Major Hypoglycemia Research Articles

Diversity in diabetes: the role of insulin aspart

Diabetes management is changing not only with novel treatments but also in patient demography. This presents clinical challenges and influences our view of diabetes therapies. Insulin analogues have been developed to overcome some of the limitations of traditional human insulins, with the aim of providing a more physiological pharmacokinetic/pharmacodynamic profile. The rapid-acting insulin analogue insulin aspart has been investigated in many clinical trials over the past 10 years and the aim of this review is to present the insulin aspart clinical trial data from across the spectrum of patients with diabetes. Five studies have looked at insulin aspart use (including continuous subcutaneous insulin infusion) in children and adolescents, where the analogue was as effective and well tolerated as soluble human insulin. One large-scale, randomized, controlled trial in pregnant women with type 1 diabetes observed trends towards a reduction in major hypoglycaemia, fewer preterm deliveries and lower birthweight with insulin aspart compared with soluble human insulin. Two 6-month, randomized, controlled, multicentre, multinational, parallel-group, open-label trials reported significant reductions in haemoglobin A(1c) and major nocturnal hypoglycaemia with insulin aspart compared with soluble human insulins in patients with type 1 diabetes. There are fewer data involving insulin analogue use in hospitals and in elderly patients with diabetes, but some recent studies have investigated insulin aspart in the emergency department, intensive/non-intensive care setting and in a pharmacokinetic/pharmacodynamic study in patients aged ≥ 65 years. In summary, the evidence would suggest that insulin aspart is suitable for use in a variety of patients with diabetes.

Insulin Analogues (NovoMix® 30 FlexPen®, or Levemir® FlexPen®, and/or NovoRapid® Flex Pen®) in the management of diabetes mellitus in the Gulf Countries

Evaluation of safety and efficacy of insulin aspart (NovoRapid® FlexPen®), insulin detemir (Levemir® FlexPen®), biphasic insulin aspart 30 (NovoMix® 30 FlexPen®), and their combination for the treatment of type 1 and type 2 diabetes in the Gulf countries in a prospective, multicenter, open label, non-interventional, observational study. A total of 5,866 patients with type 1 or type 2 diabetes were followed for 6 months. The primary efficacy endpoint was the change in glycoslyated hemoglobin (HbA1c) from baseline, while the secondary efficacy endpoints were the percentage of patients achieving HbA1c less than 7.0% approximately 12 and 24 weeks compared to baseline and changes in fasting blood sugar and postprandial blood sugar after 12 and 24 weeks of treatment compared to baseline. The primary safety endpoint was the incidence of major hypoglycemic episodes during the 24 weeks of using the study medication, while the secondary safety endpoints were changes in the number of hypoglycemic episodes in the past 4 weeks prior to the routine visits at approximately 12 and 24 weeks of treatment. The reduction in glycemic control measured by mean HbA1c from baseline to after 6 months was 2.4 (from 9.8 to 7.4, p-value < 0.0001) in all treatment groups after 24 weeks irrespective of the previous insulin regimen. The change in HbA1c after 24 weeks of treatment was 2.4 % in the Levemir® group, -2.3% in the NovoMix®30 group, 2.5% in the NovoRapid® group, 2.3 % in the combination group. The proportion of patients who achieved the target HbA1c increased from 1.7% at baseline to 26.9% after 24 weeks of treatment with insulin analogues. The change in the mean body weight after 24 weeks of treatment was 1.3 kg in the Levemir® group, 0.9 kg in the NovoMix®30 group, 0.1kg in the NovoRapid® group, and 0.7kg in the combination group. The change in major hypoglycemia was as follows: In the detemir group 2.9% at baseline to 0.2% at week 24, in the BIAsp30 group was 2.9% at baseline to 0.2% at week 24, in the aspart group 3.1% at baseline to 0% at week 24 (p < 0.0001).Switching to insulin Aspart (NovoRapid® FlexPen®), insulin detemir (Levemir® FlexPen®), biphasic insulin aspart 30 (NovoMix® 30 FlexPen®), or the combination of any of them resulted in significant lowering in HbA1c, fasting blood sugar, postprandial blood sugar, postprandial glucose increment, and the number of major hypoglycemic attacks. The percentage of patients attaining the required HbA1c below 7% was 26.9%. The body weight was reduced in all treatment groups.

Improved glycemic control with weight loss and a low risk of hypoglycemia with insulin detemir: insights from the Italian cohort of the PREDICTIVE study after 6-month observation in type 2 diabetic subjects

Objective: PREDICTIVE (Predictable Results and Experience in Diabetes through Intensification and Control to Target: an International Variability Evaluation) is a large, multinational, open-label, prospective, observational study addressed to assess the efficacy and safety of insulin detemir in clinical practice. This paper reports 26 weeks of follow-up data, from 1298 type 2 diabetes patients from Italy.Research design and methods: In this observational study, the primary end point was the incidence of serious adverse drug reactions (SADRs), including major hypoglycemia. Secondary end points were: hemoglobin A1c (HbA1c), mean self-monitored fasting glucose, within-patient fasting glucose variability and body weight change.Results: Insulin detemir significantly improved glycemic control, with a decrease in mean HbA1c, fasting glucose and within-patient fasting glucose variability. Interestingly, the improvements in glycemic control occurred in association with a small, but significant reduction in weight. The safety results of this study showed that 26 weeks of treatment with insulin detemir was associated with a very low rate of SADRs (only 14 events), which mainly consisted of hypoglycemia (78%, of which 42% were major hypoglycemia).Conclusions: Insulin detemir improves glycemic control, with low risk of hypoglycemia, no weight gain and an excellent safety profile; these data support the overall findings of PREDICTIVE.

Effects of exenatide twice daily versus sitagliptin on 24‐h glucose, glucoregulatory and hormonal measures: a randomized, double‐blind, crossover study

Aim: To compare exenatide and sitagliptin glucose and glucoregulatory measures in subjects with type 2 diabetes.Methods: An 8-week, double-blind, randomized, crossover, single-centre study. Eighty-six subjects (58% female, body mass index 35 ± 5 kg/m2, haemoglobin A1c 8.3 ± 1.0%) received either exenatide 10 µg (subcutaneous) twice daily or sitagliptin 100 mg (oral) daily for 4 weeks and crossed to the other therapy for an additional 4 weeks. Main outcome was time-averaged glucose during the 24-h inpatient visits.Results: Both treatments decreased average 24-h glucose, but exenatide had a greater effect [between-group difference: −0.67 mmol/l, 95% confidence interval (CI): −0.9 to −0.4 mmol/l]. Both treatments decreased 2-h postprandial glucose (PPG), area under the curve of glucose above 7.8 mmol/l (140 mg/dl) and 11 mmol/l (200 mg/dl) and increased the time spent with glucose between 3.9 and 7.8 mmol/l (70 and 140 mg/dl) during 24 h, but exenatide had a significantly greater effect (p < 0.05). Both treatments decreased postprandial serum glucagon, with exenatide having a greater effect (p < 0.005). Both treatments decreased fasting blood glucose to a similar degree (p = 0.766). Sitagliptin increased, while exenatide decreased, postprandial intact glucagon-like peptide-1. Both drugs improved homeostasis model assessment of β-cell function (HOMA-B), with exenatide having a significantly greater effect (p = 0.005). Both exenatide and sitagliptin decreased 24-h caloric intake, with exenatide having a greater effect (p < 0.001). There was no episode of major hypoglycaemia. Adverse events were mild to moderate and mostly gastrointestinal in nature with exenatide. No study withdrawals were due to an adverse event.Conclusion: Compared to sitagliptin, exenatide showed significantly lower average 24-h glucose, 2-h PPG, glucagon, caloric intake and improved HOMA-B.

Efficacy and Tolerability of Self-Titrated Biphasic Insulin Aspart 70/30 in Patients Aged >65 Years With Type 2 Diabetes: An Exploratory Post Hoc Subanalysis of the INITIATEplus Trial

Background The Initiation of Insulin to reach A1C Target (INITIATEplus) trial studied the effect of self-titrating biphasic insulin aspart 70/30 (BiAsp 30) twice daily during 24 weeks in insulin-naïve patients with type 2 diabetes who were poorly controlled by oral medication, and originally randomized according to frequency of dietary counseling interventions. Objective The purpose of this study was to compare the efficacy and tolerability of biphasic insulin aspart 70/30 (BIAsp 30, NovoLog Mix 70/30) in INITIATEplus patients ≤65 versus >65 years old, irrespective of dietary counseling frequency, and to test the hypothesis that self-titrating BIAsp 30 in patients >65 years old could be well-tolerated and effective in this age group. Methods An exploratory post hoc subanalysis, using standard statistical methods, was performed on patients stratified according to age. Data collected from 3492 patients in the intent-to-treat population who were ≤65 years old and 716 patients who were >65 years old compared glycosylated hemoglobin (HbA 1c) and plasma glucose changes from baseline. Hypoglycemia rates and adverse event (AE) incidence were compared for the tolerability population of 4007 patients ≤65 years old and 805 patients >65 years old. Results Baseline-adjusted HbA 1c changes for patients ≤65 versus >65 years old were –2.38% versus –2.73% ( P < 0.0001), with final HbA 1c achieving 7.55% and 7.06%, respectively. Thirty-nine percent of patients ≤65 years old achieved HbA 1c ≤7% compared with 51% of patients >65 years old. Baseline-adjusted fasting plasma glucose decreases were greater for the >65 year old population (85.2 vs 91.2 mg/dL; P = 0.004; ≤65 vs >65 years old, respectively). Minor hypoglycemia was reported in 9.7% and 7.7% of patients ≤65 versus >65 years old, respectively (0.52 vs 0.41 episodes per patient per year [ppy]; P = 0.01). Major hypoglycemia occurred in 1.5% and 3.1% of patients (0.05 vs 0.14 episodes ppy, ≤65 vs >65 years old, respectively; P < 0.0001). Nocturnal major hypoglycemia was reported for 0.4% and 0.6% of patients ( P = 0.0028), whereas nocturnal minor hypoglycemia was reported for 3.8% and 2.6% ( P = 0.007) of patients ≤65 and >65 years old, respectively. AEs were reported for 24% and 28% of patients ≤65 and >65 years old, respectively, serious AEs were reported for 4% and 9% of patients, respectively, and AE-related withdrawals were reported for 1.3% and 2% of patients, respectively. Conclusions Self-titrated biphasic insulin aspart 70/30 was found to be well-tolerated and effective in type 2 diabetes patients >65 years old, as well as in patients ≤65 years old. HbA 1c and fasting plasma glucose decreases were significantly ( P < 0.05) higher for patients >65 years old versus patients ≤65 years old. Tolerability was indicated by major and minor hypoglycemia rates at or below <0.5 episodes ppy in both age groups. Overall rates of AE and serious AEs were higher among patients > 65 years; withdrawals related to AEs were 2% compared with 1.3% in the younger age group. ClinicalTrials.gov identifier: NCT 00101751.

DURATION‐2: efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once‐weekly exenatide

AimsIn the initial 26-week, double-blind, double-dummy assessment period of the DURATION-2 trial in patients with Type 2 diabetes on metformin, the once-weekly glucagon-like peptide 1 (GLP-1) receptor agonist exenatide once-weekly resulted in greater HbA1c improvement and weight reduction compared with maximum approved daily doses of sitagliptin or pioglitazone. This subsequent, 26-week, open-label, uncontrolled assessment period evaluated the safety and efficacy of (i) continued exenatide once-weekly treatment and (ii) switching from sitagliptin or pioglitazone to exenatide once-weekly.MethodsRandomised oral medications were discontinued and all patients received exenatide once-weekly. Of the 364 patients [original baseline HbA1c 8.5 ± 1.1% (70 mmol/mol), fasting plasma glucose 9.0 ± 2.5 mmol/l, weight 88 ± 20 kg) who continued into the open-label period, 319 patients (88%) completed 52 weeks.ResultsEvaluable patients who received only exenatide once-weekly demonstrated significant 52-week improvements (least square mean ± se) in HbA1c (−1.6 ± 0.1%), fasting plasma glucose (−1.8 ± 0.3 mmol/l) and weight (−1.8 ± 0.5 kg). Evaluable patients who switched from sitagliptin to exenatide once-weekly demonstrated significant incremental improvements in HbA1c (−0.3 ± 0.1%), fasting plasma glucose (−0.7 ± 0.2 mmol/l) and weight (−1.1 ± 0.3 kg). Patients who switched from pioglitazone to exenatide once-weekly maintained HbA1c and fasting plasma glucose improvements (week 52: −1.6 ± 0.1%, −1.7 ± 0.3 mmol/l), with significant weight reduction (−3.0 ± 0.3 kg). Exenatide once-weekly was generally well tolerated and adverse events were predominantly mild or moderate in intensity. Nausea was the most frequent adverse event in this assessment period (intent-to-treat: exenatide once-weekly-only 5%; sitagliptin → exenatide once-weekly 11%; pioglitazone → exenatide once-weekly 10%). No major hypoglycaemia was observed.ConclusionsPatients who switched to once-weekly exenatide from daily sitagliptin or pioglitazone had improved or sustained glycaemic control, with weight loss.

DURATION-5: Exenatide Once Weekly Resulted in Greater Improvements in Glycemic Control Compared with Exenatide Twice Daily in Patients with Type 2 Diabetes

We wanted to understand the effects of once-weekly vs. twice-daily glucagon-like peptide-1 receptor agonism for treatment of patients with type 2 diabetes. The objective of the study was to compare effects of exenatide once weekly (ExQW) and exenatide twice daily (ExBID) on glycemic control, body weight, and safety. This was a 24-wk, randomized, open-label, comparator-controlled study. The study was conducted at 43 sites in the United States. The study population was 252 intent-to-treat patients with type 2 diabetes [baseline (mean ± SD): glycosylated hemoglobin (HbA1c) 8.4 ± 1.2%, fasting plasma glucose 171 ± 47 mg/dl, weight 96 ± 20 kg] that were drug naïve (19%) or previously treated with one (47%) or multiple (35%) oral antidiabetic medications. Interventions included ExQW 2 mg for 24 wk or ExBID 5 μg for 4 wk followed by ExBID 10 μg for 20 wk. The change in HbA1c from baseline to wk 24 was measured. At 24 wk, ExQW produced significantly greater changes from baseline (least squares mean ± SE) vs. ExBID in HbA1c (-1.6 ± 0.1% vs. -0.9 ± 0.1%; P < 0.0001) and fasting plasma glucose (-35 ± 5 mg/dl vs. -12 ± 5 mg/dl; P = 0.0008). Similar reductions in mean body weight from baseline to wk 24 were observed in both groups (-2.3 ± 0.4 kg and -1.4 ± 0.4 kg). Both treatments were generally well tolerated. Transient and predominantly mild to moderate nausea, the most frequent adverse event, was less common with ExQW (14%) than with ExBID (35%). Injection-site reactions were infrequent, but more common with ExQW. No major hypoglycemia occurred. Continuous glucagon-like peptide-1 receptor agonism with ExQW resulted in superior glycemic control, with less nausea, compared with ExBID in patients with type 2 diabetes. Both groups lost weight.

Efficacy and safety of insulin detemir once daily in combination with sitagliptin and metformin: the TRANSITION randomized controlled trial

The aim of this trial was to evaluate the efficacy and safety of the combination of once-daily insulin detemir (IDet) and sitagliptin (SITA) versus SITA ± sulphonylurea (SU), both in combination with metformin (MET) in insulin-naive subjects. In a 26-week, open-label, randomized, parallel-group study in type 2 diabetes, insulin-naive subjects concomitantly treated with MET ± second oral antidiabetic drug (OAD) were randomized 1 : 1 to IDet + SITA + MET or SITA + MET ± SU. All continued with MET treatment, and those treated with SU continued if randomized to SITA + MET ± SU. Efficacy endpoints included glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), 9-point self-measured plasma glucose (SMPG), weight, body mass index (BMI). Safety endpoints included adverse events (AEs) and hypoglycaemia. Significantly higher reductions in HbA1c, FPG and SMPG were achieved with IDet + SITA + MET compared with SITA + MET ± SU. Estimated HbA1c decreased by 1.44% in the IDet + SITA + MET group versus 0.89% in SITA + MET ± SU, p < 0.001. FPG decreased by 3.7 mmol/l (66.3 mg/dl) versus 1.2 mmol/l (22.2 mg/dl), p < 0.001, respectively. Small decreases in weight and BMI were observed in both arms, with no significant differences. AEs were mild or moderate and were more common in the SITA + MET ± SU arm than in the IDet + SITA + MET arm. There was no major hypoglycaemia. Observed rates of hypoglycaemia were very low (1.3/1.7 episodes/patient year) in both arms. The subgroup treated with MET and SUs prior to the trial achieved similar results. The combination of once-daily IDet with SITA showed a clinically and significantly better improvement in glycaemic control than SITA in combination with or without SUs. Both regimens were associated with a low rate of hypoglycaemia and slight weight reduction.

Liraglutide provides similar glycaemic control as glimepiride (both in combination with metformin) and reduces body weight and systolic blood pressure in Asian population with type 2 diabetes from China, South Korea and India: a 16-week, randomized, doubl

To assess and compare the efficacy and safety of liraglutide with those of glimepiride, both in combination with metformin for the treatment of type 2 diabetes in Asian population from China, South Korea and India. A 16-week, randomized, double-blind, double-dummy, four-arm, active control trial was carried out. In total, 929 subjects with type 2 diabetes with a mean (±s.d.) age of 53.3 ± 9.5 years, HbA₁(c) of 8.6 ± 1.0% and body weight of 68.1 ± 11.7 kg were randomized (liraglutide 0.6, 1.2 or 1.8 mg once daily or glimepiride 4 mg once daily all in combination with metformin: 1 : 1 : 1 : 1). One subject withdrew immediately after randomization and before exposure. HbA₁(c) was significantly reduced in all groups compared with baseline. Treatment with liraglutide 1.2 and 1.8 mg was non-inferior to glimepiride (mean HbA₁(c) reduction: 1.36% points, 1.45% points and 1.39% points, respectively). No significant difference was shown in the percentage of subjects reaching American Diabetes Association HbA₁(c) target <7% or American Association of Clinical Endocrinologists target ≤6.5% between liraglutide 1.2 and 1.8 mg and glimepiride. Liraglutide was associated with a 1.8-2.4 kg mean weight reduction, compared with a 0.1 kg mean weight gain with glimepiride. Liraglutide led to a significantly greater reduction in systolic blood pressure (SBP) compared with glimepiride. Two subjects in the glimepiride group reported major hypoglycaemia while none in the liraglutide groups. Liraglutide was associated with about 10-fold lower incidence of minor hypoglycaemia than glimepiride. Gastrointestinal disorders were the most common adverse events (AEs) for liraglutide, but were transient and resulted in few withdrawals. In Asian subjects with type 2 diabetes, once-daily liraglutide led to improvement in glycaemic control similar to that with glimepiride but with less frequent major and minor hypoglycaemia. Liraglutide also induced a significant weight loss and reduced SBP and was generally well tolerated. The most frequently reported AE was transient nausea. The effect of liraglutide in this Asian population is comparable to the effects seen in Caucasian, African American and Hispanic populations in global liraglutide phase 3 trials.

Multicenter, open‑label, nonrandomized, observational safety study in subjects using insulin aspart in basal‑bolus regimen for the treatment of diabetes

Basal-bolus insulin therapy is a standard method of intensifying diabetes treatment. A common adverse effect of such treatment is hypoglycemia. Data on frequency of hypoglycemia when fast-acting insulin analogue is used in everyday clinical practice is scarce. The aim of the study was to investigate the risk of hypoglycemia after the use of insulin aspart in basal-bolus therapy in patients with type 1 and 2 diabetes. It was a multicenter, open-label, noninterventional study. It involved 950 patients with type 1 and 1332 patients with type 2 diabetes who started preprandial insulin aspart in basal-bolus regimen. Patients were followed for 13 weeks. The primary endpoint was the incidence of major daytime and nocturnal hypoglycemic events assessed on the basis of patients' self-reports during follow-up compared with a 4-week period before the baseline visit. Secondary endpoints were: incidence of minor daytime and nocturnal hypoglycemia, hemoglobin A1c (HbA1c), fasting and postprandial glycemia. The rate of major hypoglycemia decreased in patients with type 1 diabetes--the incidence rate ratio (IRR) was 0.14 for daytime and 0.03 for nocturnal episodes (P <0.0001) and did not change in patients with type 2 diabetes. The rate of minor episodes decreased in patients with type 1 diabetes (IRR = 0.44 for daytime and IRR = 0.24 for nocturnal episodes, P <0.0001) and in patients with type 2 diabetes (IRR= 0.57, P <0.0001 for daytime and IRR = 0.89, P <0.05 for nocturnal episodes). HbA1c decreased by 1.28 ± 1.64% in type 1 and 1.25 ± 1.10% in type 2 diabetes (both P <0.0001). Self-measured fasting and postprandial blood glucose levels were significantly lower at the final visit compared with baseline, irrespective of diabetes type. In clinical practice, treatment with insulin aspart in basal-bolus regimen is associated with low risk of hypoglycemia and leads to a significant improvement in glucose control, irrespective of diabetes type.

Liraglutide: A once-daily human glucagon-like peptide-1 analogue for type 2 diabetes mellitus

The pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, adverse effects, and place in therapy of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, are reviewed. Liraglutide, the first once-daily human GLP-1 analogue, retains 97% homology with the endogenous hormone and shares its glucose-dependent glucose-lowering action but has a considerably longer half-life that supports once-daily dosing. After promising Phase II study results, the Liraglutide Effect and Action in Diabetes (LEAD) Phase III clinical development program, involving more than 4000 patients worldwide, investigated the efficacy and tolerability of liraglutide 1.2 or 1.8 mg daily (n = 2735) as monotherapy and in combination with various oral antidiabetic drugs. The LEAD studies yielded encouraging results indicating that patients receiving liraglutide could expect to attain glycosylated hemoglobin reductions of about 1-1.5% and fasting plasma glucose reductions of 15-43 mg/dL. Loss of body weight was consistent throughout the studies: when using liraglutide 1.8 mg as monotherapy, patients lost a mean of 2.5 kg over a 52-week period. Accompanying reductions in some cardiovascular risk endpoints, such as systolic blood pressure, were also observed. By virtue of its glucose-dependent mode of action, liraglutide was generally well tolerated in clinical trials, with only very rare episodes of major hypoglycemia reported. The most frequently observed adverse effects were gastrointestinal, with 10-40% of patients experiencing an episode of nausea, which was often mild or moderate in severity and transient in nature. Liraglutide is efficacious and well tolerated in patients with type 2 diabetes and has been found to reduce weight and blood pressure.

Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial

Most patients with type 2 diabetes begin pharmacotherapy with metformin, but eventually need additional treatment. We assessed the safety and efficacy of once weekly exenatide, a glucagon-like peptide 1 receptor agonist, versus maximum approved doses of the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the thiazolidinedione, pioglitazone, in patients treated with metformin. In this 26-week randomised, double-blind, double-dummy, superiority trial, patients with type 2 diabetes who had been treated with metformin, and at baseline had mean glycosylated haemoglobin (HbA(1c)) of 8.5% (SD 1.1), fasting plasma glucose of 9.1 mmol/L (2.6), and weight of 88.0 kg (20.1), were enrolled and treated at 72 sites in the USA, India, and Mexico. Patients were randomly assigned to receive: 2 mg injected exenatide once weekly plus oral placebo once daily; 100 mg oral sitagliptin once daily plus injected placebo once weekly; or 45 mg oral pioglitazone once daily plus injected placebo once weekly. Primary endpoint was change in HbA(1c) between baseline and week 26. Analysis was by intention to treat, for all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00637273. 170 patients were assigned to receive once weekly exenatide, 172 to receive sitagliptin, and 172 to receive pioglitazone. 491 patients received at least one dose of study drug and were included in the intention-to-treat analysis (160 on exenatide, 166 on sitagliptin, and 165 on pioglitazone). Treatment with exenatide reduced HbA(1c) (least square mean -1.5%, 95% CI -1.7 to -1.4) significantly more than did sitagliptin (-0.9%, -1.1 to -0.7) or pioglitazone (-1.2%, -1.4 to -1.0). Treatment differences were -0.6% (95% CI -0.9 to -0.4, p<0.0001) for exenatide versus sitagliptin, and -0.3% (-0.6 to -0.1, p=0.0165) for exenatide versus pioglitazone. Weight loss with exenatide (-2.3 kg, 95% CI-2.9 to -1.7) was significantly greater than with sitagliptin (difference -1.5 kg, 95% CI -2.4 to -0.7, p=0.0002) or pioglitazone (difference -5.1 kg, -5.9 to -4.3, p<0.0001). No episodes of major hypoglycaemia occurred. The most frequent adverse events with exenatide and sitagliptin were nausea (n=38, 24%, and n=16, 10%, respectively) and diarrhoea (n=29, 18%, and n=16, 10%, respectively); upper-respiratory-tract infection (n=17, 10%) and peripheral oedema (n=13, 8%) were the most frequent events with pioglitazone. The goal of many clinicians who manage diabetes is to achieve optimum glucose control alongside weight loss and a minimum number of hypoglycaemic episodes. Addition of exenatide once weekly to metformin achieved this goal more often than did addition of maximum daily doses of either sitagliptin or pioglitazone. Amylin Pharmaceuticals and Eli Lilly.

Initiation with once-daily BIAsp 30 results in superior outcome compared to insulin glargine in Asians with type 2 diabetes inadequately controlled by oral anti-diabetic drugs

We compare the efficacy and safety of once-daily biphasic insulin aspart 70/30 (BIAsp 30) and insulin glargine in Asian subjects with type 2 diabetes inadequately controlled with oral anti-diabetic drugs (OADs). In a 26-week, open-labelled, randomised, parallel-group, multinational, multicentre, treat-to-target trial, 155 insulin-naïve Asian subjects were treated with either BIAsp 30 or insulin glargine, both in combination with metformin and glimepiride. Change in HbA 1c at end of treatment with BIAsp 30 was superior to insulin glargine (BIAsp 30–glargine = −0.36%, 95% CI [−0.64; −0.07], p = 0.015). Mean self-measured plasma glucose (SMPG) at bedtime was significantly lower with BIAsp 30 than insulin glargine (7.98 ± 0.34 mmol/L vs. 9.16 ± 0.33 mmol/L, p = 0.0078). Incidences of minor and daytime hypoglycaemia were higher with BIAsp 30 than those with glargine, but the difference did not reach the statistical significance. No difference was seen in nocturnal hypoglycaemia. The incidence of adverse events was comparable between treatments, with low incidence of serious adverse events and major hypoglycaemia. Mean body weight increased slightly in both groups. In insulin-naïve Asian subjects with type 2 diabetes who are inadequately controlled with OADs, once-daily BIAsp 30 is superior to insulin glargine.

DURATION-1: Exenatide Once Weekly Produces Sustained Glycemic Control and Weight Loss Over 52 Weeks

OBJECTIVEIn the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) study, the safety and efficacy of 30 weeks of treatment with the glucagon-like peptide-1 receptor agonist exenatide once weekly (exenatide QW; 2 mg) was compared with exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in 1) patients who continued treatment for an additional 22 weeks (52 weeks total) and 2) patients who switched from exenatide BID to exenatide QW after 30 weeks.RESEARCH DESIGN AND METHODSIn this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n = 128 QW-only; n = 130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed.RESULTSPatients continuing exenatide QW maintained A1C improvements through 52 weeks (least squares mean −2.0% [95% CI −2.1 to −1.8%]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71 and 54% of all patients achieved A1C <7.0% and ≤6.5%, respectively. In both treatment arms, FPG was reduced by >40 mg/dl, and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed.CONCLUSIONExenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment. Patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss.

Improved glycaemic control with minimal hypoglycaemia and no weight change with the once‐daily human glucagon‐like peptide‐1 analogue liraglutide as add‐on to sulphonylurea in Japanese patients with type 2 diabetes

Sulphonylureas (SUs) are often used as first-line treatments for type 2 diabetes in Japan, hence it is important to study new antidiabetic drugs in combination with SUs in Japanese patients. The efficacy and safety of the once-daily human glucagon-like peptide-1 (GLP-1) analogue liraglutide were compared in 264 Japanese subjects [mean body mass index (BMI) 24.9 kg/m(2); mean glycated haemoglobin (HBA1c) 8.4%] randomized and exposed to receive liraglutide 0.6 mg/day (n = 88), 0.9 mg/day (n = 88) or placebo (n = 88) each added to SU monotherapy (glibenclamide, glicazide or glimeprimide) in a 24-week, double-blind, parallel-group trial. The mean change in HBA1c from baseline to week 24 (LOCF) was -1.56 (s.d. 0.84) and -1.46 (s.d. 0.95) with liraglutide 0.9 and 0.6 mg respectively, and -0.40 (s.d. 0.93) with placebo. HBA1c decreased in the placebo group from 8.45 to 8.06%, while liraglutide reduced HBA1c from 8.60 to 7.14%, and from 8.23 to 6.67% at the 0.6 and 0.9 mg doses respectively. Mean HBA1c at week 24 of the two liraglutide groups were significantly lower than the placebo group (p < 0.0001 for both). More subjects reached HBA1c < 7.0% with liraglutide (0.6 mg: 46.5%; 0.9 mg: 71.3%) vs. placebo (14.8%). Fasting plasma glucose (FPG) levels were significantly improved with liraglutide (difference -1.47 mmol/l and -1.80 mmol/l with 0.6 and 0.9 mg vs. placebo; p < 0.0001). Overall safety was similar between treatments: no major hypoglycaemic episodes were reported, while 84/77/38 minor hypoglycaemic episodes occurred in the 0.6 mg/0.9 mg and placebo treatment groups (all in combination with SU), reflecting lower ambient glucose levels. No relevant change in mean body weight occurred in subjects receiving liraglutide (0.6 mg: 0.06 kg; 0.9 mg: -0.37 kg), while mean body weight decreased in subjects receiving placebo (-1.12 kg). The addition of liraglutide to SU treatment for 24 weeks dose-dependently improved glycaemic control vs. SU monotherapy, without causing major hypoglycaemia or weight gain or loss.

Good control and few hypos possible with basal insulin starts

Evidence from a recently published study on the efficacy of complex insulin regimens in type 2 diabetes shows that good blood glucose control with a low rate of major hypoglycaemia is possible

Biphasic insulin aspart 30 as insulin initiation or replacement therapy: the China cohort of the IMPROVE study

Aims:To explore safety and efficacy of BIAsp 30 as initiation or replacement therapy in routine clinical practice in patients with poorly controlled diabetes in the Chinese cohort of the IMPROVE study.Methods:In the 26-week, non-interventional, observational study, Chinese subjects with diabetes started BIAsp 30 treatment in routine care. Data from patients’ diaries and medical records were transferred to CRFs by participating physicians.Clinical trial registration:NCT00659282.Results:Of the 21,729 subjects enrolled (mean age 54.0 years, BMI 24.6 kg/m, diabetes duration 4.86 years), 32.3% were treatment-naïve, 59.3% were from oral anti-diabetic drugs (OADs) only and 8.1% were from insulin ± OADs. Overall, mean HbA1c and FBG decreased by 2.82% and 5 mmol/L, respectively. In the subgroups, changes were: −3.27% and −6.06 mmol/L (treatment-naïve), −2.57% and −4.54 mmol/L (OADs only), −2.96% and 3.51 mmol/L (insulin ± OADs) all p < 0.05. HbA1c < 7% was achieved by 71.4% of patients. Only 0.1% of subjects reported major hypoglycaemia and 73 SADRs were observed without significant difference compared to those at baseline. Body weight did not change significantly.Conclusions:Regardless of previous treatments, insulin initiation or replacement with BIAsp 30 improved glycaemic control without increasing major hypoglycaemia or weight gain in Chinese patients with diabetes.

Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain: 52-week data from the PREDICTIVE™ study in a cohort of French patients with type 1 or type 2 diabetes

Aim PREDICTIVE™ (an ongoing multinational observational study) provides an opportunity to explore the impact of insulin detemir use in routine clinical practice. Here, we report on long-term (52-week) data from a French cohort of patients ( n = 1772), comprising 643 with type 1 diabetes and 1129 with type 2 diabetes. Methods Patients were prescribed insulin detemir at their physician's discretion and assessed at various visits (baseline, 12 weeks, 26 weeks and 52 weeks). The primary endpoint was the frequency of serious adverse drug reactions, including major hypoglycaemia. Secondary endpoints included minor and nocturnal hypoglycaemia, glycaemic control (HbA 1c, fasting blood glucose and variability of fasting blood glucose) and weight change. Results The incidence of serious adverse drug reactions was low throughout the study, seen in 10 patients with type 1 diabetes (14 events, 1.6%) and seven with type 2 diabetes (seven events, 0.6%). In both type 1 and type 2 diabetes cohorts, the overall minor and nocturnal hypoglycaemic events were reduced from baseline ( P < 0.001), with no clinically significant changes in weight from baseline to endpoint. After 52 weeks of treatment with insulin detemir, glycaemic control improved, with reductions in: HbA 1c, by −0.6% and −0.8% in type 1 and type 2 diabetes patients, respectively; fasting blood glucose, by −1.4 mmol/L and −1.9 mmol/L respectively; and FBG variability, by −0.8 mmol/L and −0.3 mmol/L, respectively ( P < 0.0001 for all). Conclusion Patients treated with insulin detemir in a clinical healthcare setting improved their glycaemic control with no increases in hypoglycaemia, adverse events or weight compared with baseline.

A 1c Control in a Primary Care Setting: Self-titrating an Insulin Analog Pre-mix (INITIATE plus Trial)

Purpose To study glycemic control and hypoglycemia development upon initiation of insulin through a self-titration schedule in a 24-week trial, conducted with 4875 insulin-naïve patients with poorly controlled type 2 diabetes, predominantly in a primary care setting. Methods Subjects initiated twice-daily biphasic insulin aspart 70/30 with 6 units prebreakfast and 6 units presupper, self-titrating according to self-measured blood glucose values. Subjects were randomized (1:1:1) to telephone counseling provided by a registered dietician: no counseling (NC), 1 counseling session (1C), or 3 sessions (3C). Results Mean baseline HbA 1c (9.9% across groups) decreased ∼2.5% to 7.49% ± 1.48, 7.48% ± 1.50, and 7.44% ± 1.46 in the NC, 1C, and 3C groups, respectively. Within these groups, a hemoglobin A 1c (HbA 1c) value <7% was achieved by 40.2%, 41.6%, and 41.8% of subjects, respectively. Eight-point blood glucose profiles were substantially improved from baseline for all groups. Hypoglycemia was experienced by 10.2%-11.4% of the subjects in each group. Rates of minor and major hypoglycemia were low but decreased as dietary counseling increased (minor hypoglycemia: 56 vs 50 vs 45 episodes per 100 patient-years; major hypoglycemia, 9 vs 6 vs 4 episodes per 100 patient-years, for the NC vs 1C vs 3C groups, respectively; P <.001, 3C vs NC). Weight increased by 3.13, 3.40, and 2.88 kg for the NC, 1C, and 3C groups, respectively. Conclusion In the primary care setting, self-titration of biphasic insulin aspart 70/30 was effective in achieving recommended HbA 1c goals even with minimal dietary counseling.

Comparison of insulin detemir and insulin glargine in a basal—bolus regimen, with insulin aspart as the mealtime insulin, in patients with type 1 diabetes: A 52-week, multinational, randomized, open-label, parallel-group, Treat-to-Target noninferiority trial

Objective: The primary study objective was to determine whether insulin detemir (detemir) was noninferior to insulin glargine (glargine) as the basal insulin in a basal—bolus regimen, with insulin aspart as the mealtime insulin, in terms of glycemic control at the end of 52 weeks in patients with type 1 diabetes mellitus (T1DM).Methods: This multinational, open-label, parallel-group, treat-to-target, noninferiority trial enrolled patients aged ≥18 years who had had T1DM for at least 12 months, had been taking a basal—bolus insulin regimen for at least 3 months, and had a glycosylated hemoglobin (HbA1c) value ≤11.0% at screening. Patients were randomized in a 2:1 ratio to receive either detemir or glargine for 52 weeks. The basal insulin was initially administered once daily (in the evening) in both groups; if patients in the detemir group were achieving the plasma glucose (PG) target before breakfast but not before dinner, they were switched to twice-daily administration. Glargine was administered once daily throughout the trial, according to its approved labeling. Each patient attended 13 study visits and received 16 scheduled telephone calls from the trial site. The primary efficacy end point was glycemic control (HbA1c) after 52 weeks of treatment. Secondary end points included the number of patients achieving an HbA1c value ≤7.0%, with or without a major hypoglycemic episode in the last month of treatment; fasting PG (FPG); within-patient variation in self-monitored plasma glucose (SMPG) before breakfast and dinner; and 10-point SMPG profiles. The noninferiority margin was 0.4%, consistent with US Food and Drug Administration guidelines.Results: Four hundred forty-three patients (mean [SD] age, 42 [12] years; body mass index, 26.5 [4.0] kg/m2; duration of diabetes, 17.2 [11.4] years; HbA1c, 8.1% [1.1%]) received study treatment. After 52 weeks, the estimated mean HbA1c did not differ significantly between the detemir and glargine groups (7.57% and 7.56%, respectively; mean difference, 0.01%; 95% CI, −0.13 to 0.16), consistent with the noninferiority of detemir to glargine. The corresponding estimated changes in HbA1c were −0.53% and −0.54%. In the 90 patients who completed the trial on once-daily detemir and the 173 patients who completed the trial on twice-daily detemir, the estimated changes in HbA1c were −0.49% and −0.58%, respectively. After 52 weeks, there were no significant differences in the proportions of those receiving detemir and glargine who achieved an HbA1c value ≤7.0% without major hypoglycemia (31.9% and 28.9%, respectively). In addition, there were no significant differences in estimated mean FPG (8.58 and 8.81 mmol/L; mean difference, −0.23 mmol/L; 95% CI, −1.04 to 0.58) or in basal insulin doses. The basal insulin dose was numerically higher in patients receiving detemir twice rather than once daily (0.47 vs 0.33 U/kg, respectively). The relative risks for total and nocturnal hypoglycemia with detemir versus glargine were 0.94 and 1.12, respectively (both, P = NS). Six patients (2.0%) randomized to the detemir group and 4 (2.7%) randomized to the glargine group withdrew due to adverse events.Conclusions: During 52 weeks of basal—bolus therapy in patients with T1DM, detemir was noninferior to glargine in terms of overall glycemic control (HbA1c). When used according to the approved labeling, detemir and glargine did not differ in tolerability or in terms of the occurrence of hypoglycemia.