When basal insulin is not enough: A dose-response relationship between insulin glargine 100 units/mL and glycaemic control.

AIMS: A post-hoc analysis to assess the impact in people with type 2 diabetes, of increasing doses of basal insulin on glycaemic measures, body weight and hypoglycaemia. RESEARCH DESIGN AND METHODS: We included data from prospective, randomized controlled treat-to-target trials of ≥24 weeks' duration in people with type 2 diabetes, uncontrolled on metformin and sulphonylureas, and treated with insulin glargine 100 units/mL (U100), who had at least six fasting plasma glucose (FPG) measurements. The impact of insulin dose on glycated haemoglobin (HbA1c) values, FPG, hypoglycaemia incidence (<3.9 mmol/L [70 mg/dL]), and body weight was analysed. A total of 458 participants from three eligible trials were included. RESULTS: The observed relationship between higher basal insulin doses and glycaemic control was non-linear, with increasing insulin dose leading to smaller reductions in FPG and HbA1c for doses >0.3 IU/kg/d, with a plateauing effect at 0.5 IU/kg/d. Total daily dose of insulin >0.5 IU/kg/d resulted in greater weight gain, but without higher rates of hypoglycaemia, compared with insulin doses ≤0.5 IU/kg/d. CONCLUSIONS: This analysis indicates that basal insulin doses >0.5 IU/kg/d have diminishing additional impact on improving glycaemic measures, with the disadvantage of additional weight gain. Clinicians should consider anti-hyperglycaemic treatment intensification at doses approaching 0.5 IU/kg/d.

The use of lipid-lowering therapy and effects of antihyperglycaemic therapy on lipids in subjects with type 2 diabetes with or without cardiovascular disease: a pooled analysis of data from eleven randomized trials with insulin glargine 100 U/mL.

BACKGROUND: Dyslipidaemia is a major contributor to the increased risk of cardiovascular disease (CVD) associated with type 2 diabetes (T2D). This study aimed to characterize the extent of lipid-lowering therapy use and its impact on lipid and glycaemic outcomes in people with T2D uncontrolled on oral agents who were enrolled in insulin glargine 100 units/mL (Gla-100) randomized controlled trials (RCTs). METHODS: A post hoc patient-level pooled analysis of eleven RCTs (≥24 weeks' duration) comparing Gla-100 (±oral antidiabetes drugs [OADs]) with OADs alone in people with T2D was performed. Baseline and Week 24 or study endpoint lipid status (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], non-high-density lipoprotein cholesterol [non-HDL-C] and triglycerides) and indices of glycaemic control (glycosylated haemoglobin, fasting plasma glucose [FPG]) were examined in patient groups according to treatment received and CVD status. Lipid-lowering therapy was provided at the discretion of physicians at baseline and throughout the studies. RESULTS: Of the 4768 participants included in the analysis, 41% (n = 1940) received lipid-lowering therapy. Only 51% of participants with CVD (1885/3672) were treated with lipid-lowering therapy; these participants had significantly lower levels of LDL-C, HDL-C and non-HDL-C, and higher levels of triglycerides versus patients not treated with lipid-lowering therapy at baseline and study endpoint (P < 0.001 for all). Antihyperglycaemia therapy resulted in decreases in glycosylated haemoglobin (-1.4 to -1.6%) and FPG (-68.9 to -75.3 mg/dL) at Week 24. Furthermore, slight improvements in non-HDL-C (-3.9 to -9.1 mg/dL) and triglyceride levels (-25.8 to -51.2 mg/dL) were observed. Similar changes were seen irrespective of lipid-lowering therapy or CVD status. CONCLUSIONS: In a T2D cohort included in Gla-100 clinical studies, many participants with T2D and CVD did not receive lipid-lowering therapy, and for most categories of lipid the levels were outside the optimal range. Even in patients treated with antihyperglycaemic therapy but not lipid-lowering therapy, there were modest improvements in non-HDL-C and triglyceride levels in all participants with T2D and CVD. There is a need for increased implementation of guideline recommendations such as American College of Cardiology/American Heart Association for the management of dyslipidaemia in patients with T2D.

Effects of age, gender, and body mass index on efficacy and hypoglycaemia outcomes across treat-to-target trials with insulin glargine 100 U/mL added to oral antidiabetes agents in type 2 diabetes.

AIMS: To analyse the effects of patient characteristics and different oral antidiabetes drug (OAD) use on standardised clinical outcomes in type 2 diabetes patients initiating insulin glargine 100 U/mL (Gla-100). MATERIALS AND METHODS: Patient-level data from 16 randomized, treat-to-target clinical trials that added Gla-100 to existing metformin (MET), sulfonylurea (SU) or metformin plus sulfonylurea (MET+SU) treatment in insulin-naïve patients inadequately controlled by oral therapy were analysed and patients were followed for ≥24 weeks. Change in glycated haemoglobin A1c (HbA1c) from baseline to week 24, other glycaemic endpoints and incidence of hypoglycaemia (overall, nocturnal, and severe) were analysed by age (<65 vs ≥65 years), gender (male vs female), body mass index (BMI; <25 vs ≥25 to <30 vs >30 kg/m2 ) and concomitant OAD (MET vs SU vs MET+SU). RESULTS: At baseline, the overall population (N = 3188) had a mean age of 57.7 years, BMI of 30.5 kg/m2 , HbA1c of 8.7%, fasting plasma glucose of 192 mg/dL, and 52.7% were male. Younger and older patients had similar HbA1c reductions with Gla-100 and a similar risk of hypoglycaemia. Females and patients with BMI <25 kg/m2 were less likely to achieve HbA1c targets and more likely to experience hypoglycaemia, regardless of concomitant OAD. Adding Gla-100 to SU therapy (alone or in combination with MET) increased hypoglycaemia risk across all analyses. CONCLUSIONS: Our data suggest that female patients with type 2 diabetes and normal-weight patients treated with Gla-100 and MET ± SU are less likely to achieve glycaemic targets and, therefore, may require more clinical attention. Addition of Gla-100 to SU regimens may increase hypoglycaemia risk irrespective of age, gender, or BMI.

Patient-level meta-analysis of efficacy and hypoglycaemia in people with type 2 diabetes initiating insulin glargine 100U/mL or neutral protamine Hagedorn insulin analysed according to concomitant oral antidiabetes therapy.

AIMS: Evaluate efficacy and hypoglycaemia according to concomitant oral antidiabetes drug (OAD) in people with type 2 diabetes initiating insulin glargine 100U/mL (Gla-100) or neutral protamine Hagedorn (NPH) insulin once daily. METHODS: Four studies (target fasting plasma glucose [FPG] ⩽100mg/dL [⩽5.6mmol/L]; duration ⩾24weeks) were included. Standardised data from 2091 subjects (Gla-100, n=1024; NPH insulin, n=1067) were analysed. Endpoints included glycated haemoglobin (HbA1c) and FPG change, glycaemic target achievement, hypoglycaemia, weight change, and insulin dose. RESULTS: Mean HbA1c and FPG reductions were similar with Gla-100 and NPH insulin regardless of concomitant OAD (P=0.184 and P=0.553, respectively) and similar proportions of subjects achieved HbA1c <7.0% (P=0.603). There was a trend for more subjects treated with Gla-100 achieving FPG ⩽100mg/dL versus NPH insulin (relative risk [RR] 1.09 [95% confidence interval (CI) 0.97-1.23]; P=0.135). Plasma glucose confirmed (<70mg/dL) overall and nocturnal hypoglycaemia incidences and rates were lower with Gla-100 versus NPH insulin (overall RR 0.93 [95% CI 0.87-1.00]; P=0.041; nocturnal RR 0.73 [95% CI 0.65-0.83]; P<0.001). After 24weeks, weight gain and insulin doses were higher with Gla-100 versus NPH insulin (2.7kg vs 2.3kg, P=0.009 and 0.42U/kg vs 0.39U/kg; P=0.003, respectively). Insulin doses were higher when either insulin was added to sulfonylurea alone. CONCLUSIONS: Pooled results from treat-to-target trials in insulin-naïve people with type 2 diabetes demonstrate a significantly lower overall and nocturnal hypoglycaemia risk across different plasma glucose definitions with Gla-100 versus NPH insulin at similar glycaemic control. OAD therapy co-administered with Gla-100 or NPH insulin impacts glycaemic control and overall nocturnal hypoglycaemia risk.

Improved treatment satisfaction in patients with type 1 diabetes treated with insulin glargine 100U/mL versus neutral protamine Hagedorn insulin: An exploration of key predictors from two randomized controlled trials.

AIM: Investigate contributors to treatment satisfaction in type 1 diabetes (T1D). METHODS: Post-hoc analysis using the Diabetes Treatment Satisfaction Questionnaire status version (DTSQs) in 771 T1D patients from two 28-week trials comparing once-daily insulin glargine 100U/mL (Gla-100) with once- or twice-daily NPH neutral protamine Hagedorn (NPH) insulin. RESULTS: Gla-100 was associated with a significant improvement in treatment satisfaction versus NPH (overall population adjusted mean [standard error] DTSQs change from baseline: +1.13 [0.30] versus -0.04 [0.31]; p=0.006). In the overall population, treatment satisfaction improvement with all insulin regimens was related to less frequent severe hypoglycemia (coefficient-0.077; p=0.040) and HbA1c reduction (-0.066; p=0.082). By treatment regimen, relationships between treatment satisfaction and these outcomes approached or attained statistical significance for NPH insulin, but not Gla-100. In the overall population, predictors of treatment satisfaction improvement included: Gla-100 treatment (estimate 1.17, p=0.006), lower baseline DTSQs (-0.57, p<0.001), study (-1.01, p=0.019), lower severe hypoglycemia rate (0.17, p=0.012), and higher baseline HbA1c (0.44, p=0.014). By treatment regimen, these predictors remained significant for NPH insulin. CONCLUSIONS: Gla-100 resulted in a significant improvement in treatment satisfaction versus NPH insulin, independent of baseline disease characteristics and clinical outcomes.

Achieve control: a pragmatic clinical trial of insulin glargine 300 U/mL versus other basal insulins in insulin-naïve patients with type 2 diabetes.

OBJECTIVE: This study aims to compare the effectiveness of insulin glargine 300 U/mL (Gla-300) with its accompanying patient support program with that of other basal insulin and available patient support programs in patients with type 2 diabetes (T2D) in a real-world setting in terms of achieving HEDIS (Healthcare Effectiveness Data and Information Set) individualized glycemic targets without documented symptomatic hypoglycemia. METHODS: Achieve Control is a US-based, multicenter, randomized, open-label, active-controlled, parallel group pragmatic Phase IV trial in insulin-naïve patients with T2D uncontrolled on ≥2 oral antidiabetes drugs (OAD) and/or glucagon-like peptide-1 receptor antagonists (GLP-1 RA). Inclusion criteria include a diagnosis of T2D, age ≥18 years, and glycated hemoglobin (HbA1c) between 8.0% and 11.0%. Patients will be assigned to either the Gla-300 or other basal insulin group. The primary end point is the proportion of patients achieving HEDIS HbA1c targets (<8.0% [64 mmol/mol] in patients with comorbidities or aged ≥65 years; <7.0% [58 mmol/mol] in all other patients) without occurrence of symptomatic hypoglycemia (blood glucose ≤70 mg/dL) from baseline to 6 months. Secondary end points include rates of documented symptomatic nocturnal hypoglycemia and severe hypoglycemia; change from baseline in HbA1c, fasting glucose, and body weight; treatment persistence; patient-reported outcomes; and healthcare resource utilization. Planned enrollment is 3270 patients across approximately 400 clinical sites. CONCLUSION: Pragmatic clinical trials offer the potential to assess comparative effectiveness in broadly based patient populations receiving care (with or without a corresponding educational support program) in real-world clinical settings. The results of Achieve Control should elucidate the benefits of management of T2D with Gla-300 versus other basal insulins in terms of patient outcomes, experiences, and perceptions, and its impact on healthcare resource utilization and cost. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT02451137.

Efficacy and safety of basal insulin glargine 12 and 24 weeks after initiation in persons with type 2 diabetes: a pooled analysis of data from treatment arms of 15 treat-to-target randomised controlled trials.

AIM: Evaluate early (0-12 weeks) and later (12-24 weeks) treatment outcomes in subjects with type 2 diabetes not achieving glycaemic control with oral antidiabetes drugs (OADs). METHODS: Selected data were pooled from 15 randomised, controlled treat-to-target (fasting plasma glucose < 100mg/dL [< 5.6 mmol/L]) trials adding insulin glargine to metformin, a sulphonylurea, or both. Glycaemic and hypoglycaemia parameters, insulin dose, and body weight at weeks 12 and 24 were assessed using individualised subject-level data. RESULTS: Data from 2837 subjects were analysed. HbA1c decreased from 8.8% (73 mmol/mol) at baseline by 1.4% (15 mmol/mol) at Week 12, and a further 0.2% (2 mmol/mol) at Week 24 in the pooled population. Similar reductions were observed across the different treatment groups. HbA1c < 7.0% (<53 mmol/mol) was reached by 34.8% of participants at Week 12 and an additional 24.3% by Week 24. Hypoglycaemia incidence and rates were similar during the early and continued treatment periods across all treatment combinations, but were markedly lower for insulin glargine plus metformin versus the other 2 regimens. CONCLUSIONS: Early and sustained glycaemic benefits with a low-risk of hypoglycaemia are observed after initiation of insulin glargine in a pooled type 2 diabetes cohort previously uncontrolled on OADs.

Comparing patient preferences and healthcare provider recommendations with the pen versus vial-and-syringe insulin delivery in patients with type 2 diabetes.

OBJECTIVES: This study aimed to examine healthcare provider (HCP) recommendations and patient preferences for the insulin pen versus vial-and-syringe in patients with type 2 diabetes mellitus (T2DM) and to assess clinical end points and safety outcomes. SUBJECTS AND METHODS: Using a randomized, open-label, crossover design, in total, 405 insulin-naive adults with T2DM from 60 centers received basal insulin glargine in one of two device treatment sequences (2 weeks of pen followed by 2 weeks of vial-and-syringe, or vice versa). The primary end point, patient device preference, was evaluated at Week 4 (end of the crossover period) using the Insulin Injection Preference Questionnaire. Patient preference and HCP recommendation were assessed with one global item and three subscale items (blood glucose control, reluctance to use insulin, and long-term insulin use) using a 5-point scale ranging from 1=not preferred or not recommended to 5=preferred or recommended. Patients were then re-randomized to either pen or vial-and-syringe for further observation (6, 10, and 30 weeks) to evaluate clinical end points (glycosylated hemoglobin [A1C] and fasting blood glucose levels) and safety outcomes (hypoglycemia and adverse events). RESULTS: Patients reported a significant preference for pens over vial-and-syringe, and HCPs strongly recommended pens over vial-and-syringe (both P<0.001). Consistent response patterns were observed by HCPs and patients for the three subscale items. Fasting blood glucose, A1C levels, and the incidence of hypoglycemia were comparable in the two groups. CONCLUSIONS: Patients preferred pens over vial-and-syringe, with the pen device also recommended by HCPs, when initiating basal insulin treatment in insulin-naive patients with T2DM.

A Patient-level Analysis of Efficacy and Hypoglycaemia Outcomes Across Treat-to-target Trials with Insulin Glargine Added to Oral Antidiabetes Agents in People with Type 2 Diabetes.

Background: A better understanding of hypoglycaemia risk when insulin is used in combination with one or more oral antidiabetes agents may assist in the treatment decision-making process for the clinician and address concerns regarding hypoglycaemia when initiating or intensifying insulin therapy. The objective of this study was to analyse efficacy and hypoglycaemia outcomes in people with type 2 diabetes receiving insulin glargine (IG) with metformin (MET), sulphonylurea (SU) or MET+SU. Methods: Patient-level data were pooled from 15 randomised, treat-to-target trials (fasting plasma glucose [FPG] targets <5.6 mmol/l) with a duration >24 weeks. Efficacy outcomes included glycated haemoglobin (HbA1c), FPG and HbA1c target achievement. Overall hypoglycaemia events were assessed by a confirmed PG value of <3.9, <3.1 and <2.8 mmol/l or assistance required; daytime, nocturnal (00:01-05:59 AM); and severe (assistance required or with confirmed PG <2.0 mmol/l). Results: Overall, 2,837 IG patients were analysed, with either MET (634), SU (906) or MET+SU (1,297) as background oral antidiabetes agents. Endpoint HbA1c in IG+MET and IG+MET+SU-treated patients was significantly lower than in IG+SU-treated patients (adjusted difference -0.32 %; p=0.0001 and -0.33 %; p=0.0002, respectively). Fewer patients achieved endpoint HbA1c <7.0 % with IG+SU (32 %) versus IG+MET (57 %) or IG+MET+SU (49 %). IG+SU and IG+MET+SU led to significant increases in overall, daytime and nocturnal hypoglycaemia versus IG+MET; severe hypoglycaemia was rare. Weight gain was lowest in IG+MET patients (adjusted difference -1.51 kg versus IG+SU; p<0.0001; -0.78 kg versus IG+MET+SU; p=0.0037) despite higher insulin doses (0.51 U/kg versus 0.43 and 0.42 U/kg, respectively). Conclusions: Better glycaemic goal achievement and reduced risk of hypoglycaemia and weight gain were observed with IG+MET versus IG+SU and IG+MET+SU, albeit with an increased insulin dose requirement.

Improved glycemic control with insulin glargine versus pioglitazone as add-on therapy to sulfonylurea or metformin in patients with uncontrolled type 2 diabetes mellitus.

OBJECTIVE: To compare glycemic control with add-on insulin glargine versus pioglitazone treatment in patients with type 2 diabetes. METHODS: This 48-week, multicenter, parallel-group, open-label study randomized 389 adults with poorly controlled type 2 diabetes (glycated hemoglobin A1c [A1C], 8.0% to 12.0%), despite > or =3 months of sulfonylurea or metformin monotherapy, to receive add-on therapy with insulin glargine or pioglitazone. Outcomes included A1C change from baseline to end point (primary), percentage of patients achieving A1C levels < or =7.0%, and changes from baseline in fasting plasma glucose, body mass index, weight, and serum lipids. The safety analysis included incidence of adverse events and rates of hypoglycemia. RESULTS: At end point, insulin glargine yielded a significantly greater reduction in A1C in comparison with pioglitazone (-2.48% versus -1.86%, respectively; 95% confidence interval, -0.93 to -0.31; P = .0001, 48-week modified intent-to-treat population). Insulin glargine also yielded significantly greater reductions in fasting plasma glucose at all time points (end point difference, -34.9 mg/dL; 95% confidence interval, -47.6 to -22.2; P<.0001). In comparison with pioglitazone, insulin glargine resulted in a lower overall incidence of possibly related treatment-emergent adverse events (12.0% versus 20.7%) and fewer study discontinuations (2.2% versus 9.1%), but a higher rate (per patient-year) of confirmed clinically relevant hypoglycemic episodes (blood glucose <70 mg/dL and all severe hypoglycemia) (4.97 versus 1.04; P<.0001) and severe hypoglycemia (0.07 versus 0.01; P = .0309). Weight and body mass index changes were similar between the 2 treatment groups. CONCLUSION: The addition of insulin glargine early in the diabetes treatment paradigm in patients for whom sulfonylurea or metformin monotherapy had failed resulted in significantly greater improvements in glycemic control in comparison with the addition of pioglitazone. Although severe hypoglycemia was more frequent in patients with insulin glargine therapy, hypoglycemic events occurred in <5% of patients in the insulin glargine treatment group.

A clinical trial demonstrates the analgesic activity of intravenous parecoxib sodium compared with ketorolac or morphine after gynecologic surgery with laparotomy.

OBJECTIVE: The purpose of this study was to compare the analgesic activity of 2 doses of parecoxib sodium, ketorolac, and morphine with placebo after gynecologic surgery that requires laparotomy. STUDY DESIGN: In a randomized, controlled, double-blind, parallel-group study, 208 patients, after surgical hysterectomy, received single-dose intravenous placebo, parecoxib sodium 20 mg or 40 mg, ketorolac 30 mg, or morphine 4 mg followed by multiple-dose parecoxib sodium or ketorolac as needed. Primary efficacy variables were time to onset of analgesia, pain intensity differences, pain relief, time to first rescue/remedication, and global evaluation of study medication. RESULTS: Single-dose parecoxib sodium 40 mg provided significantly better pain responses to placebo or morphine 4 mg and was comparable to ketorolac 30 mg. Multiple-dose parecoxib sodium 20 mg, 4 times daily, or 40 mg, twice daily, was comparable to ketorolac 30 mg, 4 times daily. Parecoxib sodium was well tolerated. CONCLUSION: Parecoxib sodium is an effective analgesic in the management of acute postoperative pain after laparotomy surgery.

Analgesic efficacy of preoperative parecoxib sodium in an orthopedic pain model.

The efficacy and safety of preoperative intravenous administration of parecoxib sodium, a novel parenteral prodrug of a cyclooxygenase-2 selective inhibitor, in treating postoperative pain resulting from bunionectomy were evaluated in 50 patients who were part of a larger cohort of orthopedic and podiatric patients. Following bunionectomy, the median time to rescue medication (survival analysis) was 4 hours 18 min (95% confidence interval, 3 hours 4 min to 4 hours 37 min) in the placebo group, 7 hours 5 min (95% confidence interval, 3 hours 20 min to >24 hours) in the 20-mg parecoxib sodium group, and 10 hours 43 min (95% confidence interval, 4 hours 42 min to 14 hours 7 min) in the 40-mg parecoxib sodium group (significant for 40-mg parecoxib sodium versus placebo). Four or more hours after surgery, the mean pain-intensity (categorical) score was significantly lower in both parecoxib sodium groups than in the placebo group. Preoperative administration of parecoxib sodium was well tolerated and significantly reduced postoperative pain in patients who had undergone bunionectomy.

Parecoxib sodium, a parenteral cyclooxygenase 2 selective inhibitor, improves morphine analgesia and is opioid-sparing following total hip arthroplasty.

BACKGROUND: This study examined the opioid-sparing effectiveness, analgesic efficacy, and tolerability of postoperative administration of the parenteral cyclooxygenase 2 selective inhibitor, parecoxib sodium, in total hip arthroplasty patients. METHODS: This was a multicenter, multiple-dose, randomized, double-blind, placebo-controlled study to compare the opioid-sparing effects, analgesic efficacy, and tolerability of postoperative 20 and 40 mg intravenous parecoxib sodium with placebo in hip arthroplasty patients. The first dose of study medication was administered after surgery with an intravenous bolus dose of 4 mg morphine when patients first requested pain medication; remedication with the study medication occurred at 12 and 24 h. Subsequent morphine doses (1-2 mg) were administered by patient-controlled analgesia. Efficacy was assessed by total morphine used, pain relief and pain intensity, time to last dose of morphine, and Global Evaluation rating of the study medication. RESULTS: Parecoxib sodium, 20 and 40 mg, reduced the total amount of morphine required over 36 h by 22.1% (56.5 mg morphine) and 40.5% (43.1 mg morphine), respectively, compared with placebo (72.5 mg morphine; P < 0.01). Patients receiving 20 and 40 mg parecoxib sodium experienced significantly greater maximum pain relief compared with those in the placebo group (P < 0.05). Patients who received 20 and 40 mg parecoxib sodium discontinued PCA morphine earlier than patients receiving placebo and had significantly higher Global Evaluation ratings. Parecoxib sodium, 40 mg, plus morphine demonstrated a significantly lower incidence of fever and vomiting compared with placebo plus morphine. CONCLUSIONS: Administration of parecoxib sodium with PCA morphine resulted in significantly improved postoperative analgesic management as defined by reduction in opioid requirement, lower pain scores, reduced time on PCA morphine, and higher Global Evaluation ratings.