28‐week,randomized, multicenter,open‐label,parallel‐group phase III trial to investigate the efficacy and safety of biphasic insulin aspart 70 thrice‐daily injections vs twice‐daily injections of biphasic insulin aspart 30 in patients with type 2 diabetes

Aims/Introduction: An insulin analogue formulation with a 7:3 ratio of rapid‐acting and intermediate‐acting fractions, biphasic insulin aspart 70 (BIAsp70) was developed to supplement basal insulin between meals and mimic the physiological pattern of postprandial insulin secretion. Materials and Methods: We carried out a randomized, open‐label study to compare the efficacy and safety profiles of BIAsp70 and an insulin analogue formulation with a 3:7 ratio of rapid‐acting and intermediate‐acting fractions (BIAsp30) in type 2 diabetes mellitus patients. Patients were randomized and received either thrice‐daily BIAsp70 (n = 145) or twice‐daily BIAsp30 (n = 144) for 28 weeks. The primary end‐point was glycated hemoglobin (HbA_1c) after 16 weeks of treatment. Results: Non‐inferiority of BIAsp70 vs BIAsp30 was confirmed and superiority was established with a between‐group difference (BIAsp70–BIAsp30) in HbA_1c after 16 weeks of treatment of ?0.35% (95% CI: ?0.51 to ?0.19; P < 0.0001 for superiority). The mean postprandial glucose increment (19.96 vs 54.35 mg/dL; P < 0.0001) and M‐value (12.99 vs 17.94; P < 0.0001) at 16 weeks were smaller in the BIAsp70 group than in the BIAsp30 group, and were maintained at 28 weeks. Pre‐breakfast glucose (157.9 vs 140.7 mg/dL), total insulin dose (46.8 vs 38.1 U/day) and weight gain (+1.94 vs 1.23 kg) at week 28 were greater in the BIAsp70 group. Incidence of nocturnal hypoglycemia was significantly lower with BIAsp70 vs BIAsp30 (1.23 vs 3.21 events/subject year; P = 0.0002) at week 28. Conclusions: Thrice‐daily BIAsp70 was superior to twice‐daily BIAsp30 in terms of HbA_1c change, with less variation in daytime plasma glucose profiles. BIAsp70 was well tolerated, with a lower incidence of nocturnal hypoglycemia vs BIAsp30. This trial was registered with ClinicalTrial.gov (no. NCT00318786). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00015.x, 2010)     

Efficacy and safety of switching from basal insulin to once‐daily insulin degludec/insulin aspart in Japanese patients with inadequately controlled type 2 diabetes: A 4‐week,randomized, open‐label,treat‐to‐target study

Aims/Introduction

A prospective, 4‐week, single‐center, randomized, open‐label, parallel‐group, treat‐to‐target study was carried out to develop an algorithm for safe and effective switching from basal insulin to once‐daily insulin degludec/insulin aspart (IDegAsp) in patients with inadequately controlled type 2 diabetes.

Materials and Methods

Patients were randomly assigned to continue their current basal insulin therapy (n = 10) or to switch to IDegAsp on a 1:1 unit basis (n = 10). The insulin dose could be titrated once weekly, targeting a self‐measured blood glucose of 80–100 mg/dL before breakfast. A mixed meal test was carried out at baseline and after 4 weeks.

Results

After 4 weeks, the mean daily dose of insulin was similarly increased by 60% in both groups, and there was a significant decrease of mean plasma glucose and glucose area under the glucose concentration vs time curve for 2 h in the meal test. The mean estimated treatment difference (IDegAsp group ? basal insulin group) of the mean plasma glucose level was ?28 mg/dL (95% confidence interval ?47 to ?8, P = 0.008) after 4 weeks and that of the area under the glucose concentration vs time curve for 2 h was ?2,800 mg/min/dL (95% confidence interval ?5,300 to ?350, P = 0.028), confirming the superiority of IDegAsp to basal insulin. In the IDegAsp group, the 2‐h postprandial plasma glucose level was significantly decreased to the fasting plasma glucose range. There were no confirmed hypoglycemic episodes in either group during the 4‐week study period.

Conclusions

After switching from basal insulin, the IDegAsp dose can be uptitrated by 60% based on fasting plasma glucose data. However, monitoring of postprandial glucose should be considered before further uptitration of IDegAsp.

     

Subject‐driven titration of biphasic insulin aspart 30 twice daily is non‐inferior to investigator‐driven titration in Chinese patients with type 2 diabetes inadequately controlled with premixed human insulin: A randomized,open‐label,parallel‐group,multicenter trial

Aims/Introduction

The present study was to compare the efficacy and safety of subject‐driven and investigator‐driven titration of biphasic insulin aspart 30 (BIAsp 30) twice daily (BID).

Materials and Methods

In this 20‐week, randomized, open‐label, two‐group parallel, multicenter trial, Chinese patients with type 2 diabetes inadequately controlled by premixed/self‐mixed human insulin were randomized 1:1 to subject‐driven or investigator‐driven titration of BIAsp 30 BID, in combination with metformin and/or α‐glucosidase inhibitors. Dose adjustment was decided by patients in the subject‐driven group after training, and by investigators in the investigator‐driven group.

Results

Eligible adults (n = 344) were randomized in the study. The estimated glycated hemoglobin (HbA_1c) reduction was 14.5 mmol/mol (1.33%) in the subject‐driven group and 14.3 mmol/mol (1.31%) in the investigator‐driven group. Non‐inferiority of subject‐titration vs investigator‐titration in reducing HbA_1c was confirmed, with estimated treatment difference −0.26 mmol/mol (95% confidence interval −2.05, 1.53) (–0.02%, 95% confidence interval –0.19, 0.14). Fasting plasma glucose, postprandial glucose increment and self‐measured plasma glucose were improved in both groups without statistically significant differences. One severe hypoglycemic event was experienced by one subject in each group. A similar rate of nocturnal hypoglycemia (events/patient‐year) was reported in the subject‐driven (1.10) and investigator‐driven (1.32) groups. There were 64.5 and 58.1% patients achieving HbA_1c <53.0 mmol/mol (7.0%), and 51.2 and 45.9% patients achieving the HbA_1c target without confirmed hypoglycemia throughout the trial in the subject‐driven and investigator‐driven groups, respectively.

Conclusions

Subject‐titration of BIAsp 30 BID was as efficacious and well‐tolerated as investigator‐titration. The present study supported patients to self‐titrate BIAsp 30 BID under physicians’ supervision.     

Liraglutide,a once‐daily human GLP‐1 analogue,improves pancreatic B‐cell function and arginine‐stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus

Aims To assess the effect of liraglutide, a once‐daily human glucagon‐like peptide‐1 analogue on pancreatic B‐cell function. Methods Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First‐ and second‐phase insulin release were measured by means of the insulin‐modified frequently sampled intravenous glucose tolerance test. Arginine‐stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin‐modified frequently sampled intravenous glucose tolerance test. Results The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first‐phase insulin secretion by 118 and 103%, respectively (P < 0.05). Second‐phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine‐stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P < 0.05). There was no significant treatment effect on glucose effectiveness or insulin sensitivity. Conclusions Fourteen weeks of treatment with liraglutide showed improvements in first‐ and second‐phase insulin secretion, together with improvements in arginine‐stimulated insulin secretion during hyperglycaemia.     

A multi‐centre,single‐arm,open‐label study evaluating the safety and efficacy of fixed dose rituximab in patients with refractory,relapsed or chronic idiopathic thrombocytopenic purpura (R‐ITP1000 study)

The efficacy of a fixed‐dose rituximab schedule was prospectively explored in primary/acute refractory, relapsed or chronic (platelet count >10 × 10⁹/l and ≤50 × 10⁹/l) idiopathic thrombocytopenic purpura (ITP). Patients received two doses of rituximab (1000 mg) on days 1 and 15 and were followed‐up on weeks 1–8, 12, 26, 39 and 52. A total of 122 patients were included in the safety population; efficacy was analysed in 108 patients. Overall response rate (ORR) at week 8, defined as the proportion of patients achieving complete response (CR; platelet count >150 × 10⁹/l) or partial response (PR; platelet count >50 × 10⁹/l) was 44%. Therapeutic response, defined as achieving a response at week 8, with at least a minor response (MR; platelet count >30 × 10⁹/l), sustained up to weeks 26 and 52 and accompanied by a reduction in ITP medications, was achieved in 44% (week 26) and 35% (week 52) of patients, respectively. Treatment was well tolerated with no safety concerns. While this study failed to meet its primary endpoint of an ORR of 50%, the efficacy of two fixed doses of rituximab appear to provide similar efficacy to the standard 375 mg/m² four‐dose schedule in relapsed/chronic ITP.     

Treatment of giant cell arteritis using induction therapy with high‐dose glucocorticoids: A double‐blind,placebo‐controlled,randomized prospective clinical trial

Objective

Glucocorticoid (GC) therapy for giant cell arteritis (GCA) is effective but requires prolonged administration, resulting in adverse side effects. The goal of the current study was to test the hypothesis that induction treatment with high‐dose pulse intravenous (IV) methylprednisolone permits a shorter course of therapy.

Methods

Twenty‐seven patients with biopsy‐proven GCA were enrolled in a randomized, double‐blind, placebo‐controlled study to receive IV methylprednisolone (15 mg/kg of ideal body weight/day) or IV saline for 3 consecutive days. All patients were started on 40 mg/day prednisone and followed the same tapering schedule as long as disease activity was controlled. The numbers of patients with disease in remission after 36, 52, and 78 weeks of treatment and taking ≤5 mg/day prednisone were compared. Cumulative prednisone dose, number of relapses, and development of adverse GC effects were assessed.

Results

Ten of the 14 IV GC–treated patients, but only 2 of 13 control patients, were taking ≤5 mg/day prednisone at 36 weeks (P = 0.003). This difference was maintained; there was a higher number of sustained remissions after discontinuation of treatment in the IV GC–treated group and a lower median daily dose of prednisone at 78 weeks (P = 0.0004). The median cumulative dose of oral prednisone, excluding the IV GC dose, was 5,636 mg in the IV GC–treated group compared with 7,860 mg in the IV saline–treated group (P = 0.001).

Conclusion

Initial treatment of GCA with IV GC pulses allowed for more rapid tapering of oral GCs and had long‐term benefits, with a higher frequency of patients experiencing sustained remission of their disease after discontinuation of treatment.

     

Taspoglutide,a once‐weekly glucagon‐like peptide 1 analogue,vs. insulin glargine titrated to target in patients with Type 2 diabetes: an open‐label randomized trial

Aims To compare the efficacy and safety of once‐weekly taspoglutide with insulin glargine in patients with advanced Type 2 diabetes failing metformin and sulphonylurea combination therapy. Methods This open‐label, parallel‐group, multi‐centre trial randomized 1049 patients continuing metformin 1:1:1 to taspoglutide 10 mg once weekly, taspoglutide 20 mg once weekly or insulin glargine once daily with forced titration to fasting plasma glucose ≤ 6.1 mmol/l. Sulphonylureas were discontinued before randomization. The primary endpoint was change in HbA_1c after 24 weeks. Results After 24 weeks, least‐square mean changes from baseline in HbA_1c in patients receiving taspoglutide 10 mg [?8 mmol/mol (se 1)] [?0.77% (se 0.05)] or taspoglutide 20 mg [?11 mmol/mol (se 1)] [?0.98% (se 0.05)] were non‐inferior to insulin glargine [?9 mmol/mol (se 1)] [?0.84% (se 0.05)]; treatment difference of 0.07% (95% CI ?0.06 to 0.21) and ?0.14% (95% CI ?0.28 to ?0.01), for taspoglutide 10 and 20 mg, respectively, vs. insulin glargine. Taspoglutide was associated with more adverse events (mainly gastrointestinal) and significantly less hypoglycaemia than insulin glargine. Conclusions Compared with insulin glargine, taspoglutide provided non‐inferior HbA_1c reductions associated with less hypoglycaemia, but more gastrointestinal adverse events.     

Insulin degludec compared with insulin glargine in insulin‐naïve patients with type 2 diabetes: A 26‐week,randomized, controlled,Pan‐Asian,treat‐to‐target trial

Introduction

Insulin degludec (IDeg) is an ultra‐long‐acting basal insulin with a consistent action profile of >42 h. This trial compared the efficacy and safety of IDeg with insulin glargine (IGlar) in insulin‐naïve Asian patients with type 2 diabetes.

Materials and Methods

In this multinational, 26‐week, open‐label, treat‐to‐target trial, 435 participants (202 females, 233 males; mean age 58.6 years; mean body mass index 25 kg/m²; mean glycated hemoglobin [HbA_1c] 8.5%) were randomized (2:1) to IDeg or IGlar, each administered once daily with ≥1 oral antidiabetic drug(s) (OAD).

Results

After 26 weeks, HbA_1c had decreased by 1.24 and 1.35% in the IDeg and IGlar groups, respectively (treatment difference [IDeg – IGlar] 0.11%, 95% confidence interval [CI] −0.03 to 0.24), confirming non‐inferiority. Rates of overall confirmed hypoglycemia were similar for IDeg and IGlar during the full trial period (3.0 vs 3.7 episodes/patient‐year of exposure [PYE]; rate ratio [RR] 0.82, 95% CI 0.60 to 1.11, P = 0.20), but significantly lower (by 37%) for IDeg during the maintenance period (from week 16 onward; RR 0.63, 95% CI 0.42 to 0.94, P = 0.02). No significant difference in the rate of nocturnal confirmed hypoglycemia was found between IDeg and IGlar in the full trial period (0.8 vs 1.2 episodes/PYE; RR 0.62, 95% CI 0.38 to 1.04, P = 0.07) or maintenance period (RR 0.52, 95% CI 0.27 to 1.00, P = 0.05). Adverse event rates were similar between treatments.

Conclusions

Initiating insulin therapy with IDeg in Asian patients with type 2 diabetes, inadequately controlled with OADs, provides similar improvements in long‐term glycemic control to IGlar, but at a significantly lower rate of overall confirmed hypoglycemia once stable glycemic control and insulin dosing are achieved. This trial was registered with www.clinicaltrials.gov (no. NCT01059799).