Better glycaemic control and less hypoglycaemia with insulin glargine 300 U/mL vs glargine 100 U/mL: 1‐year patient‐level meta‐analysis of the EDITION clinical studies in people with type 2 diabetes

Aims

To investigate the efficacy and safety of insulin glargine 300 U/mL (Gla‐300) vs insulin glargine 100 U/mL (Gla‐100) over 12 months in a patient‐level meta‐analysis, using data from the EDITION studies in people with type 2 diabetes (T2DM).

Methods

EDITION 1, 2 and 3 were multicentre, randomized, open‐label, 2‐arm, parallel‐group, treat‐to‐target phase IIIa studies. Similar study designs and endpoints enabled a meta‐analysis to be conducted.

Results

Reductions in glycated haemoglobin (HbA1c) were better sustained over 12 months with Gla‐300 than with Gla‐100 (least squares [LS] mean difference in change from baseline: ?0.10 % [95% confidence interval {CI} ?0.18 to ?0.02] or ?1.09 mmol/mol [95% CI ?2.01 to ?0.20]; P = .0174). Risk of confirmed (≤3.9 mmol/L) or severe hypoglycaemia was 15% lower with Gla‐300 vs Gla‐100 at night (relative risk 0.85 [95% CI 0.77–0.92]) and 6% lower at any time of day (relative risk 0.94 [95% CI 0.90–0.98]). Rates of hypoglycaemia were 18% lower with Gla‐300 vs Gla‐100 at night (rate ratio 0.82 [95% CI 0.67–0.99]), but comparable at any time of day. HbA1c <7.0 % without nocturnal hypoglycaemia was achieved by 24% more participants with Gla‐300 than with Gla‐100 (relative risk 1.24 [95% CI 1.03–1.50]). Severe hypoglycaemia was rare; in both treatment groups the incidence of events at any time of day was ≤3.6%, while rates were ≤0.08 events per participant‐year.

Conclusions

In a broad population of people with T2DM over 12 months, use of Gla‐300 provided more sustained glycaemic control and significantly lower hypoglycaemia risk at night and at any time of day compared with Gla‐100.     

Biosimilar vs originator insulins: Systematic review and meta‐analysis

Biosimilar insulins have expanded the treatment options for diabetes. We compared the clinical efficacy and safety of biosimilar insulins with those of originator insulins by conducting a meta‐analysis. A random‐effects meta‐analysis was performed on randomized controlled trials comparing biosimilar and originator insulins in adults with diabetes. Studies were obtained by searching electronic databases up to December 2017. Ten trials, in a total of 4935 patients, were assessed (2 trials each on LY2963016, MK‐1293, Mylan's insulin glargine and SAR342434, and 1 trial each on FFP‐112 and Basalog). The meta‐analysis found no differences between long‐acting biosimilar and originator insulins with regard to reduction in glycated haemoglobin at 24 weeks (0.04%, 95% confidence interval [CI] –0.01, 0.08; P for efficacy = .14, I² = 0%) or at 52 weeks (0.03%, 95% CI –0.04, 0.1), or reduction in fasting plasma glucose (0.08 mmol/L, 95% CI 0.36, 0.53), hypoglycaemia (odds ratio 0.99, 95% CI 0.96, 1.03), mortality, injection site reactions, insulin antibodies and allergic reactions. Analyses stratified by type of diabetes and prior insulin use yielded similar findings. Similarly, no significant differences were found between short‐acting biosimilar and originator insulins. In summary, our meta‐analysis showed no significant differences in clinical efficacy and safety, including immune reactions, between biosimilar and originator insulins. Biosimilar insulins can increase access to modern insulin therapy and reduce medical costs.     

The effect of pramlintide acetate on glycemic control and weight in patients with type 2 diabetes mellitus and in obese patients without diabetes: a systematic review and meta-analysis

Aim: The objective of this systematic review and meta‐analysis was to assess the effect of pramlintide on glycemic control, weight and incidence of nausea and hypoglycaemia in patients with type 2 diabetes mellitus (T2DM) and in obese patients without diabetes (OBP). Methods: Eight randomized, clinical trials were identified from multiple databases. Qualitative assessments and quantitative analyses were performed. Results: In four T2DM studies (N = 930,duration of studies 16–52weeks,120–150mcg/dose BID–TID), all patients received insulin therapy. In four obesity studies (N = 686,duration of studies 6–24weeks,120–360mcg/dose BID–TID), equivalent volumes of placebo were administered before major meals. Pramlintide significantly reduced haemoglobin A1c (HbA1c) (?0.33% [95% CI ?0.51, ?0.14], p = 0.004) and weight (?2.57 kg, [95% CI ?3.44, ?1.70], p < 0.00001) versus the control group. More patients in the control group reported hypoglycaemia of any severity versus the pramlintide group (risk ratio 0.84 [95% CI 0.69, 10.3], p = 0.09). In OBP, pramlintide caused a reduction in weight (?2.27 kg [95% CI ?2.88, ?1.66], p < 0.00001). When event data from both populations were combined, patients randomized to pramlintide were 1.8 times more likely to report nausea of any severity versus control (p = 0.0005). Conclusions: Pramlintide was associated with a small reduction in HbA1c, and a modest reduction in weight in patients with T2DM or OBP. There was increased incidence of nausea but not hypoglycaemia at any time during therapy. Studies about the long‐term effect of pramlintide on diabetes‐ and cardiovascular‐related complications and cost‐effectiveness analyses are needed.     

Glucagon-like peptide-1 receptor agonists versus insulin in inadequately controlled patients with type 2 diabetes mellitus: a meta-analysis of clinical trials

To compare the effect and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RA) with insulin therapy on type 2 diabetes mellitus (T2DM) patients inadequately controlled with metformin and/or sulfonylurea. A systematic literature search on MEDLINE, Embase and Cochrane for randomized controlled trials (RCTs) was conducted using specific search terms 'GLP-1 insulin type 2 diabetes clinical trials' and eight eligible studies were retrieved. Data on mean change in haemoglobin A1c (HbA1C), weight loss, fasting plasma glucose (FPG), incidence of hypoglycaemia and gastrointestinal adverse events were extracted from each study and pooled in meta-analysis. Data on postprandial plasma glucose (PPG) and adverse events were also described or tabulated. Data from eight RCTs enrolling 2782 patients were pooled using a random-effects model. The mean net change [95% confidence interval (CIs)] for HbA1c, weight loss and FPG for patients treated with GLP-1 RA as compared with insulin was -0.14% (-2 mmol/mol) [95% CI; (-0.27, -0.02)%; p = 0.03]; -4.40 kg [95% CI; (-5.23, -3.56) kg; p < 0.01] and 1.18 mmol/l [95% CI; (0.43, 1.93) mmol/l; p < 0.01], respectively, with negative values favouring GLP-1 and positive values favouring insulin. The GLP-1 group was associated with a greater reduction in PPG than the insulin group. Overall, hypoglycaemia was reported less in the GLP-1 group [Mantel-Haenszel odds ratio (M-H OR) 0.45 (0.27, 0.76); p < 0.01], while there was no significant difference in occurrence of severe hypoglycaemia [M-H OR 0.65 (0.29,1.45); p = 0.29]. A significantly higher number of gastrointestinal adverse events were reported with GLP-1 group [M-H OR 15.00 (5.44,41.35) p < 0.01]. GLP-1 RA are promising new agents compared with insulin. Further prospective clinical trials are expected to fully evaluate the long-term effectiveness and safety of these therapies within the T2DM treatment paradigm.     

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.     

Glycaemia and cardiac arrhythmias in people with type 1 diabetes: A prospective observational study

Aim

To investigate the impact of hypoglycaemia, hyperglycaemia and glycaemic variability on arrhythmia susceptibility in people with type 1 diabetes.

Materials and Methods

Thirty adults with type 1 diabetes were included in a 12-month observational exploratory study. Daytime and night-time incident rate ratios (IRRs) of arrhythmias were determined for hypoglycaemia (interstitial glucose [IG] <3.9 mmol/L), hyperglycaemia (IG >10.0 mmol/L) and glycaemic variability (standard deviation and coefficient of variation).

Results

Hypoglycaemia was not associated with an increased risk of arrhythmias compared with euglycaemia and hyperglycaemia combined (IG ≥ 3.9 mmol/L). However, during daytime, a trend of increased risk of arrhythmias was observed when comparing time spent in hypoglycaemia with euglycaemia (IRR 1.08 [95% CI: 0.99-1.18] per 5 minutes). Furthermore, during daytime, both the occurrence and time spent in hyperglycaemia were associated with an increased risk of arrhythmias compared with euglycaemia (IRR 2.03 [95% CI: 1.21-3.40] and IRR 1.07 [95% CI: 1.02-1.13] per 5 minutes, respectively). Night-time hypoglycaemia and hyperglycaemia were not associated with the risk of arrhythmias. Increased glycaemic variability was not associated with an increased risk of arrhythmias during daytime, whereas a reduced risk was observed during night-time.

Conclusions

Acute hypoglycaemia and hyperglycaemia during daytime may increase the risk of arrhythmias in individuals with type 1 diabetes. However, no such associations were found during night-time, indicating diurnal differences in arrhythmia susceptibility.     

Sodium‐glucose co‐transporter 2 inhibitors in addition to insulin therapy for management of type 2 diabetes mellitus: A meta‐analysis of randomized controlled trials

Given inconsistent trial results of sodium‐glucose cotransporter 2 (SGLT2) inhibitors in addition to insulin therapy for treating type 2 diabetes mellitus (T2DM), a meta‐analysis was performed to evaluate the efficacy and safety of this combination for T2DM by searching available randomized trials from PubMed, Embase, CENTRAL and ClinicalTrials.gov . Our meta‐analysis included seven eligible placebo‐controlled trials involving 4235 patients. Compared with placebo, SGLT2 inhibitor treatment was significantly associated with a mean reduction in HbA1c of ?0.56%, fasting plasma glucose of ?0.95 mmol/L, body weight of ?2.63 kg and insulin dose of ?8.79 IU, but an increased risk of drug‐related adverse events by 36%, urinary tract infections by 29% and genital infections by 357%. No significant increase was observed in risk of overall adverse events [risk ratio (RR), 1.00], serious adverse events (RR, 0.90), adverse events leading to discontinuation (RR, 1.16), hypoglycaemia events (RR, 1.07) and severe hypoglycaemia events (RR, 1.24). No diabetic ketoacidosis events were reported. Further studies are needed to establish optimal combination type and dose.     

Sodium‐glucose co‐transporter‐2 inhibitors as add‐on therapy to insulin for type 1 diabetes mellitus: Systematic review and meta‐analysis of randomized controlled trials

New treatments for type 1 diabetes are an unmet need. We investigated the efficacy and safety of adding sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors to insulin for type 1 diabetes by conducting a meta‐analysis of prospective randomized, placebo‐controlled trials. A search of electronic databases up to October 2017 identified 1361 studies, of which 14 were investigated (N = 4591). Meta‐analysis showed that SGLT2 inhibitor therapy significantly reduced glycated haemoglobin (HbA1c) concentration by 0.4% (95% confidence interval [CI] 0.35, 0.46; P < .001, I² = 0%), fasting plasma glucose by 1.14 mmol/L (95% CI 0.8,1.47), body weight by 2.68 kg (95% CI 2.0, 3.36), and systolic blood pressure by 3.37 mmHg (95% CI 1.46, 5.28). In addition, bolus insulin decreased by 3.6 units/day (95% CI 2.0, 5.3), and basal insulin decreased by 4.2 units/day (95% CI 2.2, 6.3). Continuous glucose monitoring showed a decrease in glucose excursions compared with placebo, with reduced variation of mean blood glucose, glucose standard deviation, and mean amplitude of glucose excursion. There was no significant increase in the rate of hypoglycaemia or severe hypoglycaemia; however, SGLT2 inhibitor therapy increased diabetic ketoacidosis (odds ratio [OR] 3.38) and genital tract infection (OR 3.44). Add‐on SGLT2 inhibitor therapy might be advantageous for type 1 diabetes, but its use should be considered carefully.     

Glycaemic control and hypoglycaemia in people with type 2 diabetes switching from twice‐daily basal insulin to once‐daily insulin glargine 300 U/mL or insulin glargine 100 U/mL (EDITION 1 and EDITION 2 subgroup analysis)

In this post hoc analysis we compared glycaemic control and hypoglycaemia between insulin glargine 300 U/mL (Gla‐300) and glargine 100 U/mL (Gla‐100) administered once daily in people with type 2 diabetes (T2DM) from the EDITION 1 (basal plus mealtime insulin) and EDITION 2 (basal insulin plus oral antihyperglycaemic drugs) trials who were previously receiving twice‐daily insulin. At randomization, 16.9% and 20.0% of people in EDITION 1 and 2, respectively, were receiving twice‐daily basal insulin. Glycated haemoglobin change from baseline to Month 6 was similar over 6 months with Gla‐300 or Gla‐100 (least squares mean difference ?0.01%; 95% confidence interval [CI] ?0.27 to 0.24] in EDITION 1 and 0.16%; 95% CI ?0.25 to 0.57, in EDITION 2). Participants previously receiving twice‐daily insulin in EDITION 1 had a lower risk of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia with Gla‐300 vs Gla‐100 at night (00:00–05:59 hours), but not at any time (24 hours); in EDITION 2 the risk was reduced at night and any time (24 hours). In conclusion, Gla‐300 provided similar glycaemic control with less hypoglycaemia compared with Gla‐100 in people with T2DM switching from twice‐daily to once‐daily basal insulin.     

Free and fixed‐ratio combinations of basal insulin and GLP‐1 receptor agonists versus basal insulin intensification in type 2 diabetes: A systematic review and meta‐analysis of randomized controlled trials

A meta‐analysis is presented of randomized controlled trials (RCTs) comparing free or fixed combinations of a glucagon‐like peptide‐1 receptor agonist plus basal insulin versus insulin intensification on metabolic control in patients with type 2 diabetes. Electronic databases were searched for RCTs assessing changes in HbA1c, proportion of patients at HbA1c target of <7% (53 mmol/mol), hypoglycaemia and body weight. A random‐effect model was used to calculate the weighted mean difference (WMD) or relative risk (RR) with 95% CI. Eleven RCTs were identified, lasting 24–30 weeks and involving 6176 patients. In the overall analysis, the combination therapy led to a mean HbA1c decrease significantly greater than insulin up‐titration (WMD ?0.53%, 95% CI, ?0.66, ?0.40%, P < 0.001), more patients at HbA1c target (RR 1.69, 95% CI, 1.42, 2.00, P < 0.001), similar hypoglycaemic events (RR 0.97, 95% CI, 0.84, 1.12, P = 0.114), and reduction in body weight (WMD ?1.9, 95% CI ?2.3, ?1.4, P < 0.001), with heterogeneity (I² > 71%, P < 0.001). Results did not differ in either the free or fixed combination subgroups. Combination strategies, either free or fixed, represent a good option for intensifying basal insulin therapy in patients with type 2 diabetes who need amelioration of glycaemic control.     

Efficacy of basal‐bolus insulin regimens in the inpatient management of non‐critically ill patients with type 2 diabetes: A systematic review and meta‐analysis

Hyperglycemia during hospitalization is associated with increased rates of complications and longer hospital stays. Various insulin regimens are used in the inpatient diabetes management of non‐critically ill patients. In this systematic review and meta‐analysis, we aimed to assess the efficacy and safety of basal‐bolus insulin therapy (BBI) by summarizing evidence from studies of BBI versus sliding scale insulin therapy (SSI) in the management of hospitalized non‐critically ill type 2 diabetes patients. We searched MEDLINE, EMBASE, Scopus, and the Cochrane Library for studies comparing BBI therapy with SSI therapy in hospitalized non‐critically ill patients with type 2 diabetes. Primary outcome was mean daily blood glucose (BG) during admission. Secondary outcomes were incidence of hypoglycemia and length of hospital stay. Results of included randomized controlled trials (RCT) were pooled and meta‐analysed to provide estimates of the efficacy of BBI therapy. Five RCTs and seven observational studies were included in the review. Meta‐analysis of RCTs showed significantly lower mean daily BG with BBI than SSI. Mean difference in daily BG between the two regimens ranged from 14 to 29 mg/dl. BBI therapy was associated with increased risk of mild hypoglycemia (BG ≤ 70 mg/dl, RR 5.75; 95% CI 2.79‐11.83), (BG ≤ 60 mg/dl, RR 4.21; 95% CI 1.61‐11.02) compared with SSI therapy. There was no difference in risk of severe hypoglycemia (BG ≤ 40 mg/dl) and no difference in mean length of stay. In conclusion, basal‐bolus insulin in the inpatient diabetes management results in significantly lower mean daily BG than sliding scale insulin but is associated with increased risk of mild hypoglycemia.     

Association of Thiazide‐Type Diuretics With Glycemic Changes in Hypertensive Patients: A Systematic Review and Meta‐Analysis of Randomized Controlled Clinical Trials

Patients receiving thiazide diuretics have a higher risk of impaired glucose tolerance or even incident diabetes, but the change of blood glucose level varies across different trials. The aim of this study was to investigate the glycemic changes in hypertensive patients with thiazide‐type diuretics. Twenty‐six randomized trials involving 16,162 participants were included. Thiazide‐type diuretics were found to increase fasting plasma glucose (FPG) compared with nonthiazide agents or placebo or nontreatment (mean difference [MD], 0.27 mmol/L [4.86 mg/dL]; 95% confidence interval [CI], 0.15–0.39). Patients receiving lower doses of thiazides (hydrochlorothiazide or chlorthalidone ≤25 mg daily) had less change in FPG (MD, 0.15 mmol/L [2.7 mg/dL]; 95% CI, 0.03–0.27) than those receiving higher doses (MD, 0.60 mmol/L [10.8 mg/dL]; 95% CI, 0.39–0.82), revealed by the subgroup analysis of thiazides vs calcium channel blockers. Thiazide‐type diuretics are associated with significant but small adverse glycemic effects in hypertensive patients. Treatment with a lower dose might reduce or avoid glycemic changes.     

Effect of antidiabetic agents added to metformin on glycaemic control, hypoglycaemia and weight change in patients with type 2 diabetes: a network meta-analysis

Aim: Most guidelines recommend metformin as first‐line therapy in patients with type 2 diabetes. However, the choice of a second‐line drug lacks consistent consensus. We aimed to assess available information of antidiabetic drugs added to metformin on the change in glycated haemoglobin A1c (A1C), risk of hypoglycaemia and change in body weight. Methods: PubMed and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) written in English through December 2011. We analysed direct and indirect comparisons of different treatments using Bayesian network meta‐analysis. Results: Thirty‐nine RCTs involving 17 860 individuals were included. Glucagon‐like peptide‐1 (GLP‐1) analogues resulted in greater decrease in A1C compared with sulfonylureas, glinides, thiazolidinediones, α‐glucosidase inhibitors and DPP‐4 inhibitors [?0.20% (95% CI ?0.34 to ?0.04%), ?0.31% (95% CI ?0.61 to ?0.02%), ?0.20% (95% CI ?0.38 to ?0.00), ?0.36% (95% CI ?0.64 to ?0.07%), ?0.32% (95% CI ?0.47 to ?0.17%), respectively] and was comparable with basal insulin and biphasic insulin. A1C decrease was greater for sulfonylureas compared with DPP‐4 inhibitors [?0.12% (?0.23 to ?0.03%)], and for biphasic insulin compared with glinides (?0.36%; 95% CI ?0.82 to ?0.11%). Compared with placebo, the risk of hypoglycaemia was increased in the sulfonylureas, glinides, basal insulin and biphasic insulin. Weight increase was seen with sulfonylureas, glinides, thiazolidinediones, basal insulin and biphasic insulin, and weight loss was seen with α‐glucosidase inhibitors and GLP‐1 analogues. Conclusions: Biphasic insulin, GLP‐1 analogues and basal insulin were ranked the top three drugs in terms of A1C reduction. GLP‐1 analogues did not increase the risk of hypoglycaemia and resulted in a significant decrease in body weight. Most oral antidiabetic drugs had similar effects on A1C, but some agents had a lower risk of hypoglycaemia and body weight gain.     

Effects of sodium‐glucose cotransporter (SGLT) inhibitors in addition to insulin therapy on glucose control and safety outcomes in adults with type 1 diabetes: A meta‐analysis of randomized controlled trials

Sodium‐glucose cotransporter (SGLT) inhibitors added to insulin therapy have been proposed as treatment strategy for type 1 diabetes (T1D). We thus conducted a meta‐analysis of randomized controlled trials (RCTs) to assess the efficacy and adverse effects of this combination in T1D. We searched the PubMed, EMBASE, and Cochrane Library databases and ClinicalTrials.gov for RCTs. Statistical analyses were performed using STATA 15. Ten eligible placebo‐controlled trials involving 5961 patients were included. Compared with placebo, SGLT inhibitors were associated with a reduction in HbA1c of ?0.39% (95% CI, ?0.43 to ?0.36), an improved mean amplitude of glucose excursion (MAGE) of ?14.81 mg/dL (95% CI, ?19.08 to ?10.54), and a reduction in body weight of ?3.47% (95% CI, ?3.78 to ?3.16), as well as no increased relative risk of hypoglycaemia (1.01; 95% CI, 0.99‐1.02) or severe hypoglycaemia (0.91; 95% CI, 0.77‐1.07). SGLT inhibitors decreased fasting plasma glucose and insulin requirement but increased the risk of genital infection (3.57; 95% CI, 2.97‐4.29) and diabetic ketoacidosis (3.11; 95% CI, 2.11‐4.58). However, the very low dose empagliflozin (2.5 mg) did not increase the risk of diabetic ketoacidosis (risk ratio [RR] 0.67; 95% CI, 0.11‐3.95). SGLT inhibitors had no effect on overall adverse events, urinary tract infection, or bone fracture but slightly increased the risk of serious adverse events (1.35; 95% CI, 1.16‐1.58), severe adverse events (1.84; 95% CI, 1.20‐2.84), adverse events leading to discontinuation (1.50; 95% CI, 1.22‐1.84), drug‐related adverse events (1.78; 95% CI, 1.44‐2.19), and diarrhoea (1.54; 95% CI, 1.15‐2.05). Although adverse events exist, the available data provide evidence that the combination of SGLT inhibitors with basal insulin treatment is beneficial in patients with T1D.     

More patients reach glycaemic control with a fixed‐ratio combination of insulin glargine and lixisenatide (iGlarLixi) than with basal insulin at 12 weeks of treatment: A post hoc time‐to‐control analysis of LixiLan‐O and LixiLan‐L

The present post hoc analysis of two 30‐week clinical trials compared efficacy and hypoglycaemia outcomes at early study visits with iGlarLixi (insulin glargine U100 [iGlar] and lixisenatide) vs iGlar alone in patients with type 2 diabetes (T2D) uncontrolled on oral antidiabetic drugs (OADs; LixiLan‐O trial) or basal insulin (LixiLan‐L trial). Time to control, defined as days to achieve glycated haemoglobin (HbA1c) <53 mmol/mol (<7%) or fasting plasma glucose (FPG) ≤7.2 mmol/L, was estimated using the Kaplan–Meier method. In the LixiLan‐O and LixiLan‐L trials, 60% and 46% of patients, respectively, reached HbA1c <53 mmol/mol (<7%) with iGlarLixi at 12 weeks, vs 45% and 24%, respectively, with iGlar. In the LixiLan‐O trial, the median time to target HbA1c was approximately half with iGlarLixi vs iGlar (85.0 vs 166.0 days; P < .0001). In the LixiLan‐L trial, the median time to target HbA1c was 153.0 days with iGlarLixi, while target HbA1c was never reached by 50% of patients with iGlar (P < .0001). Time‐to‐target FPG and hypoglycaemia outcomes were similar between treatments. In T2D uncontrolled on OADs or basal insulin, iGlarLixi resulted in glycaemic control in more patients than did iGlar at early treatment time points.     

An analysis of early insulin glargine added to metformin with or without sulfonylurea: impact on glycaemic control and hypoglycaemia

Aim: To evaluate the benefits of initiating insulin at an earlier versus later treatment stage, and regimens with/without sulfonylurea (SU). Methods: Pooled analysis of 11 prospective randomized clinical trials, including 2171 adults with uncontrolled type 2 diabetes initiating insulin glargine following a specific titration algorithm. Clinical outcomes were glycated haemoglobin A1c (HbA1c) reduction, per cent achieving HbA1c ≤ 7.0%, weight gain and hypoglycaemic events. Statistical analysis compared outcomes 24 weeks after basal insulin initiation in patients previously uncontrolled on 0/1 oral antidiabetic drug (OAD) versus 2 OADs, and in patients taking metformin (MET) or SU alone or in combination at baseline. A meta‐analysis was also conducted. Results: For the pooled analysis, patients on 0/1 OAD and those on MET monotherapy at baseline had the largest 24‐week reductions in HbA1c following the addition of insulin glargine (～0.44 U/kg). Of patients failing MET/SU monotherapy and MET + SU in combination, 68.1, 50.4 and 56.4% achieved HbA1c ≤ 7.0%, respectively (p = 0.0006). Weight gain was lowest when basal insulin was added to MET. Patients on 0/1 OAD at baseline had significantly less symptomatic hypoglycaemia when basal insulin was added than those on 2 OADs (p = 0.0007). Despite higher insulin doses, those taking MET alone had less hypoglycaemia than those taking SU or MET + SU. Results were confirmed in the meta‐analysis. Conclusion: Adding insulin glargine to MET monotherapy early in treatment may provide efficacy/safety benefits over regimens including SU. This may reflect treatment earlier in the disease and supports the inclusion of insulin as a second step in the American Diabetes Association/European Association for the Study of Diabetes treatment algorithm.     

Regional variations in definitions and rates of hypoglycaemia: findings from the global HAT observational study of 27 585 people with Type 1 and insulin‐treated Type 2 diabetes mellitus

Aim

To determine participant knowledge and reporting of hypoglycaemia in the non‐interventional Hypoglycaemia Assessment Tool (HAT) study.

Methods

HAT was conducted in 24 countries over a 6‐month retrospective/4‐week prospective period in 27 585 adults with Type 1 or insulin‐treated Type 2 diabetes mellitus. Participants recorded whether hypoglycaemia was based on blood glucose levels, symptoms or both.

Results

Hypoglycaemia rates were consistently higher in the prospective compared with the retrospective period. Most respondents (96.8% Type 1 diabetes; 85.6% Type 2 diabetes) knew the American Diabetes Association/European Association for the Study of Diabetes hypoglycaemia definition, but there were regional differences in the use of blood glucose measurements and/or symptoms to define events. Confirmed symptomatic hypoglycaemia rates were highest in Northern Europe/Canada for Type 1 diabetes (63.9 events/year) and in Eastern Europe for Type 2 diabetes (19.4 events/year), and lowest in South East Asia (Type 1 diabetes: 6.0 events/year; Type 2 diabetes: 3.2 events/year). Unconfirmed symptomatic hypoglycaemia rates were highest in Eastern Europe for Type 1 diabetes (5.6 events/year) and South East Asia for Type 2 diabetes (4.7 events/year), and lowest for both in Russia (Type 1 diabetes: 2.1 events/year; Type 2 diabetes: 0.4 events/year). Participants in Latin America reported the highest rates of severe hypoglycaemia (Type 1 diabetes: 10.8 events/year; Type 2 diabetes 3.7 events/year) and severe hypoglycaemia requiring hospitalization (Type 1 diabetes: 0.56 events/year; Type 2 diabetes: 0.44 events/year). The lowest rates of severe hypoglycaemia were reported in South East Asia (Type 1 diabetes: 2.0 events/year) and Northern Europe/Canada (Type 2 diabetes: 1.3 events/year), and the lowest rates of severe hypoglycaemia requiring hospitalization were in Russia (Type 1 diabetes: 0.15 events/year; Type 2 diabetes: 0.09 events/year). The blood glucose cut‐off used to define hypoglycaemia varied between regions (Type 1 diabetes: 3.1–3.6 mmol/l; Type 2 diabetes: 3.5–3.8 mmol/l).

Conclusions

Under‐reporting of hypoglycaemia rates in retrospective recall and regional variations in participant definitions of hypoglycaemia may contribute to the global differences in reported rates. Discrepancies between participant definitions and guidelines may highlight a need to redefine hypoglycaemia criteria. (Clinical Trials Registry No: NCT01696266).     

Once-weekly dulaglutide versus insulin glargine in the early control of fasting serum glucose and HbA1c

AimsTo determine the early benefit:risk balance of dulaglutide versus insulin glargine in patients with type 2 diabetes mellitus (T2DM).MethodsThis post hoc analysis used data from a randomized, open-label study (AWARD-2; modified intention-to-treat group) in which suboptimally controlled metformin + glimepiride-treated patients received dulaglutide 1.5 mg (n = 273) or insulin glargine (n = 262). Two composite endpoints were used: for weeks 2–20, fasting serum glucose (FSG) <130 mg/dL (<7.2 mmol/L) without hypoglycemia (blood glucose ≤70 mg/dL [≤3.9 mmol/L] or severe hypoglycemia); at week 26, patients with glycated hemoglobin (HbA1c) <7.0% (<53.0 mmol/mol) or reduction from baseline ≥1.0% (≥10.9 mmol/mol), no hypoglycemia (as defined above) and no weight gain. Odds ratios (ORs) were generated using logistic regression analysis.ResultsThe probability of reaching the FSG target without hypoglycemia was higher with dulaglutide than with insulin glargine at weeks 4 (OR 1.78; 95% confidence interval [CI] 1.22–2.60) and 8 (OR 1.69; 95% CI 1.15–2.48). The proportion of patients achieving the 26-week endpoint was higher with dulaglutide (37.4% vs. 10.3%; OR 5.28; 95% CI 3.28–8.48).ConclusionsDulaglutide's balanced efficacy-to-safety profile compares favorably with that of insulin glargine and is apparent soon after treatment initiation and after 6 months of therapy.     

Comparison of insulin degludec with insulin detemir in type 1 diabetes: a 1‐year treat‐to‐target trial

The long‐term safety and tolerability of insulin degludec (IDeg) was compared with that of insulin detemir (IDet), as basal treatment in participants with type 1 diabetes mellitus (T1DM). In the present multinational, 26‐week core + 26‐week extension, controlled, open‐label, parallel‐group trial, adults with T1DM were randomized to IDeg or IDet as basal insulin treatment combined with meal‐time bolus insulin aspart. IDeg was administered once daily, whilst IDet was administered once or twice daily depending on patients' glycaemic control. After 1 year, IDeg provided a 33% lower rate of nocturnal hypoglycaemia compared with IDet: estimated rate ratio (IDeg : IDet) 0.67 [95% confidence interval (CI) 0.51; 0.88]; p < 0.05. IDeg improved glycated haemoglobin after 1 year of treatment, similarly to IDet, but IDeg also provided a significantly greater reduction in fasting plasma glucose compared with IDet: estimated difference (IDeg ? IDet) ?1.11 (95% CI ?1.83; ?0.40) mmol/l; p < 0.05. The present study confirmed the long‐term safety and tolerability profile of IDeg in patients with T1DM. IDeg provided a lower risk of nocturnal confirmed hypoglycaemia than IDet.