Tg) levels (154 to 91 mg/dl), HDL levels (40 to 44 mg/dl) and hemoglobin A1c (7.6 to 6.1). Patient B: On phen/top and liraglutide, patient lost 11% over 24 months. Interestingly, this weight loss was correlated with an increase in Tg levels (116 to 231 mg/dl) and improvement in HDL (27 to 39 mg/dl). Prior to weight loss patient was on 50 units of glargine twice daily which was titrated off with improvement in hemoglobin A1c (15.1 to 6.2%). Patient C: On phen/top and liraglutide, patient had net weight loss 27% at 18 months. This weight loss was correlated with Tg improvement (129 to 83 mg/dl) and HDL improvement (32 to 38 mg/dl). Prior to weight loss, patient was on 45 units of glargine which was tapered off with an improved A1c (6.3 to 5.9%). Conclusion: The above cases highlight the potential for using multiple medications to target different areas for the treatment of obesity

4 Abbreviations: Phen/top = Phentermine/topiramate; T2DM = Type 2 diabetes; Tg = Triglyceride; HDL = High Density Lipoprotein; LDL = Low Density Lipoprotein; Mg = Milligram; DL = Deciliter; BMI = Body Mass Index; HbA1c = Hemoglobin A1C; AACE = American Association of Clinical Endocrinologists; GABA = Gamma Aminobutyric Acid; GLP1 = Glucagon-Like peptide 1. Introduction Obesity is a chronic relapsing progressive disease defined by abnormal or excessive adiposity that may impair health and is staged based upon the severity of the complications due to that adiposity (1-3). Obesity, classified as body mass index (BMI) 30, has continued to increase in prevalence including the United States. Patients with obesity and type 2 diabetes (T2DM) have increased cardiovascular risk and mortality regardless of BMI when compared to those with fewer metabolic syndrome criteria (4). Those patients thus have severe clinical obesity warranting intensive treatment targeting multiple pathways. Since 2012, four pharmacologic agents have been approved by the Food and Drug Administration for the chronic management of obesity (5). At present, these medications are used independently for the treatment of obesity and there are scant data for using them in combination. Patients and methods We present the relevant history, clinical, laboratory and interventional data of cases in our program with obesity and T2DM treated with combination therapies including phentermine/topiramate ER (phen/top) with liraglutide at 3mg.

5 Results All three patients shared several characteristics including male gender, age greater than 54, class III obesity, T2DM, metabolic syndrome and previously failed attempts at weight loss. All three patients were offered bariatric surgery at initial evaluation but declined and elected for intensive medical therapy. In addition to the medications, patients were given individualized instructions on intensive dietary and lifestyle modifications. These included regular visits with nutritionist focusing on energy restriction with improved dietary patterns and at least one visit with an exercise physiologist. Dietary plans were further reinforced at each visit. Patient A: 64-year-old male with long standing with history of obesity complicated by T2DM, hyperlipidemia, sleep apnea and hypogonadism with multiple prior failed attempts at weight loss presented to our obesity clinic. At initial evaluation, patient weighed 285lbs with BMI of 47.4 kg/m 2. Patient was diagnosed with Class III obesity complicated by T2DM, sleep apnea and obesity-associated secondary hypogonadism. Patient was treated with metformin 1000 mg twice daily, liraglutide 1.8mg and canagliflozin 100 mg for his diabetes with a baseline HbA1c of 7.0 at that time. Subsequently, patient s liraglutide was increased to 3 mg for obesity treatment and phentermine/topiramate ER was added. On combination of phen/top 7.5/46mg and liraglutide he had a net weight loss of 73 lbs (26%) with a 10 reduction in waist circumference over a 30- month period with significant improvements in triglycerides (154 to 91 mg/dl), HDL-c (40 to 44 mg/dl) and hemoglobin A1c (7.6 to 6.1). During the treatment, patient complained of tolerable dry mouth on waking up in the mornings but otherwise tolerated the medications well. Patient B:

6 57-year-old male who presented with sarcoidosis and obesity complicated by T2DM, sleep apnea, chronic kidney disease stage 3 and hypertension long standing worsened by intermittent steroid treatments due to sarcoidosis. Specifically, patient was on prednisone for four years at the time of sarcoidosis diagnosis in 1998 leading to significant weight gain. Subsequent to initial treatment, he required burst dose prednisone twice. At initial evaluation patient was 331 lbs with BMI of 42.8 kg/m 2. He was diagnosed with Class III obesity complicated by uncontrolled T2DM (A1c 15.1). At the time, patient was on glargine 50 units SQ twice a day and pioglitazone 30mg. Patient s pioglitazone was weaned off after he started liraglutide titrated to 3.0mg and over the next 10 months lost 12lbs with an improvement in HbA1c to 6.9. At that point, phen/top 7.5/46mg was added to his regimen along with canagliflozin and metformin. His insulin was titrated off. Over the next two years patient lost another 20 lbs (11%) and HbA1c remained around 7% off insulin. During this time period patient s triglyceride levels and LDL worsened (116 mg/dl to 231mg/dL for triglycerides and 55 mg/dl to 109 mg/dl for LDL) while his HDL improved from 27 mg/dl to 39 mg/dl. On further investigation, patient disclosed that he had inadvertently discontinued his rosuvastatin medication halfway through the treatment. Patient did not report any side effects from the liraglutide and phen/top regimen. Patient C: 56-year-old male presented with Class III obesity complicated by T2DM, sleep apnea and metabolic syndrome. At presentation, his weight was 344 lbs with BMI 54 kg/m 2. Patient was on metformin 1700 mg, pioglitazone 30 mg, glipizide 20 mg, glargine 45 units, canagliflozin 100 mg daily and exenatide 2 mg weekly. Glipizide was stopped and phen/top 7.5/46mg was added resulting in weight loss of 58lbs over a 6 months period. Subsequently, exenatide was replaced with liraglutide titrated to 3mg daily and over the following 12 months patient lost another 35lbs

7 for a total net of 93lbs weight loss (27%) with a 10-inch reduction in waist circumference with triglyceride improvement (129 to 83 mg/dl), LDL-c improvement (93 to 62 mg/dl), and HDL-c improvement (32 to 38 mg/dl). He tapered off pioglitazone and glargine while seeing an improved HbA1c (6.3 to 5.9%). Patient did not report any side effects from the above regimen. Discussion Patients with severe obesity classified by BMI and staged by complications, especially T2DM, warrant intensive behavioral modification prescription and pharmacotherapy in addition to the consideration for metabolic surgery consistent with the AACE Guidelines for Medical Care of Patients with Obesity (1). Obesity complicated by T2DM has a very complex pathophysiology integrating several systems regulating appetite, metabolism, and glycemic control. Treating the underlying adiposity-based disease via complimentary appetite pathways while efficiently and synergistically targeting glycemic pathways has the potential to optimize the outcomes for these patients. The above three cases highlight the potential for using multiple medications to target different processes for the treatment of obesity and the importance of using clinical outcomes beyond just weight as goals for therapy. Despite the increased morbidity and mortality of obesity, there have been very few effective pharmaceutical options available for obesity treatment until 2012, as noted earlier, targeting some of those complicated neuroendocrine pathways. Intensive obesity pharmacotherapy in addition to medical therapy for T2DM is recommended in current guidelines (6-7). Phentermine is a sympathomimetic amine acting as a norepinephrine and possibly dopamine releasing agent centrally in the arcuate nucleus to suppress appetite. Topiramate is a carbonic anhydrase inhibitor with GABA modulation approved for treating migraines and epilepsy but has also been shown to improve weight loss and glycemic measures. A meta-analysis of trials

8 exploring the risks and benefits of topiramate monotherapy in T2DM suggested a placebosubtracted HbA1c difference of 0.4% but the high doses of topiramate also resulted in significantly higher rates of adverse events (8). Topiramate combined with phentermine in extended release formulation (phen/top ER), is approved for chronic treatment of obesity. The combination of phen/top ER formulation has been shown to be superior for mean weight loss when compared to the individual components (9). The placebo-subtracted average weight loss in phase 3 clinical trials for phen/top ER ranged about 7-9% (10-11). The combination has been shown to delay the progression to T2DM in those at high risk (metabolic syndrome or pre-diabetes) (12) and in a pooled analysis of phase III clinical trials assessing phen/top ER, higher Cardiometabolic Disease Staging score predicted effectiveness of weight Loss therapy to prevent T2DM (13). A phase 2 trial of high dose phen/top in subjects with T2DM and baseline HbA1c of 8.7% resulted in an average of 7% more weight loss than placebo with corresponding improvement of HbA1c of 1.6% compared to 1.2% (14). This improvement was associated with better blood pressure and lipids along with fewer glycemic medication requirements. A sub-analysis of subjects with T2DM in the phase 3 trial CONQUER (14) showed a significantly higher proportion of those taking phen/top achieving HbA1c goals. Liraglutide is a GLP-1 receptor agonist which has been approved for the treatment of T2DM at a dose of 1.8 mg daily and approved for chronic obesity treatment at 3 mg daily. Liraglutide slows gastric emptying and in addition to incretin effects, acts centrally in the POMC neurons of the arcuate nucleus to improve satiation, reduce appetite and lower energy intake. The large phase 3 trial SCALE Obesity and Prediabetes showed nearly 6% placebo-subtracted weight loss on

9 average (15) and dramatically decreased progression to diabetes in those with prediabetes by approximately 80% over three years (16). In the SCALE diabetes trial (17), there was an average of about 4% placebo-subtracted weight loss and HbA1c reduction of 1% more than placebo and statistically better in both regards than the 1.8 mg dosing. Some limitations to further intensification and combination of these pharmacological agents involving slightly different pathways include cost, potential interactions, and optimizing benefit to risk ratios with corresponding appropriate dosing arrangements. A critical analysis of combination therapy will involve evaluating comparisons of early response to therapy to delineate which medications and combinations are of greatest benefit to the individual patient. Early response to therapy of any specification, including intensive behavioral therapy in Look AHEAD, has been associated with better long-term weight loss and improvements in obesity-related complications (18). Adhering to early response stopping criteria will help mitigate cost and improve risk to benefit relationships. The Endocrine Society Clinical Practice Guidelines for obesity pharmacology recommend stopping medications after three months if 5% weight loss has not been achieved (7). This is like the FDA prescribing recommendations with some slight differences amongst the medications. For phen/top ER, it is advised to use 3% weight loss at 12 weeks on the recommended dose to evaluate response and continuation with an option for titration to the higher dose then with a 5% goal after another 12 weeks (19). Liraglutide 3 mg prescribing information instructs a 4% goal at 16 weeks to continue medication (20). In the SCALE Obesity & PreDiabetes trial (21), the FDA-indicated early response goal of 4% was shown to be the appropriate target for stopping or continuation criteria as those who achieved that mark at 16 weeks faired very well with an

10 average of about 11% weight loss compared to 3% for non-responders at one year. In our series, clinical judgement of subjective and objective outcomes was used with those percent weight loss goal parameters to support continued combination therapy. Further investigation into how it may be best to try and continue different combinations at which doses will need to be carefully conducted. In conclusion, our case series supports rational for the potential of combination therapy of obesity pharmacological agents. This practice appears logical due to the multiple complicated pathways of appetite regulation which can be targeted concurrently. Combination therapy of currently available obesity medications may ultimately prove to enhance tolerance via lower individual doses with superior efficacy but for now is not recommended in non-fda approved manners as no long-term studies have been conducted (1). Further research through randomized control trials using several medications concomitantly are needed to evaluate the benefit of multiple treatments.

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