Safety and efficacy of insulin glargine (HOE 901) versus NPH insulin in combination with oral treatment in Type 2 diabetic patients

Aims A European, randomized, 29‐centre, open‐label study compared the safety and efficacy of two formulations of insulin glargine and neutral protamine Hagedorn (NPH) human insulin, in combination with oral agents, in patients with Type 2 diabetes mellitus (DM). Methods Two‐hundred‐and‐four patients with Type 2 DM, in whom oral treatment alone was inadequate, were randomized to insulin glargine with 30 µg/ml zinc [insulin glargine (30)], or insulin glargine with 80 µg/ml zinc [insulin glargine (80)] or NPH insulin subcutaneously once daily. Insulin was titrated to aim for fasting blood glucose (FBG) values between 4 and 7 mmol/l. All participants received oral therapy during the 3‐week titration phase and 1‐week maintenance phase of the trial. Results No differences between treatment groups were observed in adjusted mean fasting plasma glucose; significant decreases of 3.4 mmol/l, 3.5 mmol/l and 3.1 mmol/l were observed within the insulin glargine (30), insulin glargine (80) and NPH insulin groups, respectively (P < 0.0001 in each case). No differences between groups, but significant changes within groups, were observed in self‐monitored FBG, mean FBG, blood glucose profile, stability of FBG, nocturnal blood glucose, fasting serum C‐peptide, non‐esterified fatty acids, haemoglobin A_1c, fructosamine and fasting serum insulin. A significantly greater proportion of NPH insulin patients experienced symptomatic nocturnal hypoglycaemia (19.1 NPH group vs. 7.3% glargine groups; P = 0.0123). Both insulins were well tolerated; one patient in each group experienced an injection site reaction. Conclusions Insulin glargine is as safe and effective as NPH insulin given once daily and in this study caused fewer episodes of nocturnal hypoglycaemia. Diabet. Med. 20, 545–551 (2003)     

Meta‐analysis of individual patient data to assess the risk of hypoglycaemia in people with type 2 diabetes using NPH insulin or insulin glargine

Aim: To estimate absolute and relative incidence rates of hypoglycaemia when using once‐daily evening or morning regimens of insulin glargine (glargine) versus once‐daily evening NPH insulin (NPH) using individual patient data (IPD). Materials and methods: Randomized controlled trials with accessible IPD and including white European people with type 2 diabetes (T2DM) using glargine or NPH once‐daily (with oral glucose‐lowering drugs) were identified. Two study pools were analysed: evening glargine versus evening NPH (pool 1); and morning glargine versus evening NPH (pool 2). The number‐needed‐to‐treat to avoid hypoglycaemia was calculated for glargine versus NPH. Results: In study pool 1 (n = 2711), the risk of nocturnal hypoglycaemia was approximately halved with glargine compared with NPH [odds ratios (OR): 0.44–0.52, p < 0.001–0.047]. This led to a significant reduction in anytime risk of symptomatic hypoglycaemia [plasma glucose (PG) <3.9 mmol/l, OR: 0.64, p = 0.018; PG <2.0 mmol/l, OR: 0.51, p < 0.001]. In study pool 2 (n = 470), although a strong numerical reduction in all types of nocturnal hypoglycaemia was observed (OR: 0.16–0.64), statistical significance was reached only for symptomatic hypoglycaemia with PG <3.9 mmol/l (p < 0.001). Eight (pool 1) or five (pool 2) people with T2DM needed to use glargine rather than NPH to avoid one person from experiencing a nocturnal symptomatic hypoglycaemic event within a median of about 25 weeks of starting insulin. Conclusions: This meta‐analysis of open‐label studies provides confidence that reductions of around 50% of risk for nocturnal hypoglycaemia can be achieved with using glargine instead of NPH.     

Hypoglycaemia incidence and recovery during home use of hybrid closed‐loop insulin delivery in adults with type 1 diabetes

Glucose excursion was assessed prior to and post hypoglycaemia to increase understanding of hypoglycaemia incidence and recovery during hybrid closed‐loop insulin delivery. We retrospectively analysed data from 60 adults with type 1 diabetes who received, in a crossover randomized design, day‐and‐night hybrid closed‐loop insulin delivery and insulin pump therapy, the latter with or without real‐time continuous glucose monitoring. Over 4‐week study periods, we identified hypoglycaemic episodes, defined as sensor glucose <3.0 mmol/L, and analysed sensor glucose relative to the onset of hypoglycaemia. We identified 377 hypoglycaemic episodes during hybrid closed‐loop intervention vs 662 during control intervention (P < .001), with a predominant reduction of nocturnal hypoglycaemia. The slope of sensor glucose prior to hypoglycaemia was steeper during closed‐loop intervention than during control intervention (P < .01), while insulin delivery was reduced (P < .01). During both day and night, participants recovered from hypoglycaemia faster when treated by closed‐loop intervention. At 120 minutes post hypoglycaemia, sensor glucose levels were higher during closed‐loop intervention compared to the control period (P < .05). In conclusion, closed‐loop intervention reduces the risk of hypoglycaemia, particularly overnight, with swift recovery from hypoglycaemia leading to higher 2‐hour post‐hypoglycaemia glucose levels.     

Plasma glucose and hypoglycaemia following exercise in people with Type 1 diabetes: a comparison of three basal insulins

Aim The aim of this study was to compare the effects of exercise on plasma glucose excursions when using each of three basal insulins in people with Type 1 diabetes. Research design and methods This was a multinational, open‐label, randomized, three‐period, crossover clinical trial. People with Type 1 diabetes [n = 51, age 39 ± 10 (± sd ) years, 67% men] managed with mealtime plus basal insulin regimens, were exercised for 30 min, 5 h after the last mealtime and basal insulin injection when using insulin detemir, insulin glargine or neutral protamine Hagedorn (NPH) insulin. Results There were no significant differences in the plasma glucose excursions during or for 150 min after exercise. During 30 min exercise, five (11%) participants on insulin detemir developed minor hypoglycaemia, six (12%) for NPH and 18 (38%) for glargine. From the end of exercise to 150 min, five (11%) on insulin detemir developed minor hypoglycaemia, seven (14%) for NPH and nine (19%) for glargine. In total, from start of exercise to 150 min after exercise, 10 (21%) participants on insulin detemir experienced minor hypoglycaemia as compared with 13 (27%) for NPH and 27 (57%) for glargine (P < 0.001 glargine vs. detemir and NPH). Maximum plasma cortisol levels were lower on detemir and NPH than glargine. Conclusions Insulin detemir was associated with less hypoglycaemia than insulin glargine but not NPH insulin in relatively well‐controlled people with Type 1 diabetes during and after exercise.     

A comparison of glycemic effects of glimepiride, repaglinide, and insulin glargine in type 2 diabetes mellitus during Ramadan fasting

Although diabetics may be exempted from Ramadan fasting, many patients still insist on this worship. Aim of the present study is to compare the effects of glimepiride, repaglinide, and insulin glargine in type 2 diabetics during Ramadan fasting on the glucose metabolism. Patients, who were willing to fast, were treated with glimepiride (n=21), repaglinide (n=18), and insulin glargine (n=10). Sixteen non-fasting control type 2 diabetics matched for age, sex, and body mass index were also included. Fasting blood glucose (FBG), post-prandial blood glucose (PBG), HbA1c, and fructosamine as well as lipid metabolism were evaluated in pre-Ramadan, post-Ramadan, and 1-month post-Ramadan time points. There was no significant change from pre-Ramadan in FBG, PBG, and HbA1c variables in fasting diabetics at post-Ramadan and 1-month post-Ramadan. However, PBG was found higher in non-fasting control diabetics at post-Ramadan and 1-month post-Ramadan (p<0.05 and p<0.001, respectively). In fructosamine levels, a significant increase was noted both in fasting group and non-fasting group at 1-month post-Ramadan (p<0.01 for all). However, no significant difference was found in the comparison of the changes in fructosamine levels between fasting group and non-fasting group. Risk of hypoglycemia did not significantly differ between fasting and non-fasting diabetics. There was no significant difference between three drug therapies regarding glucose metabolism and rate of hypoglycemia. No adverse effects on plasma lipids were noted in fasting diabetics. In this fasting sample of patients with type 2 diabetes, glimepiride, repaglinide, and insulin glargine did not produce significant changes in glucose and lipid parameters.     

Effects of switching from NPH insulin to insulin glargine in patients with type 2 diabetes: the retrospective,observational LAUREL study in Italy

The aim was to observe the effects of switching from neutral protamine Hagedorn (NPH) insulin to insulin glargine on glycaemic control in patients with type 2 diabetes mellitus (T2DM) in everyday clinical practice in Italy. This multicenter, observational, retrospective study included 1,011 patients with T2DM who switched from NPH insulin to glargine or were maintained on NPH insulin. The primary outcome was change in HbA1c over 4–8 months. Secondary outcomes included fasting blood glucose (FBG), insulin dose, and hypoglycaemia. The intention-to-treat population consisted of 996 patients (glargine 496; NPH 500). Prior to switching, HbA1c was higher in the glargine than the NPH group [mean (±SD) 8.8 ± 1.4 vs. 7.9 ± 1.2 %; p < 0.001]. HbA1c decreased after 4–8 months with glargine (8.2 ± 1.4 %; p < 0.001) but not with NPH (8.0 ± 1.4 %; p = 0.20). Similar results were observed for FBG. The daily dose of glargine increased from 0.22 ± 0.10 U/kg at the switch to 0.26 ± 0.11 U/kg at study end, while the NPH dose remained stable (0.19 ± 0.09–0.20 ± 0.09 U/kg). While not statistically significant, the percentage of patients with hypoglycaemic episodes during the last month of treatment tended to be less with glargine. No significant change in body weight occurred in either group. Switching patients from NPH insulin to insulin glargine in a real-life setting was associated with significant improvement in glycaemic control. The increase in glargine dose was not accompanied by increased hypoglycaemia or weight gain.     

Effect of insulin glargine on glycaemic control and weight in obese and non‐obese people with type 2 diabetes: data from the AT.LANTUS trial

Aims: To explore glucose lowering response to insulin initiation or switch to insulin glargine in obese and non‐obese individuals with type 2 diabetes mellitus (T2DM) and to examine weight gain and hypoglycaemic episodes in this group. Methods: Post hoc subgroup analysis using data of obese and non‐obese participants from a large multi‐centre (4555 participants with T2DM), multi‐national 24‐week randomized controlled trial of investigator titrated insulin glargine versus patient self‐managed titrated insulin glargine. This analysis was carried out to compare two subgroups: obese (≥30 kg/m²) and non‐obese (<30 kg/m²) participants. Results: The mean body mass index (BMI) values were 33.7 kg/m²(n = 1833) and 25.9 kg/m²(n = 2755) in obese and non‐obese subjects, respectively. There was a significant reduction in glycated haemoglobin (HbA1c) from baseline in both subgroups but no significant difference between subgroups (1.15 vs. 1.15%, p = 0.50). Overall, there was a 1.21 kg (s.d. 3.3) increase in weight in individuals who were non‐obese and a 1.08 kg (s.d. 3.9) increase in obese individuals (p = 0.67). There was no significant difference in the proportion of participants achieving an HbA1c of <7.0% at 6 months in both the subgroups (28.8 vs. 27.1%, p = 0.20). In multiple logistic regression, BMI was not a prognostic factor in achieving a target of HbA1c ≤ 7.0%. There was no significant difference in severe hypoglycaemic episodes between obese and non‐obese subgroups (1.3 vs. 1.0%); however, significantly more non‐obese individuals experienced nocturnal hypoglycaemic episodes(4.5 vs. 2.4%, p < 0.05). Conclusions: In this study, treatment with insulin glargine in people with T2DM was associated with a significant reduction in HbA1c without differential increase in weight gain in obese and non‐obese subgroups. Rates of severe hypoglycaemia were not different between obese and non‐obese subgroups.     

Glargine is superior to neutral protamine Hagedorn for improving glycated haemoglobin and fasting blood glucose levels during intensive insulin therapy

AIM: To compare glycaemic control and symptomatic hypoglycaemia rates with glargine versus neutral protamine Hagedorn (NPH) in poorly controlled type 1 diabetes patients. METHODS: Patients (n = 125) received preprandial insulin lispro and either glargine (n = 62) or NPH (n = 63) at bedtime for 30 weeks in a multicentre, randomized, single-blind (a blinded investigator made titration decisions) study. Basal insulin dosage was titrated to achieve fasting blood glucose (FBG) values < 5.5 mmol/L. RESULTS: Baseline characteristics were similar for the two groups (mean diabetes duration 17.5 +/- 10.1 years) except mean glycated haemoglobin (HbA(1c)), which was lower in the glargine versus NPH group (9.2 +/- 1.1% vs 9.7 +/- 1.3%; P < 0.02). At end-point, mean HbA(1c) was 8.3 versus 9.1% for the glargine versus NPH groups. Adjusted least-squares mean (LSM) change from baseline was -1.04 versus -0.51%, a significant treatment benefit of 0.53% for HbA(1c) in favour of glargine (P < 0.01). Mean baseline FBG were similar for the glargine and NPH groups (11.2 vs 11.4 mmol/L). The means for end-point FBG were 7.9 versus 9.0 mmol/L. Adjusted LSM change from baseline was -3.46 versus -2.34 mmol/L, with a significant difference of 1.12 mmol/L in favour of glargine (P < 0.05). There were similar total numbers of daytime mild, moderate or severe hypoglycaemia episodes in the two treatment arms. However, significantly fewer moderate or severe nocturnal hypoglycaemic episodes were observed in the glargine group (P = 0.04 and P = 0.02). CONCLUSION: Glargine is superior to NPH for improving HbA(1c) and FBG levels during intensive insulin therapy in patients with type 1 diabetes, and is associated with less severe nocturnal hypoglycaemia.     

Comparison of glycaemic control in patients with Type 2 diabetes on basal insulin and fixed combination oral antidiabetic treatment: results of a pilot study

This randomised, open-label, two-way cross-over study compared the coefficient of variance (CV) of fasting and postprandial blood glucose (FBG and PPBG) with insulin glargine (glargine) versus neutral protamine Hagedorn (NPH) insulin treatment in patients with Type 2 diabetes (T2DM). Patients (N = 20) on oral antidiabetic drugs (OADs) were treated with NPH (at bedtime) or glargine (at dinnertime) for 12 weeks of each cross-over treatment period; OADs were continued. The FBG CV was calculated from self-monitored BG values and PPBG using venous blood samples, or continuous glucose monitoring system (CGMS). Both insulins provided similar improvements in glycaemic control; however, PPBG was significantly lower after a standard meal test (performed at 13:00 h the day after insulin injection) with glargine versus NPH (p = 0.02). Thirteen versus 15 patients experienced ≥1 episode of hypoglycaemia with glargine versus NPH. The results suggest that glargine plus OADs is more effective in reducing PPBG fluctuations during the day than NPH plus OADs.     

Insulin lispro (Lys(B28), Pro(B29) in the treatment of diabetes during the fasting month of Ramadan. Ramadan Study Group.

AIMS: To compare insulin lispro with soluble human insulin in patients with Type 2 diabetes mellitus fasting during Ramadan, with respect to the rate of hypoglycaemic episodes and postprandial blood glucose values after the main meal after sunset. METHODS: The insulins were compared in an open-label, randomized, cross-over study of 70 outpatients. Hypoglycaemic episodes were recorded by the patients in a self-monitoring diary. Fasting, 1-h and 2-h postprandial blood glucose values were recorded by the patient on three consecutive days at the end of each treatment period. RESULTS: The fasting blood glucose values before sunrise (P>0.4) and after sunset (P>0.6) were similar and did not differ significantly between both treatment groups. The rise in blood glucose after the main meal after sunset was 3.0+/-0.4 mmol/l after 1 h in the insulin lispro treatment group compared to 4.3+/-0.4 mmol/l in the soluble insulin treatment group (P<0.01), and 2.6+/-0.4 mmol/l after 2h with insulin lispro compared to 4.0+/-0.5 mmol/l with soluble insulin (P<0.008). Mean hypoglycaemic episodes per patient over 14 days were 1.3+/-0.1 vs. 2.6+/-0.2, P<0.002, respectively, for insulin lispro and soluble insulin. Most hypoglycaemic episodes occurred during the time period from 6 h after the before sunrise meal until breaking the fast after sunset. CONCLUSIONS: The significantly lower rate of hypoglycaemic episodes combined with better control of postprandial blood glucose suggest insulin lispro may be more suitable prandial insulin for patients treated with Type 2 diabetes who fast during Ramadan.     

Better glycaemic control with BioChaperone glargine lispro co-formulation than with insulin lispro Mix25 or separate glargine and lispro administrations after a test meal in people with type 2 diabetes

Because of its physico-chemical properties, insulin glargine is usually not mixable with rapid insulins. BioChaperone BC147 is a polyanionic amphiphilic polymer, solubilizing insulin glargine at neutral pH, and thus enabling stable glargine formulation with fast-acting insulin lispro (BioChaperone glargine lispro co-formulation [BC Combo]). We investigated pharmacokinetic (PK) endpoints and postprandial glucose (PPG) control after administration of BC Combo (75% insulin glargine, 25% insulin lispro), insulin lispro Mix25 (LMix) and separate injections of insulins glargine (75% total dose) and lispro (25% total dose [G + L]) immediately before ingestion of a mixed meal in people with type 2 diabetes mellitus (T2DM), using a randomized, double-blind, double-dummy crossover study design. Participants received individualized bolus doses (mean 0.62 U/kg) of BC Combo, LMix or G + L, together with a solid mixed meal (610 kcal, 50% carbohydrate, 30% fat, 20% protein). Insulin dosages were kept constant for each study day. Thirty-nine participants with T2DM (mean ± SD age and glycated haemoglobin 60.8 ± 7.5 years and 64 ± 6 mmol/mol, respectively) were randomized. BC Combo improved the predefined primary endpoint, early PPG control, compared to LMix (incremental area under the blood glucose concentration–time curve from 0 to 2 hours after the meal [ΔAUC_BG,0–2h] reduction of 18%; P = 0.0009) and G + L (ΔAUC_BG,0–2h reduction of 10%; P = 0.0450). The number of mealtime hypoglycaemic episodes per participant was lower with BC Combo (22 episodes in 14 participants) compared to LMix (43 episodes in 20 participants; P = 0.0028), but not significantly different from G + L (28 episodes in 19 participants; P = 0.2523). BC Combo demonstrated superior early PPG control with fewer hypoglycaemic episodes compared to LMix and superior early PPG control compared to separate G + L administrations.     

在斋月前、中、后评价2型糖尿病患者甘精胰岛素和格列美脲联合治疗的安全性

在斋月前、中、后期比较甘精胰岛素和格列美脲联合治疗2型糖尿病患者低血糖事件发生的情况.在甘精胰岛素联合格列美脲联合治疗的方案下,斋月前、中、后期低血糖的发生没有差异(P=0.238).     

Determining the optimal fasting glucose target for patients with type 2 diabetes: Results of the multicentre,open-label,randomized-controlled FPG GOAL trial

The optimal fasting blood glucose (FBG) target of achieving HbA1c less than 7.0% in type 2 diabetes (T2D) patients remains controversial. This open-label trial randomized (1:3:3) 947 adults with uncontrolled T2D (HbA1c >7% to ≤10.5%) who were using one to three oral antidiabetic drugs to achieve an FBG target of 3.9 < FBG ≤5.6 mmol/L (Group 1), 3.9 < FBG ≤6.1 mmol/L (Group 2) or of 3.9 < FBG ≤7.0 mmol/L (Group 3). Targets were achieved using a pre-defined insulin glargine 100 U/mL titration scheme. The primary endpoint was proportion of patients achieving HbA1c <7.0% at 24 weeks. At 24 weeks, 44.4%, 46.1% and 37.7% of patients achieved HbA1c <7.0% in Groups 1, 2 and 3, respectively (P = 0.017; Group 2 vs Group 3). Alert hypoglycaemia (glucose ≤3.9 mmol/L) was significantly more frequent in Group 1 than in Group 3 (38.9 vs 23.3%; P < 0.001) but was not in Group 2 vs Group 3 (27.5% vs 23.3%; P = 0.177). Clinically important hypoglycaemia (glucose ≤3.0 mmol/L) was reported in 4.8%, 2.0% and 3.8% of patients in Groups 1, 2 and 3, respectively. In conclusion, the optimal FBG target for most Chinese patients with T2D appears to be 3.9-6.1 mmol/L.     

Safety and efficacy of glargine compared with NPH insulin for the treatment of Type 2 diabetes: a meta‐analysis of randomized controlled trials

Aims We systematically analysed evidence from randomized controlled trials (RCTs) examining the safety and efficacy of neutral protamine Hagedorn (NPH) insulin and glargine in the management of adults with Type 2 diabetes. Methods Studies were identified by searching medline (1966–March 2007), embase (1974–2007), American Diabetes Association abstract database and the Cochrane Central Register of Controlled Trials using Medical Subject Headings (MeSH) diabetes mellitus, Type 2, insulin, insulin isophane, hypoglycaemic agents and the keywords glargine and NPH. Data on study design, participants, fasting plasma glucose (FPG), glycated haemoglobin (HbA_1c), body weight and hypoglycaemia were independently abstracted by two investigators using a standardized protocol. Results Data from a total of 4385 participants in 12 RCTs were pooled using a random‐effects model. The mean net change (95% confidence interval) for FPG, HbA_1c and body weight for patients treated with NPH insulin as compared with glargine was 0.21 mmol/l (?0.02 to 0.45), 0.08% (?0.04 to 0.21) and ?0.33 kg (?0.61 to ?0.06), respectively, with negative values favouring NPH and positive values favouring glargine. More participants experienced symptomatic and nocturnal hypoglycaemia on NPH than glargine, but there was no significant difference in confirmed or severe episodes. Conclusions We identified no difference in glucose‐lowering between insulin glargine and NPH insulin, but less patient‐reported hypoglycaemia with glargine and slightly less weight gain with NPH in adults with Type 2 diabetes.     

Role of γ‐aminobutyric acid signalling in the attenuation of counter‐regulatory hormonal responses after antecedent hypoglycaemia in healthy men

The attenuated counter‐regulatory response to hypoglycaemia after antecedent hypoglycaemic episodes has been observed in animals to be associated with an increase in γ‐aminobutyric acid (GABA) signalling. We therefore tested the hypothesis that the pharmacological suppression of GABAergic activity during a repeated hypoglycaemic episode enhances counter‐regulatory responses. Fourteen healthy men participated in two experimental sessions each comprising three insulin‐induced hypoglycaemic episodes. Before the third hypoglycaemic episode, participants received the GABA‐antagonistic drug modafinil (200 mg orally) and placebo, respectively. In the placebo condition, the secretion of norepinephrine, adrenocorticotropic hormone, cortisol and growth hormone, and the perception of neuroglycopenic symptoms were attenuated during the third as compared with the first hypoglycaemic episode (each p < 0.05). Modafinil reversed this effect for the noradrenergic response (p < 0.05), while not significantly altering the attenuation of other hormonal responses and symptom perception (p > 0.3). Our findings indicate that increased GABAergic transmission could contribute to aspects of the attenuated counter‐regulatory response after recurrent hypoglycaemia in humans.     

Comparing hormonal and symptomatic responses to experimental hypoglycaemia in insulin‐ and sulphonylurea‐treated Type 2 diabetes

Aims Patients with diabetes rely on symptoms to identify hypoglycaemia. Previous data suggest patients with Type 2 diabetes develop greater symptomatic and hormonal responses to hypoglycaemia at higher glucose concentrations than non‐diabetic controls and these responses are lowered by insulin treatment. It is unclear if this is as a result of insulin therapy itself or improved glucose control. We compared physiological responses to hypoglycaemia in patients with Type 2 diabetes patients treated with sulphonylureas (SUs) or insulin (INS) with non‐diabetic controls (CON). Methods Stepped hyperinsulinaemic hypoglycaemic clamps were performed on 20 subjects with Type 2 diabetes, 10 SU‐treated and 10 treated with twice‐daily premixed insulin, and 10 age‐ and weight‐matched non‐diabetic controls. Diabetic subjects were matched for diabetes duration, glycated haemoglobin (HbA_1c) and hypoglycaemia experience. We measured symptoms, counterregulatory hormones and cognitive function at glucose plateaux of 5, 4, 3.5, 3 and 2.5 mmol/l. Results Symptomatic responses to hypoglycaemia occurred at higher blood glucose concentrations in SU‐treated than INS‐treated patients [3.5 (0.4) vs. 2.6 (0.5) mmol/l SU vs. INS; P = 0.001] or controls [SU vs. CON 3.5 (0.4) vs. 3.0 (0.6) mmol/l; P = 0.05]. They also had a greater increase in symptom scores at hypoglycaemia [13.6 (11.3) vs. 3.6 (6.1) vs. 5.1 (4.3) SU vs. INS vs. CON; P = 0.017]. There were no significant differences in counterregulatory hormone responses or impairment of cognitive function among groups. Conclusions Sulphonylurea‐treated subjects are more symptomatic of hypoglycaemia at a higher glucose level than insulin‐treated subjects. This may protect them from severe hypoglycaemia but hinder attainment of glycaemic goals.     

Mechanism of disopyramide‐induced hypoglycaemia in a patient with Type 2 diabetes

Background Disopyramide, an antiarrhythmia drug, has been reported to cause hypoglycaemia. Pre‐existing factors that increase the concentration of the drug in the blood increase the risk of hypoglycaemia. Furthermore, other factors can also increase the risk of hypoglycaemia even when disopyramide levels are in the therapeutic range. It has been proposed that disopyramide‐induced hypoglycaemia is caused by inhibition of the pancreatic B‐cell K_ATP channels. Case report We report a case of severe disopyramide‐induced hypoglycaemia in a 62‐year‐old woman with Type 2 diabetes taking low‐dose glimepiride treatment. She had not experienced hypoglycaemia prior to the start of disopyramide therapy. No further hypoglycaemic episodes occurred following withdrawal of disopyramide therapy. Functional study Current recordings of K_ATP channels expressed in Xenopus oocytes showed that at their estimated therapeutic concentrations, disopyramide and glimepiride inhibited K_ATP channels by about 50–60%. However, when both drugs were applied together, K_ATP channels were almost completely closed (~95%). Such dramatic inhibition of K_ATP channels is sufficient to cause B‐cell membrane depolarization and stimulate insulin secretion. Conclusions Disopyramide therapy is not recommended for patients treated with K_ATP channel inhibitors.     

Efficacy and safety of adding once-weekly dulaglutide to basal insulin for inadequately controlled type 2 diabetes in Chinese patients (AWARD-CHN3): A randomized,double-blind,placebo-controlled,phase III trial

Aim

To determine the efficacy and safety of once-weekly dulaglutide added to basal insulin in Chinese patients with type 2 diabetes mellitus (T2DM) with inadequate glycaemic control.

Materials and Methods

In the phase III, double-blind AWARD-CHN3 study, Chinese patients with T2DM (N = 291) and glycated haemoglobin (HbA1c) ≥7.0% and ≤11.0% receiving stable doses of basal insulin glargine with metformin and/or acarbose were randomized (1:1) to receive add-on dulaglutide 1.5 mg once weekly or placebo once weekly. The primary endpoint was the superiority of dulaglutide/glargine to placebo/glargine for change from baseline in HbA1c at Week 28.

Results

The least squares (LS) mean ± standard error change in HbA1c from baseline to Week 28 was −2.0 ± 0.08% with dulaglutide/glargine and −1.1 ± 0.07% with placebo/glargine (LS mean difference: −1.0%, 95% confidence interval [CI] –1.1 to −0.8; P < 0.001), and more patients receiving dulaglutide/glargine achieved HbA1c levels <7.0% (75.9% vs. 33.8%; P < 0.001 vs. placebo/glargine). Body weight decreased with dulaglutide/glargine and increased with placebo/glargine (LS mean difference: −1.2 kg, 95% CI –1.8 to – 0.6; P < 0.001). Reductions in fasting serum glucose were greater with dulaglutide/glargine than with placebo/glargine (LS mean difference: −0.8 mmol/L, 95% CI –1.1 to – 0.5; P < 0.001). The incidence of hypoglycaemia was similar with dulaglutide/glargine and placebo/glargine (29.2% vs. 31.3%; P = 0.704); no patient in either group had severe hypoglycaemia. The most common treatment-emergent adverse events with dulaglutide/glargine were decreased appetite (22.2%), diarrhoea (13.2%) and nausea (10.4%).

Conclusions

Dulaglutide added to basal insulin was efficacious and well tolerated in Chinese patients with T2DM.     

In Type 1 diabetic patients with good glycaemic control,blood glucose variability is lower during continuous subcutaneous insulin infusion than during multiple daily injections with insulin glargine

Aims The superiority of continuous subcutaneous insulin infusion (CSII) over multiple daily injections (MDI) with glargine is uncertain. In this randomized cross‐over study, we compared CSII and MDI with glargine in patients with Type 1 diabetes well controlled with CSII. The primary end‐point was glucose variability. Methods Thirty‐nine patients [38.1 ± 9.3 years old (mean ± sd ), diabetes duration 16.6 ± 8.2 years, glycated haemoglobin (HbA_1c) 7.6 ± 0.8%], already on CSII for at least 6 months, were randomly assigned to CSII with lispro or MDI with lispro and glargine. After 4 months they were switched to the alternative treatment. During the last month of each treatment blood glucose variability was analysed using glucose standard deviation, mean amplitude of glycaemic excursions (MAGE), lability index and average daily risk range (ADRR). As secondary end‐points we analysed blood glucose profile, HbA_1c, number of episodes of hypo‐ and hyperglycaemia, lipid profile, free fatty acids (FFA), growth hormone and treatment satisfaction. Results During CSII, glucose variability was 5–12% lower than during MDI with glargine. The difference was significant only before breakfast considering glucose standard deviation (P = 0.011), significant overall using MAGE (P = 0.016) and lability index (P = 0.005) and not significant using ADRR. Although HbA_1c was similar during both treatments, during CSII blood glucose levels were significantly lower, hyperglycaemic episodes were fewer, daily insulin dose was less, FFA were lower and treatment satisfaction was greater than during MDI with glargine. The frequency of hypoglycaemic episodes was similar during both treatments. Conclusions During CSII, glucose variability is lower, glycaemic control better and treatment satisfaction higher than during MDI with glargine.     

Clinical outcomes in real‐world patients with type 2 diabetes switching from first‐ to second‐generation basal insulin analogues: Comparative effectiveness of insulin glargine 300 units/mL and insulin degludec in the DELIVER D+ cohort study

Aims

To compare clinical outcomes in patients with type 2 diabetes (T2D) switching from insulin glargine 100 units/mL (Gla‐100) or insulin detemir (IDet) to insulin glargine 300 units/mL (Gla‐300) or insulin degludec (IDeg).

Materials and Methods

We conducted a retrospective, observational study of electronic medical records for Gla‐300/IDeg adult switchers (March 1, 2015 to January 31, 2017) with active records for 12‐month baseline (glycated haemoglobin [HbA1c] used a 6‐month baseline period) and 6‐month follow‐up periods. Gla‐300 and IDeg switchers were propensity score‐matched using baseline demographic and clinical characteristics. Outcomes were HbA1c change and goal attainment (among patients with HbA1c captured at follow‐up), and hypoglycaemia with fixed follow‐up (intention‐to‐treat [ITT]; 6 months) and variable follow‐up (on‐treatment [OT]; to discontinuation or 6 months).

Results

Each matched cohort comprised 1592 patients. The mean decrease in HbA1c and HbA1c goal (<7.0% [53 mmol/mol] and <8.0% [64 mmol/mol]) attainment rates were similar for Gla‐300 (n = 742) and IDeg (n = 727) switchers. Using fixed follow‐up (ITT method), hypoglycaemia incidence decreased significantly from baseline with Gla‐300 (all hypoglycaemia: 15.6% to 12.7%; P = .006; hypoglycaemia associated with inpatient/emergency department [ED] encounter: 5.3% to 3.5%; P = .007), but not with IDeg. After adjusting for baseline hypoglycaemia, no significant differences in hypoglycaemia incidence and event rate were found at follow‐up (ITT) for Gla‐300 vs IDeg. Using variable follow‐up (OT), hypoglycaemia incidence was similar in both groups, but Gla‐300 switchers had a lower inpatient/ED hypoglycaemia event rate at follow‐up (adjusted rate ratio 0.56; P = .016).

Conclusions

In a real‐world setting, switching from Gla‐100 or IDet to Gla‐300 or IDeg was associated with similar improvements in glycaemic control and hypoglycaemia in adult patients with T2D.