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Clinical Care/Education/Nutrition ORIGINAL ARTICLE

Effect of Orlistat in Overweight and Obese Patients With Type 2 Treated With

JOHN M. MILES, MD MICHAEL DOYLE, MD glycemic cardiovascular risk factors (7– LAWRENCE LEITER, MD JOHN FOREYT, PHD 9). Metformin produces minimal weight PRISCILLA HOLLANDER, MD, PHD LOUIS ARONNE, MD gain or slight weight loss, presumably THOMAS WADDEN, PHD SAMUEL KLEIN, MD by reducing energy intake (10–12). In JAMES W. ANDERSON, MD addition, data from the U.K. Prospective Diabetes Study (UKPDS) suggest that metformin therapy decreases the inci- dence of adverse cardiovascular events OBJECTIVE — The purpose of this study was to assess the effect of orlistat, a gastrointestinal (13). Therefore, metformin may be the lipase inhibitor, on body weight, glycemic control, and cardiovascular risk factors in metformin- preferred choice for oral therapy in over- treated type 2 diabetic patients. weight or obese type 2 diabetic patients. RESEARCH DESIGN AND METHODS — A 1-year multicenter, randomized, double- The limited long-term success of non- blind, placebo-controlled trial of 120 mg orlistat t.i.d. (n ϭ 249) or placebo (n ϭ 254) combined pharmacologic weight loss interventions with a reduced-calorie was conducted in overweight and obese patients with suboptimal in patients with has in- control of type 2 diabetes. creased interest in adjunctive antiobesity pharmacotherapy. In randomized- RESULTS — After 1 year of treatment, mean (ϮSE) weight loss was greater in the orlistat than controlled trials of currently approved Ϫ Ϯ Ϫ Ϯ Ͻ in the placebo group ( 4.6 0.3% vs. 1.7 0.3% of baseline wt, P 0.001). Orlistat weight management agents in patients treatment caused a greater improvement in glycemic control than placebo, as evidenced by a with type 2 diabetes, both orlistat, which greater reduction in serum HbA , adjusted for changes in metformin and therapy 1c inhibits intestinal lipases, and sibutra- (Ϫ0.90 Ϯ 0.08 vs. Ϫ0.61 Ϯ 0.08, P ϭ 0.014); a greater proportion of patients achieving Ն Ն Ͻ mine, which inhibits monoamine re- decreases in HbA1c of 0.5 and 1.0% (both P 0.01); and a greater reduction in fasting serum glucose (Ϫ2.0 Ϯ 0.2 vs. Ϫ0.7 Ϯ 0.2 mmol/l, P ϭ 0.001). Compared with the placebo group, uptake, produced greater weight loss than patients treated with orlistat also had greater decreases in total cholesterol, LDL cholesterol, and placebo (14,15). The role of orlistat in the systolic pressure (all P Ͻ 0.05). Although more subjects treated with orlistat experienced management of the large number of met- gastrointestinal side effects than placebo (83 vs. 62%, P Ͻ 0.05), more subjects in the placebo formin-treated type 2 diabetic patients group withdrew prematurely from the study than in the orlistat group (44 vs. 35%, P Ͻ 0.05). has not previously been investigated. The tolerability of orlistat used in combination CONCLUSIONS — Orlistat is a useful adjunctive treatment for producing weight loss and with metformin is uncertain, considering improving glycemic control, serum lipid levels, and in obese patients with type that both agents cause gastrointestinal 2 diabetes who are being treated with metformin. side effects. The aim of the present study Diabetes Care 25:1123–1128, 2002 was to assess the efficacy and safety of orlistat plus a reduced-calorie diet in overweight and obese patients with met- formin-treated type 2 diabetes. ffective weight management is an es- ever, it is difficult for overweight and sential component of the long-term obese patients to achieve and maintain E treatment of type 2 diabetes (1). In weight loss, and patients with type 2 dia- RESEARCH DESIGN AND overweight and obese patients with type 2 betes have even greater difficulty in main- METHODS — Patients with type 2 di- diabetes, weight loss of 5–10% improves taining weight loss than nondiabetic abetes who were 40–65 years of age, had glycemic control and reduces the require- control subjects (5,6). The reason for this a BMI of 28–43 kg/m2, had maintained a Ն ment for antidiabetic (2). poor weight loss response may be related stable weight for 3 months, had HbA1c Moderate weight loss also lowers blood to diabetes therapy itself, because most between 7.5 and 12.0%, and had received pressure, improves dyslipidemia, and is forms of pharmacotherapy for type 2 metformin treatment at 1,000–2,550 mg/ associated with a reduction in total and diabetes promote and may day for at least 6 weeks were eligible for diabetes-related mortality (3,4). How- actually have a detrimental effect on non- the study. Sulfonylurea therapy in combi- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● nation with metformin was permitted as From the Lipid and Diabetes Research Center, St. Lukes Hospital, Kansas City, Missouri. long as the sulfonylurea dose was stable Address correspondence and reprint requests to John M. Miles, MD, Division of Endocrinology and for 12 weeks before study entry. Patients , Mayo Clinic, 200 First St. SW, Rochester, MN 55905. E-mail: [email protected]. receiving , , or Received for publication 13 August 2001 and accepted in revised form 5 April 2002. ␣ Abbreviations: UKPDS, U.K. Prospective Diabetes Study. -glucosidase inhibitors were excluded. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion Other exclusion criteria included any factors for many substances. clinical condition that might affect study

DIABETES CARE, VOLUME 25, NUMBER 7, JULY 2002 1123 Orlistat plus metformin for type 2 diabetes

␣ end points, including renal, hepatic, or trocardiogram, standard laboratory HbA1c. Therefore an -level of 0.025 was endocrine disorders, poorly controlled assessments, vital signs, and measure- used in sample size estimations. The sam- hypertension (systolic blood pressure ments of body weight, HbA1c, and serum ple size was estimated to provide 80% Ն160 mmHg or diastolic blood pressure lipids. Body weight, blood pressure (re- power to detect treatment differences in Ն ␣ϭ 100 mmHg), active gastrointestinal dis- corded in a sitting position), and fasting body weight and HbA1c separately at ease, previous bariatric , a history serum glucose were measured at every 0.025, assuming a dropout rate of 35%. of bulimia, substance abuse, or the use of clinic visit (weeks 0, 2, 4, 8, 12, 16, 20, Changes in fasting serum glucose and any weight loss . Women 24, 30, 36, 42, 48, and 52). HbA1c was in were also used to who were pregnant, lactating, or of child- measured at weeks 0, 12, 24, 36, and 52. assess efficacy. Secondary efficacy vari- bearing potential were also excluded. Serum lipids (total, LDL, and HDL cho- ables were changes in serum lipids and lesterol, LDL/HDL ratio, and triglycer- blood pressure. The null hypothesis was Study design ides) were obtained at weeks 0, 24, and that the expected mean changes in pri- This multicenter, double-blind, random- 52. mary and secondary efficacy variables in ized, placebo-controlled trial was con- Changes in body weight and HbA1c the orlistat-treated patients were not dif- ducted at 34 centers in the U.S. and 6 were the primary efficacy variables. Fast- ferent from those in the placebo-treated centers in Canada. The study consisted of ing serum glucose and changes in diabe- patients after 1 year of treatment. The sig- a 2-week screening phase followed by a tes medication were also used to assess nificance of treatment differences for 52-week treatment phase. After screen- efficacy. Other secondary efficacy vari- body weight and HbA1c was tested using ing, patients were randomized to 1 year of ables were changes in serum lipids, blood ANCOVA models that included fixed ef- treatment with 120 mg orlistat (Xenical; pressure, and waist circumference (mea- fects for treatment, center, treatment by Hoffman-La Roche, Nutley, NJ) or pla- sured midway between the lateral lower center interaction, HbA1c stratum, treat- cebo three times daily with main meals. rib margin and the iliac crest) at weeks 0, ment by HbA1c stratum interaction, and To ensure treatment group balance for 24, and 52. baseline covariate. As exploratory analy- initial glycemic control, patients were Diabetes medications were changed ses, treatment differences in the change in stratified into two groups based on HbA1c when occurred or when HbA1c were tested using an ANCOVA levels (Յ10 or Ͼ10%). A reduced-calorie deterioration in glycemic control was ob- model that included fixed effects for treat- diet (ϳ600 kcal daily deficit) based on served. The dosage of diabetes medica- ment and change in diabetes medications. Ͼ American Diabetes Association recom- tion was increased if HbA1c was 12.0% Treatment differences for changes in fast- mendations and containing 30% of calo- (or increased by Ͼ2.0% from baseline) at ing serum glucose, serum lipids, blood Ͼ ries as fat, 50% as , and 20% week 12, if HbA1c was 10.2% (or in- pressure, dose of diabetes medication, as protein, with a maximum cholesterol creased by Ͼ0.2%) at week 24, or if the and other secondary efficacy variables content of 300 mg/day, was prescribed serum glucose concentration was Ͼ19.4 were tested using an ANCOVA model for all patients. The energy content of the mmol/l (350 mg/dl) at any clinic visit. The with fixed effects for treatment, center, prescribed diet was calculated from an patients’ diabetes medications were also treatment-by-center interaction, and estimate of patients’ initial energy require- adjusted in response to documented hy- baseline covariate. Placebo-adjusted 95% ments (using the Harris-Benedict equa- poglycemia (two home blood glucose CIs of orlistat treatment effect, based on tions) and was designed to promote a measurements of Ͻ3.3 mol/l [60 mg/dl] the least squares mean, were also deter- weight loss of 0.25–0.5 kg/week. Daily in 1 week or a single value Ͻ2.8 mmol/l mined for all efficacy variables. The fre- calorie intake was reduced by an addi- [50 mg/dl] recorded by their ). quency distributions of proportions of tional 200 kcal after 6 months to com- Additional measurements of HbA1c and patients in each treatment group with de- pensate for the reduction in energy fasting serum glucose were made within 1 creases in body weight of Ն0.5 and requirements caused by weight loss, with week of alterations in diabetes therapy. Ն1.0% were compared using the Coch- a minimum intake of 1,200 kcal/day. Pa- All adverse events were recorded, re- ran Mantel-Haenszel test. tients received dietary counseling at base- gardless of their relationship to treatment. line and at regular intervals throughout To ensure consistency in reporting of gas- RESULTS — A total of 516 patients the study and were encouraged to in- trointestinal events related to orlistat were enrolled and randomized to double- crease their level of physical activity. A treatment, a glossary of standard terms blind treatment with placebo (n ϭ 261) or multivitamin supplement was prescribed was used, as defined in earlier studies orlistat (n ϭ 255). Of these, 254 patients to be taken daily at least 2 h before or after (16,17). Standard laboratory measure- in the placebo group and 250 patients the evening dose of study medication. ments, including hematology, clinical in the orlistat group had at least one effi- Written informed consent was obtained chemistry, and urinalysis were assessed cacy follow-up and were thus eligible for from all patients. The study was con- by a central laboratory. intent-to-treat analysis. A total of 311 pa- ducted according to the principles of the tients completed 1 year of treatment. In Declaration of Helsinki and was approved Statistical analyses the safety population, more patients with- by the Ethics Committee or Institutional Statistical analyses were applied to data drew prematurely in the placebo group Review Board at all study sites. from the intent-to-treat population, de- (n ϭ 115, 44%) than in the orlistat group fined as all patients who were randomized (90, 35%) (P Ͻ 0.05). The most common Assessments to treatment and had at least one fol- reasons for premature withdrawal were The initial screening visit included a med- low-up assessment (18). The two primary treatment refusal (57 placebo vs. 36 ical history, physical examination, elec- efficacy variables were body weight and orlistat), loss to follow-up (35 vs. 25), ad-

1124 DIABETES CARE, VOLUME 25, NUMBER 7, JULY 2002 Miles and Associates

Table 1—Baseline characteristics of the weight loss than patients in the placebo Glycemic control study population plus diet group (4.7 Ϯ 0.3 kg [4.6 Ϯ The frequency distribution of changes in Ϯ Ϯ Ͻ 0.3%] vs. 1.8 0.3 kg [1.7 0.2%], P HbA1c after 1 year of treatment were con- 120 mg 0.0001) (Fig. 1A). Differences in the rate sistent with the weight loss data; more pa- Placebo Orlistat of weight loss between groups were ap- tients treated with orlistat had a mean Ն Ն n 254 250 parent within 4 weeks of starting double- reduction in HbA1c of 0.5 or 1.0% Sex (% M/F) 52/48 52/48 blind treatment, with orlistat-treated compared with placebo (61.3 vs. 43.3%, Age (years) 53.7 Ϯ 0.4 52.5 Ϯ 0.4 patients losing weight more rapidly than P ϭ 0.003 and 46.0 vs. 29.0%, P ϭ 0.008, Race placebo-treated patients over that period respectively). Caucasian 201 (79) 211 (84) of time (mean rates of Ϫ0.48 and Ϫ0.33 After 1 year, mean reduction in HbA1c Ϯ ϭ Black 36 (14) 24 (10) kg/week, respectively, P Ͻ 0.05). More was 0.75 0.08% (P 0.0001 vs. base- Other 17 (7) 15 (6) than twice as many orlistat-treated pa- line) in the orlistat group compared with Ϯ Ϯ Ϯ ϭ Weight (kg) 101.1 1.0 102.1 1.1 tients lost Ն5% of baseline body weight 0.41 0.08% (P 0.012 vs. baseline) in Ϯ Ϯ Height (cm) 169.4 0.6 169.1 0.6 compared with the placebo group (39.0 the placebo group (data not shown). Al- 2 Ϯ Ϯ BMI (kg/m ) 35.2 0.2 35.6 0.3 vs. 15.7%, P ϭ 0.008). In addition, more though the decrease in HbA1c in patients Ϯ Ϯ HbA1c (%) 8.79 0.07 8.87 0.07 treated with orlistat was not statistically Ϯ Ϯ patients in the orlistat than in the placebo Fasting glucose 11.1 0.2 11.6 0.2 group lost Ն10% of baseline body weight significantly different from the decrease (mmol/l) (14.1 vs. 3.9%; P ϭ 0.003). observed in the placebo group, the com- Data are means Ϯ SE or n (%). parison was confounded by changes in diabetes medications. The greater reduc- verse events (12 vs. 25), protocol viola- Diabetes medications tions in diabetes medication in the orlistat tions (5 vs. 0), and treatment failure (2 vs. Changes in treatment with diabetes med- group would be expected to dampen the mean reductions in HbA , thereby un- 0). ications over the 1-year study period were 1c derestimating the true effect of orlistat on Baseline characteristics were similar significantly different between the orlistat glycemic control. Conversely, increasing in the two treatment groups (Table 1). and placebo groups. Compared with pla- medication doses in the placebo group Similar proportions of patients in the pla- cebo treatment, orlistat therapy was asso- cebo and orlistat groups were receiving could exaggerate the treatment effect on ciated with reductions in both daily HbA in those patients. Two approaches metformin monotherapy (39 and 44%, metformin dose (Ϫ16 Ϯ 24 vs. 49 Ϯ 24 1c respectively) or metformin in combina- were taken to control for the potential mg/day, P ϭ 0.013) and relative sulfonyl- tion with (60 and 55%, re- confounding effect of differences in dia- urea dose, expressed as percent change, spectively) (P ϭ NS between groups). betes treatment: 1) HbA1c values that with doses standardized to a percentage were obtained after changes in diabetes Most individuals treated with sulfonyl- Ϫ Ϯ ϭ of maximum daily dose ( 11.5 3.6 vs. medications occurred were excluded ureas received either glyburide (n 160) Ϫ Ϯ ϭ or (n ϭ 99). Only 1% of patients 0.9 2.6%, P 0.027). Moreover, from the analysis, carrying the last obser- in each group were receiving metformin twice as many patients in the orlistat than vation before such changes forward; and in combination with a nonsulfonylurea in the placebo group either reduced or 2) an ANCOVA model, including fixed diabetes medication. In general, glycemic discontinued one or more diabetes medi- effects for treatment and change in diabe- control was poor at baseline, as evidenced cations (17.1 vs. 8.2%). Conversely, tes medication, was applied to the change more placebo- than orlistat-treated by mean HbA1c values of 8.8 and 8.9% in in HbA1c from baseline to the end of treat- the placebo and orlistat groups, respec- patients required additional or in- ment. The results of these two analyses tively. creased dosages of diabetes medication were consistent: in the first analysis, the (21.7 vs. 12.2%). These changes in diabe- mean reduction in HbA1c was signifi- Body weight tes medication usage were significantly cantly greater in the orlistat group than in After 1 year of treatment, patients in the different between treatment groups (P ϭ the placebo group (0.73 Ϯ 0.08 vs. orlistat plus diet group achieved greater 0.0004). 0.36 Ϯ 0.09%, P ϭ 0.0024); in the

Figure 1—Mean (ϮSE) changes in body weight (%) (A) and fasting plasma glucose (mmol/l) (B) over 1 year of treatment with diet plus 120 mg orlistat t.i.d. or placebo.

DIABETES CARE, VOLUME 25, NUMBER 7, JULY 2002 1125 Orlistat plus metformin for type 2 diabetes

Table 2—Serum lipid levels and blood pressure at baseline and after 52 weeks, and changes occurred during the early phase of treat- from baseline to end of treatment (ITT, LOCF) ment. Hypoglycemic episodes occurred in Placebo Orlistat P 10% of orlistat-treated patients compared with 4% of placebo-treated patients. No n 254 250 patient required medical intervention for Total cholesterol (mmol/l) hypoglycemia, with symptoms reported Baseline 5.40 Ϯ 0.06 5.40 Ϯ 0.06 as mild to moderate in intensity in both Week 52 5.46 Ϯ 0.07 5.13 Ϯ 0.06 groups. Change (%) 2.6 Ϯ 1.0 Ϫ4.1 Ϯ 0.9 Ͻ0.0001 LDL cholesterol (mmol/l) CONCLUSIONS — Weight loss is an Baseline 3.23 Ϯ 0.06 3.14 Ϯ 0.06 important element in the management of Week 52 3.18 Ϯ 0.07 2.89 Ϯ 0.06 overweight and obese patients with type 2 Change (%) 3.9 Ϯ 2.7 Ϫ2.8 Ϯ 2.3 0.044 diabetes because of the beneficial effects HDL cholesterol (mmol/l) of weight loss on insulin sensitivity and Baseline 0.98 Ϯ 0.02 0.98 Ϯ 0.02 glycemic control. Unfortunately, weight Week 52 1.08 Ϯ 0.02 1.07 Ϯ 0.02 loss is particularly difficult to achieve in Change (%) 13.8 Ϯ 1.45 13.0 Ϯ 1.52 0.821 patients with type 2 diabetes using con- LDL/HDL ratio ventional diet therapy, and pharmacolog- Baseline 3.51 Ϯ 0.09 3.43 Ϯ 0.09 ical treatment of type 2 diabetes is usually Week 52 3.07 Ϯ 0.08 2.86 Ϯ 0.07 associated with weight gain (5,8,9). Met- Change Ϫ0.46 Ϯ 0.08 Ϫ0.60 Ϯ 0.07 0.027 formin is considered by many to be the (mmol/l) of choice in the treatment of over- Baseline 2.63 Ϯ 0.09 2.81 Ϯ 0.11 weight and obese type 2 diabetic patients Week 52 2.66 Ϯ 0.13 2.56 Ϯ 0.11 and has been shown to decrease food con- Change (%) 9.0 Ϯ 3.6 Ϫ0.8 Ϯ 2.76 0.503 sumption in diabetic patients (19,20). Systolic blood pressure (mmHg) The favorable effects of this agent on gly- Baseline 132.1 Ϯ 0.9 132.7 Ϯ 0.9 cemic control may therefore be due in Week 52 131.8 Ϯ 0.9 130.6 Ϯ 0.9 part to reduced energy intake. Orlistat has Change (mmHg) Ϫ0.4 Ϯ 0.9 Ϫ2.1 Ϯ 0.8 0.017 been shown to produce weight loss and Data are means Ϯ SE. improvement in glycemic control in pa- tients with type 2 diabetes treated with sulfonylureas (14). The present study is latter analysis, the change in HbA1c,ad- diastolic blood pressure was not signifi- the first randomized-controlled trial to justed for changes in diabetes medication, cantly different between the orlistat and evaluate the efficacy of orlistat therapy in was also significantly different between placebo groups. conjunction with a reduced-calorie diet in the two treatment groups (0.90 Ϯ 0.08 vs. overweight and obese metformin-treated 0.61 Ϯ 0.08%, P ϭ 0.014) (not shown). type 2 diabetic patients. The results of the After 1 year, fasting serum glucose de- Tolerability study indicate that, compared with pla- creased significantly more in the orlistat- Overall, more patients in the placebo cebo, orlistat therapy enhances weight treated patients compared with the group withdrew prematurely from the loss, improves glycemic control, and im- placebo group (Ϫ2.0 Ϯ 0.2 vs. Ϫ0.7 Ϯ study than in the orlistat group (44 vs. proves other important cardiovascular 0.2 mmol/l, P ϭ 0.001). This significant 35%, P Ͻ 0.05). Of these patients, more risk factors (LDL cholesterol and blood difference between the study groups was orlistat- than placebo-treated patients (10 pressure). apparent within 2 weeks of starting treat- vs. 5%, P Ͻ 0.05) discontinued treatment In our subjects, there was improve- ment and was then maintained for the du- because of an adverse event. Adverse ment in a number of metabolic and ration of the study (Fig. 1B). event profiles were similar in the two clinical variables related to diabetes treatment groups, with the exception of a management: 1) a greater reduction in Lipids and blood pressure higher incidence of gastrointestinal ef- fasting serum glucose; 2) a greater reduc- Cardiovascular risk factors are shown in fects associated with orlistat therapy. A tion in HbA1c when changes in diabetes Table 2. Treatment with orlistat was asso- total of 83% of patients in the orlistat medication were taken into account; 3)a ciated with significantly greater improve- group experienced at least one gastroin- greater proportion of patients achieving Ն Ն ments in total and LDL cholesterol and testinal event compared with 62% of pa- decreases in HbA1c of 0.5 and 1.0%; LDL/HDL ratio compared with placebo. tients in the placebo group. Common and 4) a greater percentage of patients Changes in HDL cholesterol and triglyc- gastrointestinal events included oily or who decreased or discontinued at least eride levels did not differ significantly be- liquid stools, oily spotting, and fecal ur- one diabetes medication and a lower per- tween the two treatment groups. At 1 gency. More than 75% of patients who centage of patients who required an in- year, the decline in systolic blood pres- had gastrointestinal events reported only crease in diabetes medication dose or an sure was greater in orlistat- than in place- a single episode. The majority of gastro- additional agent. The benefit of orlistat bo-treated patients. The change in intestinal events were mild, transient, and was observed within 2 weeks of initiation

1126 DIABETES CARE, VOLUME 25, NUMBER 7, JULY 2002 Miles and Associates of treatment, before there was a signifi- terol is of clinical importance because se- glycemic control and other cardiovascu- cant difference in weight loss between rum LDL cholesterol concentration is an lar risk factors. Although lifestyle changes study groups. This finding is consistent important predictor of cardiovascular to decrease energy intake and increase with previous studies demonstrating that events in patients with diabetes (13) and physical activity should remain the cor- acute negative energy balance itself low- is particularly noteworthy in view of a nerstone of weight loss therapy, data from ers fasting blood glucose and improves substantial (13%) increase in HDL choles- the present study suggest that antiobesity insulin-mediated glucose uptake in pa- terol. Orlistat therapy was also associated medications can enhance weight loss and tients with type 2 diabetes (21,22). There- with a greater decrease in systolic blood provide benefits in the management of fore, our results suggest that greater pressure than placebo therapy. Therefore, patients with type 2 diabetes. negative energy balance occurs with or- orlistat improves glycemic control and listat than with placebo in the early phase other risk factors for coronary heart dis- of treatment, before there are detectable ease, the major cause of mortality in pa- Acknowledgments— This study was sup- differences in weight loss. tients with diabetes. ported by a grant from F. Hoffmann-La Roche The improvement in glycemic control Metformin is associated with gastro- and has previously been published in abstract form [Miles JM, Aronne LJ, Hollander P, Klein associated with orlistat therapy in this intestinal events that tend to subside with S: Effect of overweight and obese type 2 dia- study (HbA1c lowering of 0.3–0.4% com- time (31). Orlistat therapy, due to its betes patients treated with metformin. Diabe- pared with placebo) is of a smaller mag- effect on dietary fat absorption, is also as- tes 50 (Suppl. 2):A442–A443, 2001]. nitude than the reported improvements sociated with transient gastrointestinal in HbA1c and fasting serum glucose pro- events. Because of this, we were con- duced by sulfonylureas or metformin, but cerned that the additive effects of the two References similar to the improvements observed in agents could cause excessive gastrointes- 1. American Diabetes Association: Nutrition some studies of the effects of thiazo- tinal symptoms and thereby lead to pre- recommendations and principles for peo- lidinediones and ␣-glucosidase inhibitors mature study withdrawal. However, ple with diabetes mellitus (Position State- when these agents were used as mono- although gastrointestinal events were ment). Diabetes Care 24:S44–S47, 2001 therapy or in combination with insulin or more frequent in the metformin plus or- 2. Wing R, Koeske R, Epstein L, Nowalk MP, Gooding W, Becker D: Long-term effects sulfonylureas (23–26). The overall lower- listat than in the metformin plus placebo of modest weight loss in type II diabetic ing of HbA1c in the orlistat patients in the groups, combined therapy did not lead to patients. Arch Intern Med 147:1749– present study (0.75%) was significantly a greater drop-out rate. In fact, the overall 1753, 1987 greater than that observed in the placebo rate of withdrawal was actually higher in 3. Lean ME, Powrie JK, Anderson AS, Garth- group when changes in diabetes medica- the placebo group than in the orlistat waite PH: , weight loss and prog- tions were taken into account. The group (43 vs. 35%, P Ͻ 0.05), a finding nosis in type 2 diabetes. Diabet Med 7: UKPDS has demonstrated that relatively consistent with earlier reports (16). This 228–233, 1990 Ͻ 4. Williamson DF, Thompson TJ, Thun M, small reductions ( 1%) in HbA1c were indicates that gastrointestinal events are associated with reduced microvascular generally not a cause for discontinuation Flanders D, Pamuk E, Byers T: Intentional complications (13). Moreover, no thresh- of orlistat therapy. In fact, the lower with- weight loss and mortality among over- weight individuals with diabetes. Diabetes old of risk was observed for any end point drawal rate in the orlistat group suggests Care 23:1499–1504, 2000 in the UKPDS study (27). Oral mono- that patients receiving orlistat perceived a 5. Wing RR, Marcus MD, Epstein LH, Salata therapy of type 2 diabetes fails to produce benefit that was not apparent to patients R: Type II diabetic subjects lose less weight satisfactory glycemic control in at least taking placebo. Whether this benefit was than their overweight spouses. Diabetes 75% of patients with type 2 diabetes using related to greater weight loss or to better Care 10:536–536, 1987 Ͻ8.0% as a target and is presumably even glycemic control is not clear. The overall 6. Guare JC, Wing RR, Grant A: Comparison of obese NIDDM and nondiabetic wom- less successful in achieving HbA1c values difference in the incidence of gastrointes- Ͻ7.0% (28). Thus, the vast majority of tinal side effects between the orlistat and en: short- and long-term weight loss. Obes patients will require combination therapy placebo groups in the present study was Res 3:329–335, 1995 to achieve optimal glycemic control. In similar to that previously observed be- 7. Kudlacek S, Schernthaner G: The effect of insulin treatment on HbA1c, body weight fact, it is commonplace for three to tween orlistat and placebo groups in type and lipids in type 2 diabetic patients with be required for satisfactory glycemic con- 2 diabetic patients receiving sulfonylurea secondary failure to sulfonylureas. Horm trol (29). monotherapy (14). Therefore, a decision Metab Res 24:478–483, 1992 Orlistat therapy also had beneficial ef- to use orlistat in the management of over- 8. Edelman SV, Henry RR: Insulin therapy fects on other risk factors for cardiovascu- weight and obese patients with type 2 di- for normalizing glycosylated hemoglobin lar disease. Compared with placebo, abetes should not be based on the type of in type II diabetes. Diabetes Rev 3:308– orlistat therapy was associated with a diabetes medications the patients are re- 334, 1995 6–7% improvement in serum total and ceiving. 9. Fuchtenbusch M, Standl E, Schatz H: LDL cholesterol concentrations. 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