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Emerging Treatments and Technologies ORIGINAL ARTICLE

A Randomized, Double-Blind, Placebo- Controlled, Multicenter Study to Assess the Efficacy and Safety of Controlled Release in the Treatment of Obese Type 2 Diabetic Patients

1 4 JULIO ROSENSTOCK, MD RICHARD STRAUSS, MD besity and weight gain are major 2 4 PRISCILLA HOLLANDER, MD ALBERT LEUNG, MD, PHD factors for type 2 (1,2), and 3 KISHORE M. GADDE, MD FOR THE OBD-202 STUDY GROUP 4 nearly 90% of the population with IANG UN PHD O X S , type 2 diabetes is considered overweight or obese (3). Weight reduction can signif- icantly improve multiple parameters of OBJECTIVE — This is a randomized, placebo-controlled study of the weight-loss efficacy metabolic control (4). and safety of a controlled-release (CR) formulation of topiramate in overweight and obese Topiramate has been approved in many patients with type 2 diabetes treated with diet and exercise alone or in combination with countries for the treatment of seizure disor- metformin. ders and the prophylaxis of migraine head- aches (5). Weight loss was incidentally but RESEARCH DESIGN AND METHODS — Patients with type 2 diabetes, BMI Ն27 consistently observed in most of the studies kg/m2, A1C Ͼ6.5 and Ͻ11.0%, treated with diet and exercise alone or in combination with in these neurologic indications, despite no metformin monotherapy were enrolled. Patients were randomized to placebo or topiramate CR specific dietary interventions. Recently re- titrated up to 175 mg/day. Treatment consisted of a 7-week titration phase followed by a 9-week ported placebo-controlled trials performed maintenance phase. in nondiabetic and diabetic populations have shown that treatment with topiramate RESULTS — A total of 111 subjects were randomized and analyzed. By the end of week (immediate release formulation dosed twice 16, patients in the placebo and topiramate groups lost 2.5 and 6.0 kg, which represented 2.3 daily) can induce significant weight loss (6– and 5.8%, respectively, of their baseline body weight (P Ͻ 0.001 vs. placebo). A1C im- 11). The controlled-release (CR) formula- proved from a baseline of 7.4% in the placebo and 7.6% in the topiramate groups to 7.1 and tion of topiramate that utilizes an osmotic 6.7%, respectively, representing a 0.4 and 0.9% reduction from baseline, respectively (P Ͻ pump technology was developed to deliver 0.001 vs. placebo). Topiramate also significantly reduced and urinary albu- once-daily dosing with improved tolerabil- min excretion. Adverse events were predominantly neuropsychiatric or central and periph- ity (12). eral nervous system related. This study aimed to evaluate the effi- cacy and safety of topiramate CR as a phar- CONCLUSIONS — Topiramate CR treatment produced significant weight loss and mean- macological adjunct in patients with type 2 ingful improvements in A1C and blood pressure in obese patients with type 2 diabetes treated diabetes treated with diet and exercise alone with diet and exercise or in combination with metformin. However, the central nervous system or in combination with metformin. and psychiatric adverse event profile of topiramate CR makes it unsuitable for the treatment of obesity and diabetes.

Diabetes Care 30:1480–1486, 2007 RESEARCH DESIGN AND METHODS — This study was spon- sored by Johnson & Johnson Pharmaceu- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● tical Research & Development, LLC From the 1Dallas Diabetes and Endocrine Center, Dallas, Texas; 2Baylor Hospital, Dallas, Texas; 3Duke (Raritan, NJ), conducted in accordance University School of Medicine, Durham, North Carolina; and 4Johnson & Johnson Pharmaceutical Research with the Declaration of Helsinki and ICH & Development, Raritan, New Jersey. Good Clinical Practice, and approved by Address correspondence and reprint requests to Julio Rosenstock, MD, Dallas Diabetes and Endocrine Center at Medical City, 7777 Forest Lane, C-685, Dallas, TX 75230. E-mail: [email protected]. ethics committees at all sites. All patients Received for publication 25 September 2007 and accepted in revised form 6 March 2007. provided full written informed consent Published online ahead of print at http://care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/ before enrollment. dc06-2001. Clinical trial reg. no. NCT00231647, clinicaltrials.gov. This study was performed at 22 outpa- Abbreviations: CNS, central nervous system; CR, controlled release; DIS, Diagnostic Interview Schedule; HOMA, model assessment; OGTT, oral tolerance test. tient clinical centers in the U.S. that enrolled This report describes an investigational use of topiramate. Topiramate is not approved in any country for obese patients with type 2 diabetes treated the treatment of obesity or diabetes. with diet and exercise alone or in combina- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion tion with metformin. Eligible patients had factors for many substances. BMI between 27 and 50 kg/m2, A1C 6.5– © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby 11.0%, and plasma glucose 7.0– marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 13.3 mmol/l. Patients were excluded if they

1480 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Rosenstock and Associates had uncontrolled (systolic pletion or early withdrawal, the study Statistical analysis blood pressure Ն180 mmHg and diastolic drug was tapered over 2 weeks, and a final The sample size was selected to achieve at blood pressure Ն100 mmHg), diabetic mi- assessment was performed after a 2-week least 95% power to detect a 2.7% differ- crovascular complications, severe recurrent off-drug follow-up period. After the 1st ence between the mean percentage hypoglycemic episodes, any condition week of the study, a single reduction to weight loss in the placebo and the topira- likely to affect body weight, clinically signif- the next lower dose in a double-blind mate CR–treated arms. These calculations icant hepatic or renal disease, personal or manner was allowed if patients experi- used an SD of 3.8%, which was estimated family history of stones, history of enced intolerable adverse events. Patients from the results of studies on immediate- neuropsychiatric disorder or central ner- on topiramate doses of 100 mg/day or release formation of topiramate (10,11). vous system (CNS) condition, including higher were down-titrated to 75 mg/day. The primacy efficacy analysis set was neuropsychiatric disorders diagnosed at Patients on topiramate doses of 75 and 50 predefined as a modified intention-to- screening using an abbreviated 11-item Di- mg/day were down-titrated to 50 and 25 treat analysis set, which consisted of all agnostic Interview Schedule (DIS) (13). In mg/day, respectively, and patients on randomized subjects who received at least addition, patients using ex- one dose of study drug and provided at topiramate 25 mg/day were withdrawn pected to influence weight or glycemic con- least one postbaseline efficacy evaluation. from the study. Placebo dose adjustments trol or using psychotropic medication were The primary end point was mean percent- were done similarly. also excluded. Patients receiving any an- age change in body weight from baseline tidiabetes medication, other than a stable to week 16 using the last observation car- dose of metformin, were excluded. Patients ried forward (LOCF) approach, which with changes in or antihypertensive Assessments was analyzed by using ANCOVA with within 2 months of the study Weight was measured using calibrated treatment and diabetes treatment as fac- were also excluded. scales. Blood pressure was measured with tors and with baseline weight as covariate. This study was a randomized, dou- a wall-mounted sphygmomanometer and Response rates were analyzed using the ble-blind, placebo-controlled, multi- assessed as the mean of three sitting mea- Cochran-Mantel-Haenszel test stratified center, parallel-group study. There was surements taken after 5 min rest. Other by baseline diabetes treatment. Missing a 1-week screening phase, and eligible measurements included lipid profile, C- values were imputed on the basis of patients were randomized to placebo or reactive , and adiponectin. Oral LOCF. topiramate treatment and entered a glucose tolerance tests (OGTTs) (75 g) 7-week titration phase followed by a were administered at baseline and at the 9-week maintenance phase, a 2-week end of the maintenance phase (week 16) RESULTS taper, and a 2-week follow-up phase. with blood samples taken at 30 and 120 Randomization used an interactive min for the measurement of plasma glu- voice response system with a computer- Patient baseline characteristics and generated randomization schedule. Pa- cose, insulin, and C-peptide levels. A ho- disposition meostasis model assessment (HOMA) tients were stratified by concomitant ␤ The study began recruitment on 4 Febru- metformin monotherapy and study cen- was used to derive estimates of - ary 2004, and the last patient completed ter. Treatment assignment was blinded function and insulin sensitivity (14). Uri- the study on 16 December 2004. The to the investigators, study site staff, and nary albumin-to- ratio was clinical centers screened 345 patients for patients. measured from a random single void participation in the study, of which 113 urine collection. Adverse events were re- were randomized and 111 included in the ported either spontaneously or in re- analysis. Two patients were excluded Nonpharmacologic treatment sponse to general, nondirect questions. from the analysis: one did not take any Patients were instructed to follow a non- Blood glucose monitors and diaries were study drug postrandomization, and the pharmacologic lifestyle intervention pro- distributed for recording of hypoglycemic other withdrew from the study (due to gram (Pathways to Change, Johnson & episodes. During the study, an abbrevi- possible anemia) after taking one dose of Johnson Healthcare Systems, Piscataway, ated six-item DIS was administered at ev- study drug but before any measurements NJ) for the duration of the study, includ- ery visit to screen for newly emergent had been made. Overall, 81% of placebo ing the follow-up period. The program and/or suicidal ideation. patients (n ϭ 46) and 72% of topiramate consisted of an individualized 600 kcal patients (n ϭ 39) completed the study. deficit diabetes diet, a behavioral modifi- Among patients treated with topiramate cation program, and a physical activity who completed the study, final dosing program. Patient withdrawal was 175 mg (n ϭ 34), 150 mg (n ϭ 1), 75 Patients were withdrawn from the study if mg (n ϭ 3), and 50 mg (n ϭ 1). they met predefined criteria for persistent Among the patients who withdrew Pharmacologic treatment , unexplained severe hypo- from the study, the reasons for with- Eligible patients were randomized to pla- glycemia, frequent mild or moderate hy- drawal included adverse events (placebo cebo or topiramate CR 175 mg/day. Pa- poglycemia, or persistent asymptomatic 7%, topiramate 9%), patients’ choice (pla- tients randomized to topiramate had their . Also, patients whose re- cebo 4%, topiramate 7%), loss to fol- dosage titrated upward by 25 mg/day sponses to the DIS suggested a diagnosis low-up (placebo 2%, topiramate 6%), each week over a 7-week period and then of depression or suicidal thoughts were and unknown (placebo 7%, topiramate continued on the 175 mg/day dose during withdrawn and referred for mental health 6%). Among patients treated with topira- the maintenance phase. On study com- consultation. mate who did not complete the study, fi-

DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1481 Topiramate in obese diabetic patients

Table 1—Patient characteristics at baseline (modified intent to treat)

Placebo Topiramate CR 175 mg/day Total n 57 54 111 Age (years) 53.5 Ϯ 11.1 51.8 Ϯ 11.5 52.7 Ϯ 11.3 Male (%) 42 22 32 White (%) 79 70 75 Body weight (kg) 110.2 Ϯ 19.4 106.0 Ϯ 17.2 108.1 Ϯ 18.4 BMI (kg/m2) 37.7 Ϯ 5.7 38.1 Ϯ 5.3 37.9 Ϯ 5.5 Fasting plasma glucose (mmol/l) 9.3 Ϯ 2.0 9.2 Ϯ 2.0 9.3 Ϯ 2.0 A1C (%) 7.5 Ϯ 0.82 7.6 Ϯ 0.93 7.5 Ϯ 0.87 Baseline diabetes treatment (%) Diet only 30 22 26 Diet and metformin 70 78 74 Data are means Ϯ SD unless otherwise indicated. nal dosing was 175 mg (n ϭ 7), 150 mg the placebo and topiramate groups, re- Other end points (n ϭ 1), 100 mg (n ϭ 2), 75 mg (n ϭ 2), spectively (P ϭ 0.078 vs. placebo). The A significant improvement was observed and 50 mg (n ϭ 4). hip circumference was reduced by 1.0 in systolic and diastolic blood pressure in Baseline characteristics and demo- and 3.2 cm in the placebo and topira- the topiramate compared with the pla- graphics of the patients are shown in Ta- mate groups, respectively (P ϭ 0.012 cebo group (Table 2). Topiramate treat- ble 1. The two treatment groups were vs. placebo). ment was also associated with a similar except that the placebo group had Glycemic control. Fasting plasma levels significant reduction in urinary albumin- a higher proportion of men. The propor- were reduced by 0.6 and 1.6 mmol/l from to-creatinine ratio (Table 2). tions of patients receiving concomitant a baseline of 9.3 and 9.2 mmol/l in the A comprehensive lipid profile per- antihypertensive or lipid-lowering agents placebo and topiramate groups, respec- formed at baseline and week 16 revealed were 59 and 29%, respectively. Over 95% tively (P ϭ 0.002 vs. placebo). A1C im- reductions in total, LDL, and HDL choles- of patients did not have any change in proved from a baseline of 7.4% in the terol and with topiramate these concomitant medications or doses placebo and 7.6% in the topiramate treatment. These changes were not statis- over the study period. tically significant except for HDL choles- groups to 7.1 and 6.7%, respectively, rep- terol. However, there were no differences resenting a between-treatment group dif- in the total-to-HDL cholesterol ratio and Efficacy Ͻ ference of 0.5% (P 0.001) in the change LDL-to-HDL cholesterol ratio. There was Weight. Topiramate significantly re- from baseline. The treatment groups be- a nonsignificant reduction in C-reactive duced body weight during the 16 weeks gan to separate in A1C by week 4 of titra- protein and an increase in adiponectin of treatment (Table 2). By the end of tion (Fig. 1B). (P ϭ 0.058) with topiramate treatment. week 16, patients in the placebo and The proportion of patients having an topiramate groups lost 2.5 and 6.0 kg, absolute A1C reduction of at least 0.7% at which represented 2.3 and 5.8%, re- week 16 in the placebo and topiramate Safety spectively, of their baseline body weight groups was 25 and 48%, respectively Table 3 lists common adverse events that Ͻ (P 0.001 vs. placebo) or a placebo- (P ϭ 0.009 vs. placebo), and the propor- occurred in at least 5% of topiramate- subtracted weight loss of 3.5%. The tion of patients having an A1C reduction treated patients and at a greater incidence treatment groups began to diverge in of at least 1.0% was 21 and 35%, respec- versus placebo. These adverse events weight by week 2 of titration (Fig. 1A). tively (P ϭ 0.100 vs. placebo). The pro- were generally related to the CNS or pe- Similar differences in weight loss be- ripheral nervous system or were psychiat- portion of patients having achieved A1C tween topiramate and placebo were ob- ric in nature. The onset of CNS and Ͻ7.0% at week 16 in the placebo and served when completers were analyzed. psychiatric adverse events occurred pri- topiramate groups was 46 and 69%, re- The proportion of patients who lost ϭ marily during the 7-week titration phase Ն5% of baseline body weight at week spectively (P 0.014 vs. placebo). in the topiramate-treated subjects. Of the 16 in the placebo and topiramate Compared with placebo, patients on 23 topiramate-treated subjects with CNS groups was 19 and 50%, respectively topiramate also demonstrated a signifi- adverse events, 2 subjects had adverse (P Յ 0.001 vs. placebo), and the pro- cantly greater improvement in fasting events that persisted at the end of the portion of patients who lost Ն10% of plasma glucose and 2-h glucose following study. For the 18 topiramate-treated sub- baseline body weight was 2 and 20%, an OGTT. Consistent with these changes, jects with psychiatric adverse events, 4 respectively (P ϭ 0.002 vs. placebo). there were significant increases in 2-h insu- subjects had adverse events that per- Consistent with the effects of topira- lin and C-peptide values in the topiramate sisted. There was only one serious adverse mate on body weight, there were greater compared with the placebo group. Calcula- event in the topiramate group, a case of reductions in BMI and waist and hip tions based on HOMA revealed no signifi- renal considered possibly drug- circumferences in the topiramate- cant differences between the two treatment related by the investigator. There were no treated patients. The waist circumfer- groups in basal pancreatic ␤-cell function or deaths in the study. ence was reduced by 2.3 and 4.2 cm in insulin resistance. The overall incidence for withdrawal

1482 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Table 2—Mean changes from baseline (modified intent to treat, last observation carried forward) in primary and key secondary end points 1483

P for Placebo Topiramate CR 175 mg/day between- treatment Mean change Mean change group n Baseline Week 16 from baseline n Baseline Week 16 from baseline difference Ϯ Ϯ Ϫ Ϯ Ϯ Ϯ Ϫ Ϯ Ͻ

Rosenstock and Associates Body weight (kg) 55 109.7 19.6 107.3 19.7 2.5 3.1 54 106.0 17.2 100.0 18.1 6.0 5.2 0.001 % change from baseline Ϫ2.3 Ϯ 2.9 Ϫ5.8 Ϯ 4.8 Ͻ0.001 Anthropomorphic measurements BMI (kg/m2) 55 37.7 Ϯ 5.8 36.9 Ϯ 5.9 Ϫ0.8 Ϯ 1.1 54 38.1 Ϯ 5.3 36.0 Ϯ 5.9 Ϫ2.1 Ϯ 1.8 Ͻ0.001 Waist circumference (cm) 52 114.7 Ϯ 11.9 112.5 Ϯ 11.6 Ϫ2.3 Ϯ 4.7 47 115.4 Ϯ 11.4 111.2 Ϯ 12.7 Ϫ4.2 Ϯ 5.7 0.078 Hip circumference (cm) 52 123.0 Ϯ 13.1 122.0 Ϯ 13.1 Ϫ1.0 Ϯ 4.7 47 122.2 Ϯ 12.1 119.0 Ϯ 12.7 Ϫ3.2 Ϯ 4.5 0.012 Glycemic control parameters A1C (%) 55 7.4 Ϯ 0.83 7.1 Ϯ 0.89 Ϫ0.4 Ϯ 0.80 52 7.6 Ϯ 0.92 6.7 Ϯ 0.85 Ϫ0.9 Ϯ 0.77 Ͻ0.001 Fasting plasma glucose (mmol/l) 55 9.3 Ϯ 2.1 8.7 Ϯ 1.8 Ϫ0.6 Ϯ 1.8 52 9.2 Ϯ 2.1 7.6 Ϯ 2.2 Ϫ1.6 Ϯ 2.0 0.002 HOMA Pancreatic ␤-cell function (%) 50 43.7 Ϯ 36.0 43.6 Ϯ 26.6 Ϫ0.1 Ϯ 27.9 45 54.7 Ϯ 69.4 54.8 Ϯ 75.7 0.0 Ϯ 71.5 0.665 Insulin resistance 50 4.8 Ϯ 4.6 4.0 Ϯ 2.3 Ϫ0.8 Ϯ 4.3 45 5.7 Ϯ 4.3 4.6 Ϯ 4.1 Ϫ1.1 Ϯ 3.6 0.583 OGTT Fasting plasma glucose (mmol/l) 44 9.2 Ϯ 1.9 8.6 Ϯ 1.8 Ϫ0.6 Ϯ 1.8 39 9.3 Ϯ 2.1 7.4 Ϯ 2.3 Ϫ1.9 Ϯ 1.8 0.001 2-h plasma glucose (mmol/l) 48 16.4 Ϯ 3.8 15.3 Ϯ 3.7 Ϫ1.1 Ϯ 2.9 42 15.7 Ϯ 3.2 13.1 Ϯ 4.1 Ϫ2.6 Ϯ 4.1 0.018 Baseline plasma insulin (␮IU/ml) 52 11.3 Ϯ 9.7 10.3 Ϯ 5.1 Ϫ1.1 Ϯ 8.4 45 13.6 Ϯ 10.1 12.7 Ϯ 10.1 Ϫ1.0 Ϯ 6.62 0.279 2-h plasma insulin (␮IU/ml) 47 34.6 Ϯ 27.4 34.1 Ϯ 23.3 Ϫ0.5 Ϯ 18.2 41 45.1 Ϯ 48.5 54.5 Ϯ 43.6 9.5 Ϯ 40.0 0.009 Mean blood pressure Systolic (mmHg) 55 127.9 Ϯ 15.16 123.7 Ϯ 14.3 Ϫ4.2 Ϯ 12.9 54 127.2 Ϯ 12.5 117.1 Ϯ 11.8 Ϫ10.2 Ϯ 12.8 0.004 Diastolic (mmHg) 55 78.4 Ϯ 8.9 76.8 Ϯ 10.6 Ϫ1.6 Ϯ 8.7 54 79.1 Ϯ 7.1 73.8 Ϯ 8.5 Ϫ5.3 Ϯ 8.5 0.032 Urinary albumin-to-creatinine 43 0.031 Ϯ 0.047 0.029 Ϯ 0.051 Ϫ0.002 Ϯ 0.038 39 0.046 Ϯ 0.086 0.018 Ϯ 0.025 Ϫ0.028 Ϯ 0.071 0.033 ratio (mg/mg creatinine) Lipid profile* Total cholesterol (mmol/l) 53 5.37 Ϯ 1.01 5.28 Ϯ 1.03 Ϫ1.4 Ϯ 11.6* 46 5.53 Ϯ 1.31 5.16 Ϯ 1.22 Ϫ5.9 Ϯ 12.2* 0.109

LDL cholesterol (mmol/l) 53 3.27 Ϯ 0.89 3.34 Ϯ 0.90 3.4 Ϯ 19.1* 46 3.40 Ϯ 1.04 3.29 Ϯ 0.98 Ϫ1.7 Ϯ 16.1* 0.250 2007 HDL cholesterol (mmol/l) 53 1.25 Ϯ 0.33 1.28 Ϯ 0.31 3.5 Ϯ 13.2* 46 1.18 Ϯ 0.31 1.15 Ϯ 0.28 Ϫ1.6 Ϯ 11.3* 0.016 UNE Triglycerides (mmol/l) 52 1.73 Ϯ 0.67 1.76 Ϯ 0.72 6.4 Ϯ 40.0* 46 2.02 Ϯ 1.22 1.72 Ϯ 1.09 Ϫ7.3 Ϯ 34.6* 0.246 Total-to-HDL cholesterol ratio 53 4.54 Ϯ 1.30 4.29 Ϯ 1.04 Ϫ0.25 Ϯ 0.68 46 4.93 Ϯ 1.63 4.66 Ϯ 1.34 Ϫ0.28 Ϯ 0.89 0.410 6, J LDL-to-HDL cholesterol ratio 53 2.79 Ϯ 1.03 2.73 Ϯ 0.84 Ϫ0.06 Ϯ 0.53 46 3.06 Ϯ 1.25 2.99 Ϯ 1.06 Ϫ0.06 Ϯ 0.68 0.413

Other end points NUMBER Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Adiponectin (ng/ml) 52 5,068 2,729 5,514 3,641 446 1,655 45 4,644 2,464 5,741 3,146 1,098 1,862 0.058 30, C-reactive protein (mg/l) 53 7.1 Ϯ 6.7 7.1 Ϯ 7.5 0.0 Ϯ 3.9 46 7.7 Ϯ 6.1 6.7 Ϯ 7.6 Ϫ1.1 Ϯ 6.3 0.522 Data are means Ϯ SD. *Changes in lipid parameters are listed as mean percentage change from baseline. VOLUME , ARE C IABETES D Topiramate in obese diabetic patients

bonate levels at the final visit. No other significant changes in laboratory ana- lytes were observed.

CONCLUSIONS — This randomized trial demonstrated the efficacy of topira- mate in a CR formulation as adjunctive therapy in obese individuals with type 2 diabetes treated with diet and exercise alone or in combination with metformin. Treatment with topiramate induced rapid and meaningful weight reduction and im- provement in glycemic control compared with placebo. These results are consistent with previously reported results in obese patients with type 2 diabetes treated with topiramate (10,11) or other weight-loss– inducing agents (15,16). The by which topiramate causes weight loss is not known. studies suggest that cen- tral action may potentially reduce appe- tite and/or intake (17,18). Studies in rodent models suggest that topiramate may also affect energy utilization, possi- bly due to stimulation of in adipose tissue and skeletal mus- cle (19). It is not known whether topiramate’s effects on glycemic control parameters are independent of its weight loss effect. The HOMA analyses were inconclusive, but there was a significantly higher level of insulin secretion 2-h post-OGTT with im- proved glucose responses. Apart from effects on body weight and A1C, treatment with topiramate led to significant reductions in systolic and diastolic blood pressure compared with Figure 1—Mean percentage change in body weight (A) and A1C (B) from baseline over time. F, placebo. The degree of blood pressure re- topiramate treatment; E, placebo treatment. duction is similar to that observed in the trials of antihypertensive agents. A reduc- tion in urinary albumin excretion was also due to adverse events was 7% (four pa- the topiramate group had dose reduction observed, most likely related to improve- tients) in the placebo group and 9% (five or interruption of treatment due to intol- ments in blood pressure and glycemic patients) in the topiramate group. In the erable adverse events. control. The observed changes in these placebo group, two patients withdrew Three patients in each treatment surrogate markers suggest a potential for due to depression and two due to hyper- group reported hypoglycemic symptoms, improvement in the cardiovascular risk glycemia or worsening of diabetes con- but only one patient in the placebo group profile for this population of obese dia- trol. In the topiramate group, five patients had hypoglycemia confirmed by a low betic patients. However, the effect of topi- withdrew due to adverse events. Three of blood glucose value (40 mg/dl). The other ramate on is neutral. There was a these patients had adverse events that patients reported hypoglycemic symp- small reduction in HDL cholesterol, with were considered drug related: one patient toms only. the ratios of total cholesterol and LDL had renal calculus, one had depression, Consistent with the carbonic anhy- cholesterol to HDL cholesterol not being and one patient had fatigue, dizziness, drase inhibitory effect of topiramate, different between the two treatment and confusion. The other two patients asymptomatic decrease in groups. The large variation in lipid mea- had non–drug-related adverse events of was observed. The changes from base- surements among subjects, as well as the anxiety and dizziness as judged by the in- line were 1.1 and 1.1 mmol/l for the small sample size, makes interpretation vestigator. One (2%) patient in the pla- placebo and topiramate groups, respec- difficult. Although C-reactive protein cebo group and seven (13%) patients in tively. All patients had normal bicar- level was reduced with topiramate treat-

1484 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Rosenstock and Associates

Table 3—Adverse events (safety population) tion: Prevalence of Overweight and Obe- sity Among Adults With Diagnosed Diabetes–United States, 1988–1994 and Topiramate 1999–2002. MMWR 53:1066–1068, CR 175 2004 Placebo mg/day 4. Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, n 57 54 Ն Dahlgren S, Larsson B, Narbro K, Sjos- Patients with 1: trom CD, Sullivan M, Wedel H, Swedish Adverse event 42 (74) 49 (91) Obese Subjects Study Scientific Group: Serious adverse event 2 (4) 1 (2) Lifestyle, diabetes, and cardiovascular Adverse event resulting in discontinuation 4 (7) 5 (9) risk factors 10 years after bariatric sur- Common treatment-emergent adverse events* gery. N Engl J Med 351:2683–2693, Gastrointestinal system disorders 21 (37) 19 (35) 2004 Constipation 4 (7) 7 (13) 5. Topiramate (Topamax). In Physicians’ Dyspepsia 3 (5) 4 (7) Desk Reference. Montvale, NJ, Medical Gastroenteritis 2 (4) 3 (6) Economics Co, Inc, 2005, p. 2541–2549 6. Bray GA, Hollander P, Klein S, Kushner R, Body as a whole: general disorders 18 (32) 17 (31) Levy B, Fitchet M, Perry BH, for the U.S. Fatigue 2 (4) 6 (11) Topiramate Research Group: The effect of Pain 3 (5) 3 (6) topiramate on weight loss in obese sub- Central and peripheral nervous system disorders 12 (21) 23 (43) jects: a 6-month randomized placebo- Paresthesia 0 15 (28) controlled dose-ranging trial. Obes Res 11: Dizziness 2 (4) 8 (15) 722–733, 2003 Neuropathy 1 (2) 3 (6) 7. Wilding J, Van Gaal L, Rissanen A, Ver- Hypoesthesia 0 3 (6) cruysse F, Fitchet M, for the OBES-002 Respiratory system disorders 15 (26) 13 (24) Study Group: A randomized double- Upper respiratory tract infection 8 (14) 9 (17) blind placebo-controlled study of the long-term efficacy and safety of topira- Sinusitis 1 (2) 4 (7) mate in the treatment of obese subjects. Psychiatric disorders 6 (11) 18 (33) Int J Obes 28:1399–1410, 2004 Anxiety 2 (4) 4 (7) 8. Astrup A, Caterson I, Zelissen P, Guy- Difficulty with memory 0 4 (7) Grand B, Carruba M, Levy B, Sun X, Insomnia 1 (2) 3 (6) Fitchet M, for the OBES-004 Study Somnolence 0 4 (7) Group: Topiramate: long-term mainte- Appetite increased 0 3 (6) nance of weight loss induced by a low- Data are n (%). *Occurring in at least 5% of topiramate-treated patients and at a greater incidence than in calorie diet in obese subjects. Obes Res 12: placebo-treated patients, n (%). 1658–1669, 2004 9. Tonstad S, Tykarski A, Weissgarten J, Ivleva A, Levy B, Kumar A, Fitchet M: Efficacy and safety of topiramate in the treatment of ment, the difference from placebo was not verse event profile of topiramate CR obese subjects with . significant. makes it unsuitable for the treatment of Am J Card 96:243–251, 2005 The timing and frequency of CNS and obesity and diabetes. 10. Toplak H, A Hamann A, Moore R, Masson psychiatric adverse events reported were E, Gorska M, Vercruysse F, Sun X, Fitchet similar to those previously reported in M: Efficacy and safety of topiramate in obese nondiabetic and diabetic patients Acknowledgments— Principal investigators combination with metformin in the treat- (6–11) and also similar to those reported in the OBD-202 Study Group include: J. ment of obese subjects with type 2 diabe- on the topiramate label. There were sub- Anderson, L. Aronne, R. Atkinson, B. Feaver, tes: a randomized, double-blind, placebo- K. Gadde, H. Glatte, P. Hollander, L. Klaff, S. stantially more CNS and psychiatric ad- controlled study. Int J Obes (Lond) 31: Klein, D. Kreiger, T. Littlejohn, P. O’Neill, X. 138–146, 2007 verse events in patients treated with Pi-Sunyer, G. Raad, E. Riffer, J. Rosen, J. 11. Stenlof K, Rossner S, Vercruysse F, Kumar topiramate. These results, therefore, indi- Rosenstock, S. Schwartz, D. Smith, N. Soler, R. 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