Improved glycaemic control of thrice-daily biphasic insulin aspart compared with twice-daily biphasic human insulin; a randomized, open-label trial in patients with type 1 or type 2 diabetes

Aim:  This trial evaluated the potential for improving glycaemic control by intensifying a conventional twice-daily therapy with premixed human insulin (HI) to a thrice-daily regimen using premixed formulations of biphasic insulin aspart (BIAsp) in patients with type 1 or type 2 diabetes.
Methods:  This was a multicentre, open-label, parallel group trial. After a 4-week run-in period, patients were randomized 1 : 1 to 16 weeks of treatment. A total of 748 patients were screened, 664 were exposed to trial drug and 604 completed the trial.
Results:  Haemoglobin A_1c, the primary efficacy endpoint, was shown to be significantly lower for the BIAsp treatment group compared with the biphasic HI (BHI) 30 group [estimated mean difference: −0.32, 95% confidence interval (CI) (−0.48; −0.16), p = 0.0001]. The average blood glucose level was significantly lower in the BIAsp group [estimated mean difference: −0.79, 95% CI (−1.17; −0.40), p = 0.0001]. There were few major hypoglycaemic episodes, 11 in the BIAsp group and 7 in the BHI 30 group. Although intensification of insulin therapy with BIAsp three times a day was associated with a higher risk of minor hypoglycaemia (relative risk = 1.58, p = 0.0038), the overall rate of minor hypoglycaemia remained low with both the BIAsp and the BHI treatments (13.1 vs. 8.3 episodes/patient year respectively). Overall safety and patient satisfaction were similar with the two insulin therapies.
Conclusions:  This trial confirmed that a thrice-daily BIAsp regimen can safely be used to intensify treatment for patients inadequately controlled on twice-daily BHI. A treat-to-target trial is required to explore the full potential of the BIAsp regimens and evaluate their use as a viable alternative to intensification with a basal-bolus regimen.     

Long-term efficacy and safety of biphasic insulin aspart in patients with type 2 diabetes

BACKGROUND: In this study, we sought to compare the long-term safety and efficacy of biphasic insulin aspart 30 (BIAsp30) with that of biphasic human insulin 30 (BHI30) over a period of 24 months in patients with type 2 diabetes. METHODS: Patients with type 2 diabetes (n=125) were assigned to twice-daily BIAsp30 or BHI30 and participated in both a 3-month initial period and a 21-month extension of a randomized, controlled, multinational trial. RESULTS: No significant difference was found in mean HbA(1c) after 24 months [BIAsp30, 8.35+/-0.20%; BHI30 8.13+/-0.16%; adjusted mean difference (BIAsp30-BHI30) 0.03 (90% CI -0.29 to 0.34)%, P=0.89]. The proportion of patients experiencing major hypoglycaemia was also similar during the first year (BIAsp30, 5%; BHI30, 8%; P=0.72), but it was significantly lower with BIAsp30 than with BHI30 during the second year (BIAsp30, 0%; BHI30, 10%; P=0.04). The proportion experiencing minor hypoglycaemia was not significantly different. No significant difference was recorded in changes in nonspecific insulin antibody levels after 24 months (BIAsp30, 4.87+/-1.92%; BHI30; 1.00+/-1.66%; P=0.13). Body weight change was 0.05+/-0.81 kg in the BIAsp30 group and 2.00+/-0.69 kg in the BHI30 group (P=0.07). CONCLUSIONS: Reduced major hypoglycaemia compared with BHI30 during the second year of treatment and comparable HbA(1c) levels after 24 months appear to support the hypothesis that the improved pharmacokinetic profile of BIAsp30 may favourably affect the balance between hypoglycaemia and hyperglycaemia in insulin-treated type 2 diabetes.     

Postprandial glycemic control with biphasic insulin aspart in patients with type 1 diabetes

We sought to investigate the ability of biphasic insulin aspart 30 (BIAsp 30) to control postprandial hyperglycemia and hyperlipidemia in a meal-test comparison with biphasic human insulin 30 (BHI 30). In this randomised crossover trial, 50 patients with type 1 diabetes (mean age, 35.7 +/- 9.4 years; body mass index [BMI], 24.0 +/- 2.6 kg/m(2); HbA(1c), 8.6% +/- 1.1%) were studied on 3 separate days, where the following treatments were given in random order: BIAsp 30 injected immediately before a standard breakfast, BHI 30 injected 30 minutes before breakfast (BHI 30(t=-30)), and BHI 30 injected immediately before breakfast (BHI 30(t=0)). The dose was 0.40 U/kg for all 3 treatments. BIAsp 30 reduced the area under the baseline adjusted 4-hour postprandial serum glucose curve (AUC(0-4h)) by 23% compared with BHI 30(t=0) (P <.0001) and by 9% compared with BHI 30(t=-30) (P =.013). Maximum serum glucose concentration (C(max)) was lower for BIAsp 30 compared with BHI 30(t=0) (14.0 +/- 2.4 v 16.5 +/- 2.8 mmol/L, P <.0001), and time to maximal serum glucose concentration (t(max)) was approximately 20 minutes shorter for BIAsp 30, irrespective of timing of BHI 30 injection (P <.0001). There were no significant differences among the 3 treatments with respect to postprandial levels of free fatty acids or triglycerides. The pharmacokinetic results were consistent with the above observations, ie, significantly larger insulin AUC(0-4h), higher C(max) and shorter t(max) were observed for BIAsp 30 compared with BHI 30, irrespective of timing of BHI 30 injection. We conclude that postprandial glycemic control was more effective with BIAsp 30 than with BHI 30, irrespective of timing of BHI 30 injection.     

Pre-meal insulin aspart compared with pre-meal soluble human insulin in type 1 diabetes

Insulin aspart has been shown, in medium-term studies, to achieve reductions in HbA(1c) without increasing the risk of major hypoglycaemia compared with pre-meal human insulin. The aim of the present 3-year study was to evaluate the long-term safety and efficacy of insulin aspart in people with type 1 diabetes. This was a 30-month extension of a multinational, multicentre, open-label, parallel-group study of 753 people with type 1 diabetes, originally randomly allocated to treatment with insulin aspart or unmodified human insulin before meals, with NPH insulin as basal insulin. Main outcomes measures were hypoglycaemia (major or minor), adverse events and HbA(1c). As insulin aspart became commercially available in some countries before the end of the trial, analyses of HbA(1c) used 30-month data to maintain statistical power. The relative risk estimate of major hypoglycaemia was similar between treatment groups (relative risk [RR] 1.00 [95% CI 0.72, 1.39]). The risk of having a minor hypoglycaemic episode was higher with insulin aspart than with human soluble insulin (RR 1.24 [1.09, 1.39] p=0.024). Insulin aspart was significantly superior to human insulin with respect to overall glycaemic control, with a baseline-adjusted HbA(1c) difference of -0.16 (-0.32, -0.01)% (p=0.035). Insulin aspart was well tolerated and effective during long-term treatment. The HbA(1c) advantage was maintained with insulin aspart without any adverse impact on the rate of major hypoglycaemia.     

Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart.

AIM: To compare blood glucose control when using insulin glargine twice daily at breakfast- and dinner-times with insulin glargine once daily at dinner time, in unselected people with Type 1 diabetes using insulin aspart at meal-times. METHODS: In this 8-week, two-way, cross-over study, 20 people with Type 1 diabetes were randomized to insulin glargine injection once daily at dinner-time or twice daily at breakfast- and dinner-times, both plus meal-time insulin aspart. Each 4-week treatment period concluded with a 24-h inpatient metabolic profile. RESULTS: Insulin doses, HbA1c, fructosamine concentration and pre-breakfast self-monitored blood glucose (SMBG) concentration did not differ between treatment periods. SMBG concentrations after breakfast, after lunch and before dinner were lower with twice-daily compared with once-daily dinner-time glargine [9.3 +/- 0.5 (+/- se) vs. 6.7 +/- 0.5 mmol/l, P = 0.003; 10.2 +/- 0.9 vs. 7.0 +/- 0.9 mmol/l, P = 0.024; 9.6 +/- 0.5 vs. 6.6 +/- 0.5 mmol/l, P = 0.001]. Mean 24-h SMBG concentration was lower with twice-daily glargine (7.1 +/- 0.5 vs. 8.8 +/- 0.5 mmol/l, P = 0.031). Within-day variability of SMBG concentration was lower with twice-daily glargine (sd 3.2 +/- 0.2 vs. 4.0 +/- 0.3 mmol/l, P = 0.044). Plasma free insulin concentration was higher in the afternoon with twice-daily glargine (21.9 +/- 1.4 vs. 16.1 +/- 1.3 mU/l, P = 0.009), but lower overnight (12.1 +/- 1.7 vs. 17.8 +/- 1.7 mU/l, P = 0.030), compared with once-daily injection. Plasma glucose concentration overnight was higher with twice-daily compared with once-daily glargine (mean 9.0 +/- 0.4 vs. 6.6 +/- 0.4 mmol/l, P = 0.001). CONCLUSIONS: Blood glucose concentration rises in the late afternoon in association with falling plasma insulin levels towards the end of the 24-h period after insulin glargine injection in some people with Type 1 diabetes using once-daily glargine at dinner-time plus a rapid-acting insulin analogue at meal-times. This is prevented by twice-daily injection of insulin glargine.     

Short-term fully closed-loop insulin delivery using faster insulin aspart compared with standard insulin aspart in type 2 diabetes

We evaluated the efficacy and safety of short-term fully closed-loop insulin delivery using faster versus standard insulin aspart in type 2 diabetes. Fifteen adults with insulin-treated type 2 diabetes underwent 22 hours of closed-loop insulin delivery with either faster or standard insulin aspart in a double-blind randomized crossover design. Basal-bolus regimen was replaced by model predictive control algorithm-directed insulin delivery based on sensor glucose levels. The primary outcome was time with plasma glucose in target range (5.6–10.0 mmol/L) and did not differ between treatments (mean difference [95% CI] 3.3% [−8.2; 1.7], P = 0.17). Mean glucose and glucose variability were comparable, as was time spent below and above target range. Hypoglycaemia (<3.5 mmol/L) occurred once with faster insulin aspart and twice with standard insulin aspart. Mean total insulin dose was higher with faster insulin aspart (mean difference [95% CI] 3.7 U [0.7; 6.8], P = 0.021). No episodes of severe hypoglycaemia or other serious adverse events occurred. In conclusion, short-term fully closed-loop in type 2 diabetes may require higher dose of faster insulin aspart compared with standard insulin aspart to achieve comparable glucose control.     

门冬胰岛素50治疗肝源性糖尿病患者初步疗效研究*

目的观察门冬胰岛素50治疗肝源性糖尿病（HD）患者的临床疗效。方法117例HD患者被随机分为两组,分别接受甘精胰岛素联合阿卡波糖治疗58例和门冬胰岛素50治疗59例,观察12 w。观察两组患者空腹血糖（FPG）、餐后2 h血糖（2 hPBG）、糖化血红蛋白（HbA1c）、胰岛素用量、血糖达标时间、低血糖发生情况等指标的变化,从而比较治疗效果及其安全性。结果在治疗12 w末,门冬胰岛素50治疗组FBG为（5.97±1.26） mmol/L,与甘精胰岛素治疗组的【（5.54±1.48） mmol/L】比,无显著差异（P>0.05）;门冬胰岛素50组PBG为（7.45±2.56） mmol/L,显著低于甘精胰岛素组【（8.95±2.44） mmol/L,P<0.05】, HbA1c为（6.81±0.23）%,显著低于甘精胰岛素组的【（7.56±0.31）%,P<0.05】,每日胰岛素用量为（37.2±7.0） U·d-1,与甘精胰岛素组的【（35.1±6.8） U·d-1】比,无显著统计学差异（P>0.05）,血糖达标时间为（14.2±2.8）d,与甘精胰岛素组的【（14.5±3.2） d】比,无显著统计学差异（P>0.05）,轻微低血糖发生率为3.5%,与甘精胰岛素组的5.1%比,无统计学差异（P>0.05）。结论门冬胰岛素50治疗HD患者疗效肯定,对餐后血糖的控制存在优势,且安全性良好。     

Postprandial versus preprandial dosing of biphasic insulin aspart in elderly type 2 diabetes patients

Preprandial dosing (within 5 min before meal) and postprandial dosing (15-20 min after meal onset) of NovoLog Mix 70/30 (BIAsp 30, a biphasic formulation of insulin aspart, 30% soluble and 70% protamine-crystallized) were compared in elderly (> or =65 years) type 2 diabetes patients in this open-label, 12-week, crossover study. Ninety-three patients were treated with b.i.d. preprandial injections of BIAsp 30 during a 2-week run-in period and subsequently randomized to a 4-week treatment with either pre- or postprandial b.i.d. BIAsp 30, followed by crossover to the other regimen for 4 weeks. Mean plasma glucose values during a 4-h mealtest at the end of each treatment were similar for pre- and postprandial BIAsp 30 (153 +/- 58 mg/dl and 161 +/- 59 mg/dl, respectively, difference not significant). However, the mean blood glucose increment from self-measured blood glucose values was slightly but significantly greater after postprandial injection than after preprandial injection (treatment difference: 16.3mg/dl; 95% CI: [0.5, 29.3]). Fifty-six percent of patients reported a hypoglycemic episode; postprandial injection did not increase the incidence of hypoglycemia as compared to preprandial injection (113 episodes versus 125 episodes, respectively). For some elderly type 2 diabetes patients, postprandial injection of BIAsp 30 may be an acceptable alternative to standard preprandial injection.     

Multiple mealtime administration of biphasic insulin aspart 30 versus traditional basal-bolus human insulin treatment in patients with type 1 diabetes

AIM: The aim of this study was to compare the effect of multiple mealtime injections of biphasic insulin aspart 30 (30% fast-acting insulin aspart in the formulation, BIAsp30) to traditional basal-bolus human insulin regimen (HI) on glycaemic control in patients with type 1 diabetes. METHODS: Twenty-three patients (eight women and 15 men) aged 44.8 (20.6-62.5) years (median and range) with a diabetes duration of 19.5 (1.6-44.6) years completed the study. All eligible patients were randomly assigned to BIAsp30 thrice daily supplied with bedtime NPH insulin when necessary, or basal-bolus HI for 12 weeks and then switched to the alternative regimen for another 12 weeks. The insulin dose adjustments were made by patients on the basis of advice from a diabetes nurse. At end of each treatment period, the patients attended two profile days, 1 week apart for pharmacodynamic and pharmacokinetic assessments. HbA1C was measured at baseline and at the end of each treatment period. A seven-point self-monitored blood glucose (SMBG) was obtained twice weekly. RESULTS: In comparison with HI, multiple mealtime injections of BIAsp30 resulted in a significant reduction in HbA1C[HI vs. BIAsp30 (%, geometric mean and range): 8.6 (7.4-11.4) vs. 8.3 (6.7-9.8), p = 0.013]. During treatment with BIAsp30, nighttime glycaemic control was significantly improved. Day-to-day variation in pharmacodynamics and pharmacokinetics and the rate of hypoglycaemia were not increased with BIAsp30 compared with HI. Conclusions: In type 1 diabetics, multiple mealtime administration of BIAsp30 compared with traditional basal-bolus human insulin treatment significantly improves long-term glycaemic control without increasing the risk of hypoglycaemia. Despite a higher proportion of intermediate-acting insulin, thrice-daily injections with BIAsp30 do not increase the day-to-day variations in insulin pharmacokinetics and pharmacodynamics.     

双时相门冬胰岛素50与双时相人胰岛素50治疗2型糖尿病的临床对比研究

目的 比较双时相门冬胰岛素和双时相人胰岛素治疗2型糖尿病（T2DM）的有效性和安全性.方法 选取2012年2月至2013年2月于江苏省盐城市亭湖区人民医院住院的T2DM患者50例为研究对象,按分层随机化分为2组,分别应用门冬胰岛素50（A组,25例）和人胰岛素50R（B组,25例）治疗.观察两组不同治疗方案患者2周和12周后空腹血糖（FPG）、餐后2h血糖（2 hPG）、糖化血红蛋白（HbA1c）、每日胰岛素（INS）用量、低血糖发生及体质指数（BMI）变化的情况.计量资料的比较采用成组t检验,计数资料比较用χ^2检验.结果 治疗2周后,两组患者血糖都明显下降,其中A组在早餐后、中餐后、晚餐后下降更明显,差异有统计学意义（t=3.342、3.393、2.504,均P＜0.05）;而B组在晚餐前、睡前下降更明显,差异亦有统计学意义（t=2.532、3.066,均P＜0.05）.治疗12周后,A组在HbA1c及2 hPG方面较B组下降更明显,A组HbA1c由治疗前的（10.6±1.9）％降至治疗后的（6.7±0.5）％,B组HbA1c由治疗前的（10.5±1.5）％降至治疗后的（7.1±0.6）％,组间比较差异有统计学意义（t=3.808,P＜0.05）,A组2 hPG由治疗前的（21±5）mmol/L降至治疗后的（7.1 ±0.9） mmol/L,B组2 hPG由治疗前的（21±5）mmol/L降至治疗后的（8.4±1.6） mmol/L,组间比较差异有统计学意义（t=3.331,P＜0.05）,而在空腹血糖方面差异无统计学意义（均P＞0.05）;在胰岛素用量方面,12周后两组胰岛素用量都明显减少,部分患者胰岛素停用,其中A组较B组减少更明显,A组胰岛素用量由治疗2周时的（50±13） U/d降至治疗12周时的（32±12） U/d,B组胰岛素用量由治疗2周时的（59±10） U/d降至治疗12周时的（39±6） U/d,组间比较差异有统计学意义（t =3.399,P＜0.05）;治疗前两组患者体重差异无统计学意义,治疗12周后两组患者体重与治疗前比较差异亦无统计学意义（均P ＞0.05）,但组间比较差异有统计学意义（t=2.319,均P＜0.05）;在低血糖发生方面,两组均无严重低血糖发生,A组低血糖发生率明显低于B组（χ^2=4.500,P＜0.05）.结论 双时相门冬胰岛素能更平稳地降低T2DM患者的血糖水平,特别是控制餐后血糖而不增加低血糖的风险及日胰岛素的用量,体重增加亦不明显.     

Post-prandial administration of the insulin analogue insulin aspart in patients with Type 1 diabetes mellitus.

AIMS: In intensified insulin therapy, the recent development of short-acting insulin analogues with a very rapid onset of action forces a new discussion in terms of the optimal injection-meal interval. This study evaluated prandial glycaemia in patients with Type 1 diabetes following the subcutaneous injection of soluble human insulin (HI) and the insulin analogue insulin aspart (IAsp) at different injection-meal intervals and investigated whether administration of IAsp after the meal might provide satisfactory metabolic control. METHODS: In a randomized, double-blind, double-dummy, four-period crossover study, 20 Type 1 diabetic patients were investigated. Prandial insulin was administered 15 min before the start of the meal (HI(-15min)), immediately before the meal (HI(0min); IAsp(0min)) and 15 min after the start of the meal (IAsp(+15min)). RESULTS: Plasma glucose excursions from baseline levels during the 4 h (PGexc) were highest with HI(0min) (17.9 mmol.l(-1).h; P < 0.05 vs. other treatments) and were not statistically different for HI(-15min), IAsp(0min) and IAsp(15min) (13.6, 11.9 and 14.2 mmol.l(-1).h, respectively). Maximum concentration of plasma glucose (PGmax) was lowest with IAsp(0min) (11.2 mmol/l; P < 0.05 vs. other treatments). PGmax was comparable with HI(-15min), HI(0min) and IAsp(+15min) (13.3, 14.1 and 13.2 mmol/l, respectively). CONCLUSIONS: With regard to prandial glycaemia IAsp(+15min) is as effective as HI(-5min) and superior to HI(0min). Thus, post-prandial dosing of the insulin analogue IAsp offers an attractive and feasible therapeutic option for well-controlled patients with Type 1 diabetes mellitus.     

重组人门冬胰岛素注射液对2型糖尿病患者餐后血糖影响的观察

目的比较重组人门冬胰岛素注射液(IASP)和可溶性人胰岛素(HSI)对2型糖尿病病人餐后血糖的影响。方法2002-102003-05对中日友好医院的42例已接受每日多次人胰岛素治疗的2型糖尿病患者经过2周的导入期治疗后随机分为两组,分别以IASP和HSI治疗4周,比较两组餐后1h、2h血糖的变化。结果经过4周的治疗,IASP组餐后1h血糖下降幅度显著大于HSI组[(2·1±2·0)mmol/L对(0·9±1·9)mmol/L,P<0·05],两组空腹血糖、餐后2h血糖和果糖胺的水平差异无显著性。HSI组治疗期间发生1例低血糖事件,两组均未发生严重低血糖事件和其他严重不良事件。结论与人HSI相比,IASP注射液能更有效地降低餐后1h血糖,安全性和耐受性良好。     

每日3次诺和锐30治疗2型糖尿病疗效观察

目的 比较不同胰岛素强化治疗对T2DM的疗效.方法 240例T2DM患者随机分为两组:诺和锐30组(124例)日3次诺和锐30皮下注射;诺和灵组(116例)日4次重组人胰岛素治疗(三餐前半小时注射诺和灵R,睡前注射诺和灵N).结果 两组相比,诺和锐30组控制血糖更快,胰岛素用量更少,低血糖发生率更低.结论 日3次注射诺和锐30,能更有效控制血糖,但需警惕低血糖发生.     

Starting patients with type 2 diabetes on insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin

Transitioning safely to insulin therapy when oral antidiabetic agents fail to provide adequate glycemic control is a critical aspect of care for the patient with type 2 diabetes mellitus (T2DM). We evaluated the clinical effectiveness of starting patients on a relatively simple regimen of once-daily injections of either biphasic insulin aspart 70/30 (10 min before dinner), NPH insulin (at 10 p.m.), or biphasic human insulin 70/30 (30 min before dinner) in combination with metformin. Enrolled patients had T2DM and inadequate glycemic control (AlC≥7.5%) on a previous regimen of metformin as monotherapy or in combination with a sulphonylurea. One hundred and forty (140) patients received metformin monotherapy for 4 weeks followed by 12 weeks of combination treatment with metformin and once-daily insulin injections. AlC levels decreased from baseline by 1.1–1.3% for patients in each of the three treatment groups. Overall, FPG values decreased from baseline by 31% (biphasic insulin aspart), 37% (NPH insulin), and 28% (biphasic human insulin). Subjects whose final FPG level was <126 mg/dl experienced the largest decreases in AlC values (−2.3%, −1.9%, −1.8%, respectively). All three treatment regimens were well tolerated. The results indicate that patients with T2DM can safely and effectively begin insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin.     

Biphasic insulin aspart 30 plus metformin: an effective combination in type 2 diabetes

AIM: This study compared glycaemic control achieved with biphasic insulin aspart 30 (BIAsp 30) monotherapy, BIAsp 30 plus metformin and glibenclamide plus metformin in patients with type 2 diabetes not adequately controlled with metformin. METHODS: In this multinational, open-labelled, parallel group, 16-week trial, 341 patients (patients not adequately controlled with metformin for at least 1 month) with type 2 diabetes were studied. Patients were randomized to receive BIAsp 30, twice daily (n = 107 exposed to treatment), or BIAsp 30, twice daily, plus metformin (n = 108) or glibenclamide plus metformin (n = 114). The primary endpoint was HbA(1c) at end of trial; adverse events, hypoglycaemia episodes, blood lipids and weight were also monitored. RESULTS: In the total population (HbA(1c) 7.5-13.0% at screening), end-of-trial HbA(1c) levels were lower in patients receiving BIAsp 30 plus metformin compared with those receiving BIAsp 30 only [mean treatment difference (+/-s.e.m), 0.39 +/- 0.15%, p = 0.007]. In a subpopulation (HbA(1c) > or = 9.0% at baseline, n = 193), patients receiving BIAsp 30 plus metformin had significantly lower HbA(1c) levels at the end of the trial compared with those receiving glibenclamide plus metformin (treatment difference, 0.46 +/- 0.21%, p = 0.027). Mean body weight (+/-s.d) at the end of the trial was significantly lower in patients receiving glibenclamide plus metformin compared with those receiving BIAsp 30 only (84.3 +/- 13.3 kg vs. 88.9 +/- 16.9 kg, p < 0.001). No major hypoglycaemic episodes were recorded during the trial, and incidence rates for minor and symptoms-only hypoglycaemia were low and similar between treatment groups (0.03-0.04 events/patient/week). CONCLUSION: BIAsp 30 added to metformin could be an appropriate therapeutic option for achieving good glycaemic control, compared with the addition of a second oral agent, particularly where HbA(1c) > or = 9%.