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Clinical Care/Education/Nutrition ORIGINAL ARTICLE

Acarbose Improves Glycemic Control in Overweight Type 2 Diabetic Patients Insufficiently Treated With

1 4 PATRICK PHILLIPS, MA, FRACP DENNIS WILSON, MD, FRACP have investigated metformin as adjunc- 2 5 JEFF KARRASCH, FRACP ROBERT MOSES, MD tive therapy to (3–5); one 3 RUSSELL SCOTT, MD study compared metformin and sulfonyl- urea (glyburide) efficacy as monotherapy and in various combinations (6), and sev- eral recent studies have described the ef- fect of add-on therapy to metformin using OBJECTIVE — To investigate the efficacy and safety of as add-on therapy in over- the secretagogue (7), weight type 2 patients with inadequately controlled by metformin. the insulin sensitizers (8) and hydrochloride (9), and RESEARCH DESIGN AND METHODS — This study adopted a multicenter, random- ized, double-blind, placebo-controlled, parallel group design. After a 4-week placebo run-in the (10). period, subjects were randomized to either acarbose (titrated up to 100 mg b.i.d.) or placebo. Chiasson et al. (11) were the first to examine the use of acarbose as adjunctive The primary efficacy variable was the change in HbA1c from baseline to the end of the 24-week treatment period. Change in fasting blood was assessed as a secondary efficacy para- therapy to metformin. The ␣-glucosidase meter. inhibitor acarbose delays glucose absorp- tion and thus attenuates postprandial RESULTS — The intention-to-treat analysis from baseline to week 24 (81 patients for HbA1c rises in blood glucose and insulin. It has and 82 for fasting blood glucose) showed statistically significant differences between acarbose ϭ proven efficacious as first-line therapy and placebo treatment in HbA1c (1.02%; 95% CI 0.543–1.497; P 0.0001) and fasting blood ϭ (12–14) and in combination with sulfo- glucose (1.132 mmol/l; 95% CI 0.056–2.208; P 0.0395) (adjusted least square means). In all, nylureas or insulin (15–17). In combina- 18 patients (47%) in the acarbose group were classified as responders with a Ն5% reduction in ϭ tion with metformin, acarbose has been HbA1c (relative to baseline) at the end point compared to 6 (14%) in the placebo group (P 0.001). The safety profiles were similar for both treatment groups except for the higher incidence shown to improve long-term glycemic of gastrointestinal side effects during acarbose therapy. control (HbA1c measurement) by 0.8% (12), 0.65% (18), and 0.9% (19). Acar- CONCLUSIONS — The addition of acarbose to metformin monotherapy provides an effi- bose and metformin are both associated cacious and safe alternative for glycemic improvement in overweight type 2 patients inade- with beneficial effects on , quately controlled by metformin alone. hyperinsulinemia, body weight, and, in some studies, triglyceride levels (20). Be- Diabetes Care 26:269–273, 2003 cause these factors are part of a cluster of risk factors for cardiovascular disease (21), combining the two drugs may be anagement of lowering effect results from reduced useful. In long-term clinical studies, acar- strives to achieve near-normal hepatic glucose production and increased bose has shown a favorable safety profile M glycemic control to reduce the glucose utilization. (22,23). risk of diabetic complications. When di- Monotherapy using any oral antidia- This study was conducted as a further etary measures fail, oral antidiabetic betic agent is unfortunately limited as a investigation into the efficacy and safety agents are the first treatment choice. long-term strategy. The U.K. Prospective of concurrent use of acarbose and met- In the treatment of obese type 2 pa- Diabetes Study found that ϳ50% of pa- formin in type 2 diabetes overweight tients, metformin is often used as first-line tients needed more than one pharmaco- patients. therapy because it lowers blood glucose logical agent after 3 years of treatment concentrations without causing hypogly- because monotherapy did not achieve RESEARCH DESIGN AND cemia or weight gain (1). Its glucose- HbA1c target values (2). Several studies METHODS — The study was de- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● signed as a multicenter, randomized,

1 2 double-blind, placebo-controlled paral- From the Department of Endocrinology, The Queen Elizabeth Hospital, Woodville, Australia; the Penin- lel group comparison between the two sula Specialist Centre, Kippa Ring, Australia; the 3Lipid and Diabetes Research Group, Christchurch Hos- pital, Christchurch, New Zealand; the 4Department of Endocrinology, The Canberra Hospital, Garran, treatment arms, acarbose and placebo. Australia; and the 5Diabetes Centre Wollongong, Wollongong, Australia. Patients whose type 2 diabetes was insuf- Address correspondence and reprint requests to Dr. Patrick Phillips, Department of Endocrinology, The ficiently controlled by metformin and Queen Elizabeth Hospital, Woodville SA 5011, Australia. E-mail: [email protected]. who were on a stable twice-daily dose for Received for publication 19 June 2002 and accepted in revised form 4 November 2002. Abbreviations: FBG, fasting blood glucose; ITT, intention to treat; PP, per protocol. at least 3 months before the start of the A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion study were recruited by five centers, four factors for many substances. in Australia and one in New Zealand. The

DIABETES CARE, VOLUME 26, NUMBER 2, FEBRUARY 2003 269 Acarbose and metformin in type 2 diabetes study period consisted of a 4-week pla- into the study (visit 1, week –4) and con- patients who were treatment responders cebo run-in phase and a 24-week treat- tinued their usual metformin dose was also determined. The definition con- Ն ment phase. Patients aged 40 years with throughout the study period. During the sidered a patient a responder if HbA1c lev- a BMI of 25–35 kg/m2 were included first visit, a physical examination and as- els showed a Ն5% relative reduction from in the study if they had an HbA1c level of sessment of demographic data, medical baseline at the end of the study. 7–10% at screening (week –4) and 6.8– history and concomitant , All randomized patients were in- 10.2% at baseline (week 0). Further in- body weight, height, vital signs, and diet cluded in the safety analysis. Safety was clusion criteria were a history of type 2 were carried out. Samples for HbA1c, fast- evaluated by examining vital signs, rou- diabetes for 6 months or longer and an ing blood glucose (FBG), thyroid stimu- tine laboratory parameters, and reports of 80–120% compliance record during the lating hormone/free T4, and routine adverse events. run-in period. Patients were excluded laboratory analysis were taken. Patients Data analysis was performed using from the study if any of the following con- were then provided with placebo tablets the SAS program system (Version 6.12; ditions applied at the screening or base- identical to the active tablets to be taken SAS Institute, Cary, NC). End point de- line visits: having taken an antidiabetic twice daily for the next 4 weeks in a sin- termination of the efficacy variables used medication other than metformin during gle-blind placebo run-in phase. At visit 2 the “last observation carried forward” ap- the last 3 months; presence of significant (week 0) patients fulfilling inclusion cri- proach for missing data. ANCOVA with diseases or conditions, including emo- teria were randomly assigned to either 50 treatment and center as factors and base- tional disorders and substance abuse, mg acarbose b.i.d. or matching placebo line as covariate was used, and treatment likely to alter the course of diabetes or the for 2 weeks followed by a 22-week period by center interaction was included in the patient’s ability to complete the study; on 100 mg acarbose b.i.d. or matching model for HbA1c data. Model-adequate presence of gastrointestinal diseases likely placebo. If this regimen was not well tol- least square means and 95% CIs for mean to be associated with abnormal gut mobil- erated, the dosage could be reduced to 50 differences between the two treatment ity or altered absorption of nutrients; mg b.i.d. Patients were instructed to take groups were calculated. A repeated- medication causing a significant change one with the first mouthful of their measure ANOVA was used to assess effi- in gastrointestinal mobility and/or ab- morning and evening meals. Drug com- cacy parameters over the course of the sorption, such as cholestyramine; admin- pliance was determined at each visit by study. The difference between treatment istration of oral neomycin; treatment with tablet count. Patients were assessed at 0, arms in the proportion of responders was preparations containing digestive en- 2, 4, 12, and 24 weeks for weight and vital determined using ␹2 tests or Fisher’s exact zymes, such as amylase or pancreatin; signs, diet, concomitant medication, rou- test. These tests were also used to assess conditions that might be aggravated by tine laboratory parameters, and adverse treatment differences regarding the inci- abnormally large amounts of gas in the events. Efficacy variables were measured dence of adverse events. intestine, including gastrocardiac syn- at weeks 0, 12, and 24, with an additional drome, significant hernias, intestinal recording taken for FBG at week 4. A sec- RESULTS — A total of 83 patients stenoses, and active ulcers; chronic pan- ond physical examination was conducted were randomized to the two treatment creatitis; or concomitant medication af- at the end of the study (week 24). arms. Of those, 2 patients were excluded fecting glucose homeostasis, such as Both intention-to-treat (ITT) and per- from the ITT analysis for HbA1c (acarbose glucocorticoids within 8 weeks before protocol (PP) analyses were performed as n ϭ 38, placebo n ϭ 43) and 1 patient had screening (␤-blockers, ACE-inhibitors, or efficacy analyses. Patients included in the no baseline fasting blood glucose data and thiazide diuretics could be continued if ITT analysis had received at least one dose was thus excluded from the ITT analysis unchanged during the study and stable of study medication, had efficacy data at for FBG (acarbose n ϭ 39, placebo n ϭ for 8 weeks before the study). Patients baseline, and had at least one postbaseline 43). In the PP population, 71 patients were excluded if they had a currently un- measurement of the respective variable. were included for HbA1c analysis (acar- controlled thyroid function, transami- To be included in the PP analysis, patients bose n ϭ 33, placebo n ϭ 38) and 74 for nases elevated three times the upper limit also had to meet all protocol criteria and FBG analysis (acarbose n ϭ 35, placebo of normal, or serum creatinine Ն2 mg/dl comply with the study medication regi- n ϭ 39). All randomized patients were or if they had any infections likely to affect men. Because the first postbaseline mea- included in the safety analysis (acarbose glucose metabolism. Neither pregnant or surement of FBG was carried out in week n ϭ 40, placebo n ϭ 43). Baseline demo- lactating women nor patients receiving 4 and the first measurement of HbA1c,in graphic data and efficacy variables of all any other investigational drug or partici- week 12, some patients were included in randomized subjects compared well be- pating in any other clinical study within 8 the efficacy analysis for FBG but not tween the treatment groups (Table 1). weeks before screening were allowed to HbA1c. The ITT analysis was regarded as Both treatment groups received the same participate. The study was conducted in the primary efficacy analysis. The primary median dosage of metformin (1,700 mg/ accordance with Good Clinical Practice efficacy parameter was the change in day). and the Declaration of Helsinki. The pro- HbA1c from baseline to the end of the Figure 1A shows the change in mean tocol and subsequent amendments were study at week 24. HbA1c values were de- HbA1c levels during the study course (ITT approved by the ethics committee of each termined using a DCA 2000 clinical ana- analysis). Significant differences between participating center. Written informed lyzer ( Diagnostics, Tarrytown, NY). the treatment groups compared to base- consent was obtained from all participat- The change in fasting blood glucose levels line were seen for weeks 12 and 24 (P ϭ ing patients. from baseline to end point was assessed as 0.0009 and P ϭ 0.0023, respectively). A total of 89 patients were enrolled a secondary variable. The proportion of Mean HbA1c levels increased in the pla-

270 DIABETES CARE, VOLUME 26, NUMBER 2, FEBRUARY 2003 Phillips and Associates

Table 1—Baseline demographic characteristics and efficacy variables of patients valid for P ϭ 0.0395). PP analyses for both vari- safety analysis ables showed similar results, but were not statistically significant for treatment dif- Characteristics Acarbose Placebo P ferences concerning FBG. Of the 83 patients valid for safety n 40 43 analysis, 76 completed the study. Mean Age (years) 58.37 Ϯ 10.7 62.39 Ϯ 8.02 0.127* study duration was 169 days for both Sex (%) 0.259† acarbose (29–184 days) and placebo Female 35.0 23.3 (39–176 days). Overall compliance (80– Male 65.0 76.7 120% compliance) was 100% for acar- Ethnicity (%) bose and 95.3% for placebo patients. In White 80.0 97.7 all, five patients reduced the medication Asian 5.0 0.0 dose to 50 mg b.i.d. because of adverse Others 15.0 2.3 events (acarbose, n ϭ 3; placebo, n ϭ 2); Ϯ Ϯ Weight (kg) 89.77 12.73 87.88 11.7 0.632* three of these patients later reverted back 2 Ϯ Ϯ BMI (kg/m ) 30.75 2.96 30.09 2.85 0.086* to the original dosage. Patients in both Ϯ Ϯ Duration of diabetes (years) 5.32 4.55 6.06 5.32 0.757‡ treatment groups experienced a small Daily metformin dosage (mg) 1,700 (500–4,000) 1,700 (500–3,000) 0.490‡ mean weight reduction over the study pe- Ϯ Ϯ HbAlc (%) 8.05 0.89 7.82 0.83 0.498* riod (1.32 Ϯ 2.37 kg for acarbose vs. Ϯ Ϯ FBG (mmol/l) 9.97 2.47 9.41 1.99 0.719* 0.43 Ϯ 2.9 kg for placebo patients), Data are n, means Ϯ SD, or median (min–max). *ANOVA with center and center by treatment interaction; which was not significantly different (P ϭ †Cochran-Mantel-Haenszel test adjusting for center effect; ‡Wilcoxon’s rank-sum test. 0.13). There were also no significant changes in vital signs. Changes in routine cebo group from 7.82 Ϯ 0.83% at base- tion of responders in the acarbose group laboratory parameters were similar in line to 8.1 Ϯ 1.06% at week 12 and 8.5 Ϯ (n ϭ 18; 47%) than in the placebo group both treatment groups, except for one pa- 1.44% at study end. The mean increase (n ϭ 6; 14%) (P ϭ 0.001) at the end of the tient (acarbose group) with elevated liver after 24 weeks was 0.68 Ϯ 1.17%, with a study. function enzymes who was withdrawn significant overall time effect (P ϭ Mean levels of the secondary efficacy from the study. In total, seven patients 0.0001). In the acarbose group, levels de- variable FBG increased in the placebo arm were prematurely withdrawn from the creased from 8.02 Ϯ 0.85% at baseline to from baseline (9.41 Ϯ 1.99 mmol/l) to study during the 24-week treatment pe- 7.78 Ϯ 1.0% at week 12 (P ϭ 0.0261). week 4 (10.06 Ϯ 2.43 mmol/l) and con- riod: four because of treatment-emergent Levels then increased to 7.97 Ϯ 1.1% at tinued to increase to the end of study adverse events, one patient on placebo be- study end (mean change after 24 weeks (10.77 Ϯ 3.39 mmol/l), whereas levels in cause of constipation and depression, and was –0.05 Ϯ 0.8%). There was no signif- the acarbose arm varied only slightly from three patients on acarbose with flatu- icant overall time effect for acarbose. The baseline (Fig. 1B). The mean increase was lence, flatulence accompanied by abdom- adjusted least square means for the 1.36 Ϯ 2.88 mmol/l for the placebo and inal pain, and the aforementioned Ϯ change in HbA1c from baseline to week 24 0.08 1.98 mmol/l for the acarbose elevated liver enzymes. A serious adverse showed a reduction of 0.16 Ϯ 0.18% in group. The adjusted least square means event with remote or no relation to the the acarbose arm compared to an increase showed an increase at end point in both study medication was experienced by two of 0.86 Ϯ 0.16% in the placebo group, groups: 0.34 Ϯ 0.42 mmol/l for acarbose acarbose patients and one placebo pa- with a statistically significant difference compared to 1.48 Ϯ 0.39 mmol/l for pla- tient; no fatalities occurred. Treatment- between the treatment arms of 1.02% cebo patients, with a statistically signifi- emergent adverse events with a relation to (95% CI 0.543–1.497, P ϭ 0.0001). cant difference of 1.132 mmol/l between the study medication rated as “possible” There was a significantly greater propor- the two groups (95% CI 0.056–2.208, or “probable” were reported by 75% of

F E Figure 1—Change in mean HbA1c (A) and mean FBG (B) during a 24-week treatment period with acarbose ( ) or placebo ( ) adjunctive therapy in the ITT population.

DIABETES CARE, VOLUME 26, NUMBER 2, FEBRUARY 2003 271 Acarbose and metformin in type 2 diabetes

Table 2—Most frequently reported treat- The proportion of patients with a Taking into account the repaglinide and ment-emergent adverse events Ն5% relative reduction from baseline in glimepiride treatment results (7,10), acar- HbA1c (“responders”) was significantly bose showed a better safety profile owing Adverse event Acarbose Placebo higher in the acarbose group (47%) than to the clinical advantage associated with in the placebo group (14%). This out- the lack of hypoglycemic episodes. The n 40 43 come differed from other metformin/ unchanged or slightly reduced weight ex- 57.5* 27.9 acarbose combination studies in which perienced during acarbose treatment is 15.0 14.0 the number of patients classified as re- also a contributing factor, suggesting that Abdominal pain 10.0 7.0 sponders according to protocol definition acarbose is an appropriate drug for the Ͻ Enlarged abdomen 7.5 4.7 (an absolute HbA1c value 7% or a de- treatment of overweight patients. The fre- Nausea 5.0 2.3 crease of at least 15% of baseline value) quency of gastrointestinal complaints re- Chest pain 5.0 2.3 was 40% (11) and 42% (19). Higher dos- sulting from acarbose’s mode of action Dyspnea 5.0 0.0 ages of acarbose in those studies might might be minimized in clinical practice Constipation 2.5 7.0 account for the difference: patients in the where the physician can lower the dosage Any 75.0 55.8 Canadian study received up to 600 mg/ to the individual requirement of the pa- Data are %. Possible or probable relation to study day acarbose (11) and patients in the tient (22). medication given. *P ϭ 0.0064 vs. placebo. French study were given up to 300 mg/ This study has demonstrated that day (19). acarbose represents a good treatment ap- acarbose and 55.8% of placebo patients. Major side effects included gastroin- proach in combination therapy, espe- The main difference between the treat- testinal with flatulence, similar to findings cially in overweight patients whose ment groups was the higher frequency of in other acarbose/metformin combina- diabetes is inadequately controlled by gastrointestinal complaints in the acar- tion studies (11,18,19). Incidences of di- metformin monotherapy. bose group (Table 2). arrhea and abdominal pain were similar in both treatment groups and were prob- CONCLUSIONS — Oral antidiabetic ably attributable to metformin (27). No Acknowledgments— This work was spon- drugs such as acarbose or metformin that hypoglycemic episodes occurred during sored by Bayer AG, Leverkusen, Germany. do not induce hyperinsulinemia are use- treatment, and body weight decreased ful treatments for type 2 diabetes (24). more in acarbose patients. References The present study demonstrated the ben- Several other studies have described 1. 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