Low Rate Of Hypoglycaemia Research Articles

The study of once- and twice-daily biphasic insulin aspart 30 (BIAsp 30) with sitagliptin, and twice-daily BIAsp 30 without sitagliptin, in patients with type 2 diabetes uncontrolled on sitagliptin and metformin—The Sit2Mix trial

AimsInvestigate efficacy and tolerability of intensifying diabetes treatment with once- or twice-daily biphasic insulin aspart 30 (BIAsp 30) added to sitagliptin, and twice-daily BIAsp 30 without sitagliptin in patients with type 2 diabetes (T2D) inadequately controlled on sitagliptin. MethodsOpen-label, three-arm, 24-week trial; 582 insulin-naïve patients were randomized to twice-daily BIAsp 30+sitagliptin (BIAsp BID+Sit), once-daily BIAsp 30+sitagliptin (BIAsp QD+Sit) or twice-daily BIAsp 30 without sitagliptin (BIAsp BID), all with metformin. ResultsAfter 24 weeks, HbA1c reduction (%) was superior with BIAsp BID+Sit vs. BIAsp QD+Sit (BIAsp BID+Sit minus BIAsp QD+Sit difference: −0.36 [95% CI –0.54; –0.17], P<0.001) and BIAsp BID (BIAsp BID minus BIAsp BID+Sit difference: 0.24 [0.06; 0.43], P=0.01). Observed final HbA1c values were 6.9%, 7.2% and 7.1% (baseline 8.4%), and 59.8%, 46.5% and 49.7% of patients achieved HbA1c <7.0%, respectively. Confirmed hypoglycaemia was lower with BIAsp QD+Sit vs. BIAsp BID (P=0.015); rate: 1.17 (BIAsp QD+Sit), 1.50 (BIAsp BID+Sit) and 2.24 (BIAsp BID) episodes/patient-year. Difference in bodyweight change favoured BIAsp QD+Sit vs. both BID groups (P<0.001). ConclusionsAdding BIAsp 30 to patients with T2D poorly controlled with sitagliptin and metformin is efficacious and well tolerated; however, while BIAsp BID+Sit showed superior glycaemic control, BIAsp QD+Sit had a lower rate of hypoglycaemia and showed no weight gain.

Combinación de metformina frente a inhibidores de la dipeptidilpeptidasa y sulfonilureas en el tratamiento de la diabetes tipo 2: impacto clínico y económico

Determine the clinical repurcussions of adherence, metabolic control, hypoglycemia and cardiovascular events (CVE) and economics (resources and costs) in the combination therapy of metformin vs DPP-4 (dipeptidyl peptidase-4) inhibitors and sulfonylureas in patients with type 2 diabetes. Materials and methods. Observational-multicenter and retrospective design. We evaluated patients ≥ 30 years of age in treatment with metformin and who started a second oral antidiabetic treatment during 2008-2009. 2 study groups were established: a) metformin + DPP-4 inhibitors, and b) metformin + sulfonylurea. comorbidity, metabolic control (HbA1c <7%), compliance and complications (hypoglycemia, CVE). Follow up was conducted over two years. The cost model differentiated between direct healthcare costs (primary/ specialty care), and indirect costs (labor productivity). logistic regression and ANCOVA models. Results. 1,405 patients were recruited (average age 67.1 years old; 56.2% male). 37.0% started a second treatment with DPP-4 inhibitors, and 63.0% with sulfonylureas. After two years of follow up, patients treated with DPP-4 inhibitors showed greater treatment adherence (70.3% vs. 60.6%; p <0.001); better metabolic control (64.3% vs. 60.6%; p<0.001), and a lower proportion of hypoglycemia (13.9% vs. 40.4%; p <0.001, respectively). The average/unit of adjusted total costs was € 2,341 vs. € 2,512; p = 0.038. CVE and renal failure rates were 3.7% vs. 6.4%; p = 0.027. Vildagliptin was the most used drug among DPP-4 inhibitors. Conclusions. Sulfonylureas were the most used drug for diabetes treatment. Patients treated with DPP-4 inhibitors had higher adherence and control of diabetes, with lower rates of hypoglycemia and CVE, resulting in lower healthcare costs.

Hypocaloric Enteral Nutrition Protects against Hypoglycemia Associated with Intensive Insulin Therapy Better than Intravenous Dextrose

Intensive insulin therapy treats hyperglycemia but increases the risk of hypoglycemia. Typically, intravenous dextrose is given to prevent hypoglycemia; however, enteral nutrition is preferred. We hypothesized that the provision of hypocaloric enteral nutrition would protect against hypoglycemia. A retrospective analysis was performed evaluating patients treated with intensive insulin therapy comparing the use of enteral nutrition versus a dextrose-only intravenous solution. Nutrition in the 2 hours before each blood glucose test was assessed, and the association with hypoglycemia (50 mg/dL or less) evaluated. Risk of hypoglycemia as a function of nutrition type and rate was estimated by multivariable regression. A total of 26,140 blood glucose tests were collected on 1289 patients. Hypoglycemia occurred in 6.4 per cent of patients. In regression models, enteral nutrition was the strongest protective factor against hypoglycemia (P < 0.001) with the largest risk reduction (steepest portion of the curve) occurring at 60 per cent goal. Hypocaloric enteral nutrition showed a greater risk reduction than a peripheral dextrose-only intravenous solution alone. In the setting of intensive insulin therapy, the provision of enteral nutrition, even if hypocaloric, is sufficient to protect against hypoglycemia. Future prospective studies should evaluate the efficacy of enteral nutrition in reducing the risk of hypoglycemia and whether lower rates of hypoglycemia correspond to improved outcomes.

SGLT2 inhibitors: New medicines for addressing unmet needs in type 2 diabetes.

The prevalence of type 2 diabetes mellitus (T2DM) is rising in Australia. Sodium glucose co-transporter 2 (SGLT2) inhibitors are an emerging treatment for T2DM. SGLT2 inhibitors offer a novel approach to lowering hyperglycaemia by suppressing renal glucose reabsorption and increasing urinary glucose excretion. The increased urinary glucose excretion has also been associated with caloric loss and osmotic diuresis. Dapagliflozin and canagliflozin are the SGLT2 inhibitors that are approved for clinical use in the US, the European Union (EU), and Australia. Their use results in reductions in HbA1c and body weight across a broad range of patient populations ranging from drug-naive patients to those who require additional therapy due to inadequate glycaemic control on their existing treatment. In addition, reductions in blood pressure (BP), particularly systolic BP, have also been noted. SGLT2 inhibitors are generally well tolerated with low rates of adverse events. Episodes of hypoglycaemia were mostly classified as minor, with low and balanced rates of severe hypoglycaemia across studies. The proportions of patients with genital infections and urinary tract infections were higher with dapagliflozin and canagliflozin versus their comparators. However, these infections were generally mild-to-moderate in intensity, treated with standard antimicrobial therapies, and rarely led to discontinuation. No dosage adjustments for dapagliflozin and canagliflozin are recommended for normal-to-mild renal impairment. Dapagliflozin and canagliflozin are not recommended for use in patients with eGFR<60 and <45mL/min/1.73m(2), respectively. Overall, SGLT2 inhibitors have shown the potential to become an important addition to the treatment armamentarium for effective management of patients with T2DM.

Effects of Pramlintide in Patients with Type 2 Diabetes Mellitus: An Analysis Using Daily Insulin Dose Tertiles

The purpose of the analysis was to investigate if the efficacy and tolerability of 6 months of pramlintide therapy in patients with type 2 diabetes mellitus (T2DM) differed with increasing levels of concomitant insulin doses, using data from 3 previously described clinical trials. In this post hoc analysis, data from 2 pooled, placebo-controlled pivotal trials and 1 clinical practice trial were evaluated by baseline insulin use tertile in patients with T2DM. In the pivotal trials, both glycated hemoglobin (A1C) and body weight decreased similarly across tertiles with pramlintide. A1C decreased slightly and body weight remained relatively unchanged across tertiles with placebo. Similarly, in the clinical practice trial, pramlintide was associated with decreases in A1C, body weight, and total daily insulin use across the tertiles. Overall, the most common adverse events were gastrointestinal in nature, and the rate of severe hypoglycemia was low. These results suggest that pramlintide therapy was associated with improved A1C and decreased body weight, with a low rate of severe hypoglycemia, among patients with T2DM, regardless of baseline insulin use.

The cost-effectiveness and budget impact of stepwise addition of bolus insulin in the treatment of type 2 diabetes: evaluation of the FullSTEP trial

Background and aims:Intensification of basal insulin-only therapy in type 2 diabetes is often achieved through addition of bolus insulin 3-times daily. The FullSTEP trial demonstrated that stepwise addition (SWA) of bolus insulin aspart was non-inferior to full basal-bolus (FBB) therapy and reduced the rate of hypoglycemia. Here the cost-effectiveness and budget impact of SWA is evaluated.Methods:Cost-effectiveness and budget impact models were developed to assess the cost and quality-of-life (QoL) implications of intensification using SWA compared with FBB in the US setting. At assessment, SWA patients added one bolus dose to their current regimen if the HbA1c target was not met. SWA patients reaching three bolus doses used FBB event rates. Outcomes were evaluated at trial end and projected annually up to 5 years. Models captured hypoglycemic events, the proportion meeting HbA1c target, and self-measured blood glucose. Event rates and QoL utilities were taken from trial data and published literature. Costs were evaluated from a healthcare-payer perspective, reported in 2013 USD, and discounted (like clinical outcomes) at 3.5% annually. This analysis applies to patients with HbA1c 7.0–9.0% and body mass index <40 kg/m2.Results:SWA was associated with improved QoL and reduced costs compared with FBB. Improvement in QoL and cost reduction were driven by lower rates of hypoglycemia. Sensitivity analyses showed that outcomes were most influenced by the cost of bolus insulin and QoL impact of symptomatic hypoglycemia. Budget impact analysis estimated that, by moving from FBB to SWA, a health plan with 77,000 patients with type 2 diabetes, of whom 7.8% annually intensified to basal-bolus therapy, would save USD 1304 per intensifying patient over the trial period.Conclusions:SWA of bolus insulin should be considered a beneficial and cost-saving alternative to FBB therapy for the intensification of treatment in type 2 diabetes.

An exploratory trial of basal and prandial insulin initiation and titration for type 2 diabetes in primary care with adjunct retrospective continuous glucose monitoring: INITIATION study

AimsTo evaluate basal and prandial insulin initiation and titration in people with type 2 diabetes mellitus (T2DM) in primary care and to explore the feasibility of retrospective-continuous glucose monitoring (r-CGM) in guiding insulin dosing. The new model of care features General Practitioners (GPs) and Practice Nurses (PNs) working in an expanded role, with Credentialed Diabetes Educator – Registered Nurse (CDE-RN) support. MethodsInsulin-naïve T2DM patients (HbA1c >7.5% [>58mmol/mol] despite maximal oral therapy) from 22 general practices in Victoria, Australia commenced insulin glargine, with glulisine added as required. Each was randomised to receive r-CGM or self-monitoring of blood glucose (SMBG). Glycaemic control (HbA1c) was benchmarked against specialist ambulatory patients referred for insulin initiation. ResultsNinety-two patients mean age (range) 59 (28–77) years; 40% female; mean (SD) diabetes duration 10.5 (6.1) years participated. HbA1c decreased from (median (IQR)) 9.9 (8.8, 11.2)%; 85 (73, 99) mmol/mol to 7.3 (6.9, 7.8)%; 56 (52, 62) mmol/mol at 24 weeks (p<0.0001). Comparing r-CGM (n=46) with SMBG (n=42), there were no differences in major hypoglycaemia (p=0.17) or ΔHbA1c (p=0.31). More r-CGM than SMBG participants commenced glulisine (26/48 vs. 7/44; p<0.001). Results were comparable to 82 benchmark patients, with similar low rates of major hypoglycaemia (2/89 vs. 0/82; p=0.17) and less loss to follow up in the INITIATION group (3/92 vs. 14/82; p=0.002). ConclusionsInsulin initiation and titration for T2DM patients in primary care was safe and improved HbA1c with low rates of major hypoglycaemia. CDE-RNs were effective in a new consultant role. r-CGM use in primary care was feasible and enhanced post-prandial hyperglycaemia recognition.Trial registration ACTRN12610000797077.

Association of Glycemic Control Parameters with Clinical Outcomes in Chronic Critical Illness

Chronic critical illness (CCI) is a term used to designate patients requiring prolonged mechanical ventilation and tracheostomy with associated poor outcomes. The present study assessed the impact of glycemic parameters on outcomes in a CCI population. A retrospective case series was performed including 148 patients in The Mount Sinai Hospital Respiratory Care Unit (2009-2010). Utilizing a semi-parametric mixture model, trajectories for the daily mean blood glucose (BG), BG range, and hypoglycemia rate over time identified low- (n = 87) and high-risk (n = 61) hyperglycemia groups and low- (n = 90) and high-risk (n = 58) hypoglycemia groups. The cohort was also classified into diabetes (DM, n = 48), stress hyperglycemia (SH, n = 85), and normal glucose (n = 15) groups. Hospital- (28% vs. 13%, P = .0199) and 1-year mortality (66% vs. 46%, P = .0185) rates were significantly greater in the high- versus low-risk hyperglycemia groups, respectively. The hypoglycemia rate (<70 mg/dL) was lower among ventilator-liberated patients compared to those who failed to liberate (0.092 vs. 0.130, P<.0001). In the SH group, both hospital mortality (high-risk hyperglycemia 48% and low-risk hyperglycemia 15%, P = .0013) and 1-year mortality (high-risk 74% and low-risk 50%, P = .0482) remained significantly different, while no significant difference in the diabetes group was observed. There were lower hypoglycemia rates with SH compared to diabetes (<70 mg/dL: 0.086 vs. 0.182, P<.0001; <40 mg/dL: 0.012 vs. 0.022, P = .0118, respectively). Tighter glycemic control was associated with improved outcomes in CCI patients with SH but not in CCI patients with diabetes. Confirmation of these findings may lead to stratified glycemic control protocols in CCI patients based on the presence or absence of diabetes.

The design and discovery of lixisenatide for the treatment of type 2 diabetes mellitus

Introduction: Lixisenatide is a once-daily short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) used in the treatment of type 2 diabetes mellitus (T2DM). It is used in combination with oral antidiabetics and/or basal insulin in patients inadequately controlled on these medications and who are undergoing diet and lifestyle modification. GLP-1RAs glucose-dependently increase insulin secretion, decrease glucagon secretion, and slow gastric emptying, thereby improving glycemic control. GLP-1RAs are associated with body weight benefits and low rates of hypoglycemia which are welcome in patients with T2DM.Areas covered: The authors describe the identification of GLP-1RAs as suitable targets for modification with structure-inducing probe technology to improve stability and resistance to proteolytic degradation. Clinical studies have assessed lixisenatide across > 5000 patients as a monotherapy or add-on to a variety of commonly used antidiabetic medications. These studies highlighted the effects of lixisenatide on gastric emptying, explaining its particular improvements in postprandial plasma glucose (PPG) excursions and underscoring its efficacy in combination with insulin glargine. Lixisenatide was well tolerated, with nausea and vomiting being the most frequently reported adverse events.Expert opinion: The once-daily administration of lixisenatide as well as its substantial sustained effect on gastric emptying and, hence, PPG excursions are all important features compared with the other GLP-1RAs. The combination of two injectables, such as basal insulin to lower fasting plasma glucose and a GLP-1RA that curtails PPG excursions, is clinically valuable and could differentiate lixisenatide from other GLP-1RAs, especially from those continuously acting GLP-1RAs with little effect on gastric emptying and PPG excursions.

Why is insulin pump treatment rarely used in adolescents and young adults with cystic fibrosis-related diabetes?

In type 1 diabetes (T1D), the use of continuous subcutaneous insulin infusion (CSII) has increased steadily in the last years. Compared with conventional insulin injection regimes, major advantages might be a nearly physiological insulin secretion, lower rates of hypoglycemia, higher flexibility in daily life, and increased quality of life. Data on CSII in cystic fibrosis-related diabetes (CFRD) are scarce. To analyze current use of insulin pumps in CFRD and compare demographics of pump-treated patients between CFRD and T1D. Data from the prospective German/Austrian diabetes patient registry on insulin-treated patients with either CFRD (n = 515) or T1D (n = 43 165) aged >10 yr at manifestation of diabetes were analyzed. A total of 4.1% (n = 21) of CFRD and 17.7% (n = 7647) of T1D patients received insulin pump treatment within the recent year of care (p < 0.001). Pump-treated patients with CFRD had a significantly shorter duration of diabetes [median (Q1 ; Q3 ): 5.8 (2.9; 9.5) vs. 7.8 (4.3; 20.4) yr, p = 0.026] and tended to be younger [22.0 (18.2; 30.1) vs. 24.9 (17.3; 45.9) yr] than pump-treated T1D patients. Age at initiation of CSII seemed to be lower in CFRD [19.2 (16.5; 29.2) vs. 23.3 (14.8; 43.5) yr]. Insulin pump therapy was used slightly more often in male CFRD patients than females (4.7 vs. 3.6%), whereas in T1D the opposite was observed (14.9 vs. 21.2%, p < 0.001). Discontinuation rate of CSII was higher in CFRD than T1D (30.0 vs. 12.7%, p = 0.005). Despite potential advantages, insulin pump therapy was rarely used among adolescent and young adult CFRD patients.

Reducing the risk of hypoglycemia associated with intravenous insulin: experience with a computerized insulin infusion program in 4 adult intensive care units.

Computerized insulin infusion protocols have facilitated more effective blood glucose (BG) control in intensive care units (ICUs). This is particularly important in light of the risks associated with hypoglycemia. End stage renal disease (ESRD) increases the risk of insulin-induced hypoglycemia. We evaluated BG control in 210 patients in 2 medical ICUs and in 2 surgical ICUs who were treated with a computerized insulin infusion program (CIIP). Our CIIP was programmed for a BG target of 140-180 mg/dL for medical ICU patients or 120-160 mg/dL for surgical ICU patients. In addition, we focused on BG control in the 11% of our patients with ESRD. Mean BG was 147 ± 20 mg/dL for surgical ICU patients and 171 ± 26 mg/dL for medical ICU patients. Of both surgical and medical ICU patients, 17% had 1 or more BG 60-79 mg/dL, while 3% of surgical ICU and 8% of medical ICU patients had 1 or more BG < 60 mg/dL. Mean BG in ESRD patients was 147 ± 16 mg/dL similar to 152 ± 23 mg/dL in patients without ESRD. Of ESRD patients, 41% had 1 or more BG < 79 mg/dL as compared with 17.8% of non-ESRD patients (P < .01). A higher BG target for medical ICU patients as compared with surgical ICU patients yielded comparably low rates of moderate or severe hypoglycemia. However, hypoglycemia among ESRD patients was more common compared to non-ESRD patients, suggesting a need for a higher BG target specific to ESRD patients.

Use of metformin and vildagliptin for treatment of type 2 diabetes in the elderly.

BackgroundThe aim of this study was to describe the clinical (treatment adherence, metabolic control, hypoglycemia, and macrovascular complications) and economic (resource use and costs) consequences of using a combination of metformin + vildagliptin to treat type 2 diabetes in elderly patients seen in daily clinical practice.MethodsWe conducted a multicenter, retrospective, observational study that included patients aged ≥65 years treated with metformin who started a second oral antidiabetic therapy during the years 2008–2009. There were two groups of patients: a study group receiving metformin + vildagliptin and a reference group receiving metformin + other oral antidiabetics (sulfonylureas or glitazones). The main measures were comorbidity, compliance/persistence, metabolic control (glycosylated hemoglobin <7%), complications (hypoglycemic, macrovascular), and total costs. The patients were followed for 2 years.ResultsWe recruited 987 patients (49.1% male) of mean age 74.2 years. There were 270 (27.4%) patients in the metformin + vildagliptin group and 717 (72.6%) in the reference group. Vildagliptin-treated patients had significantly (P<0.05) improved compliance (68.3% versus 62.5%, respectively), persistence (61.5% versus 55.1%), and metabolic control (63.3% versus 57.6%). They also had lower rates of hypoglycemia (17.4% versus 42.8%) and cardiovascular events (4.4% versus 8.6%) and lower total costs (€2,544 versus €2,699, P<0.05).ConclusionPatients treated with metformin and vildagliptin showed better adherence and metabolic control and lower rates of hypoglycemia, resulting in lower health care costs for the national health system.

Impact of initiating insulin glargine disposable pen versus vial/syringe on real-world glycemic outcomes and persistence among patients with type 2 diabetes mellitus in a large managed care plan: a claims database analysis.

Diabetes accounts for almost 15% of all direct healthcare expenditures. Managed care organizations try to reduce costs and improve patient outcomes. Increasing patient persistence with antidiabetes treatment could help achieve these goals. A retrospective study was conducted using the Optum Research Database (Optum, Eden Prairie, MN) to analyze clinical and economic outcomes associated with initiation of insulin glargine via a disposable pen (GLA-P) or vial and syringe (GLA-V) among adult, insulin-naive patients with type 2 diabetes mellitus (T2DM). Propensity-matched patient cohorts were assessed for persistence with insulin therapy, glycated hemoglobin (A1C), hypoglycemic events (based on diagnosis codes), and healthcare costs (total paid amount of adjudicated claims) after follow-up at 1 year. In 1,308 matched patients, persistence was significantly higher (P=0.011) and longer (P=0.001) with GLA-P. Follow-up A1C values were significantly lower (P=0.038), and decreases in A1C from baseline significantly larger (P=0.043), in GLA-P than in GLA-V. Significantly fewer hypoglycemic events (P=0.042) were experienced, and a lower rate of diabetes-related inpatient admissions (P=0.008) was reported in GLA-P than GLA-V. Despite higher study drug costs with GLA-P than GLA-V, all-cause and diabetes-related healthcare costs were similar. In insulin-naive patients with T2DM, initiation of insulin glargine using the disposable pen rather than the vial and syringe is associated with higher persistence, better A1C control, and lower rates of hypoglycemia. The higher study drug costs associated with pen use do not increase total all-cause or diabetes-related healthcare costs. This may help treatment selection for patients with T2DM in a managed care setting.

Efficacy and safety of the glucagon-like peptide-1 receptor agonist lixisenatide versus the dipeptidyl peptidase-4 inhibitor sitagliptin in young (

ObjectiveTo compare the efficacy and safety of the once-daily prandial glucagon-like peptide-1 receptor agonist lixisenatide with the dipeptidyl peptidase-4 inhibitor sitagliptin in patients aged <50 years affected by obesity and type 2 diabetes mellitus (T2DM). Materials and methodsThis was a 24-week, double-blind, randomized, parallel-group study. Obese patients with T2DM inadequately controlled on metformin were randomized to lixisenatide 20 μg once-daily injection (n = 158) or once-daily oral sitagliptin 100 mg (n = 161). The primary endpoint was the proportion of patients with a glycated hemoglobin (HbA1c) <7% and ≥5% weight loss at 24 weeks. ResultsThe proportion of patients that achieved the primary endpoint was 12.0% for lixisenatide versus 7.5% for sitagliptin; weighted average of proportion difference: 4.6%, p = 0.1696). A total of 40.7% of patients achieved HbA1c <7% with lixisenatide versus 40.0% with sitagliptin. Lixisenatide produced greater reductions in body weight (LS mean difference: −1.3 kg, p = 0.0006) and postprandial plasma glucose after a standardized meal test (LS mean difference: −34.4 mg/dL [−1.9 mmol/L], p = 0.0001) versus sitagliptin. There was a similar incidence of treatment-emergent adverse events (63.9% vs. 60.9%) and serious treatment-emergent adverse events (1.9% vs. 1.9%), with low rates of symptomatic hypoglycemia (0.6% vs. 1.9%) for lixisenatide and sitagliptin, respectively, and no cases of severe hypoglycemia. ConclusionIn obese patients aged <50 years with T2DM, the proportion of patients with an HbA1c <7% with weight loss ≥5% was similar between groups. Lixisenatide, however, resulted in significantly greater reductions in body weight and postprandial plasma glucose excursions than sitagliptin. Tolerability was similar between groups.

Ipragliflozin improves glycemic control in Japanese patients with type 2 diabetes mellitus: the BRIGHTEN study

Ipragliflozin is a sodium–glucose co-transporter 2 inhibitor under clinical development for treating type 2 diabetes mellitus (T2DM). In this Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, 129 Japanese patients with T2DM were randomized to either 50 mg ipragliflozin (n = 62) or placebo (n = 67) once daily for 16 weeks. Hemoglobin A1c (HbA1c) levels decreased significantly from baseline to the end of treatment in the ipragliflozin group (−0.76 %) but increased in the placebo group (+0.54 %), resulting in a placebo-adjusted mean change from baseline of −1.24 % (P < 0.001). Fasting plasma glucose (FPG) levels also decreased significantly in the ipragliflozin group (−40.2 mg/dL) but not in the placebo group (+6.3 mg/dL). The changes in body weight (−2.31 kg vs. −1.03 kg, P < 0.001) and waist circumference (−1.61 cm vs. −0.41 cm, P = 0.028) from baseline to the end of treatment were significantly greater in the ipragliflozin group than in the placebo group. Treatment-emergent adverse events occurred in 53.2 % and 59.7 % of patients in the ipragliflozin and placebo groups, respectively. All of the events were mild to moderate in severity. Hypoglycemia (ipragliflozin vs. placebo 1.6 % vs. 0 %), genital infections (3.2 % vs. 0 %), and urinary tract infection (0 % vs. 1.5 %) were rare. In conclusion, treatment with 50 mg ipragliflozin once daily for 16 weeks achieved significant improvements in HbA1c, FPG, body weight, and waist circumference compared with placebo in Japanese patients with T2DM. Ipragliflozin was well tolerated with low rates of genital infection and hypoglycemia.

Glycaemic Control and Long-Term Outcomes following Transition from Modified Intensive Insulin Therapy to Conventional Glycaemic Control

This retrospective observational cohort study compared glycaemic control and long-term outcomes following transition from a modified intensive insulin therapy (mIIT) regimen to conventional glycaemic control (CGC) in adult patients admitted to a tertiary adult general intensive care unit, during two 24-month periods, before and after the publication of the Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation (NICE-SUGAR) trial. The before NICE-SUGAR cohort received mIIT (target glycaemic ranges 4.4 to 7.0 mmol/l), while the after NICE-SUGAR cohort received CGC (target glycaemic range 7.1 to 9.0 mmol/l). A total of 5202 patients were included in the study. With transition from mIIT to CGC, the mean time-weighted glucose increased from 6.94 mmol/l to 8.2 mmol/l (P <0.0001). A similar increase was observed in other glycaemic indices (mean, highest and lowest glucose values, P <0.0001 for all). The adjusted 90-day odds ratio for mortality decreased by 47% with transition from mIIT to CGC (odds ratio 1.47 (95% confidence interval, 1.22 to 1.78) (P <0.0001). The rate of severe and moderate hypoglycaemia also decreased from 1.2 to 0.4% (P=0.004) and from 23.3 to 5.9% (P <0.0001), respectively. mIIT was associated with an increased risk of moderate and severe hypoglycaemia compared to CGC (odds ratio 3.1 (1.51 to 6.39) (P=0.002), 6.29 (5.1 to 7.75) (P <0.0001)). Changes in recommended glycaemic control were translated into practice, with increased glycaemic indices and decreased rates of severe and moderate hypoglycaemia after the introduction of CGC. The associated decrease in 90-day mortality suggests mIIT was not superior to CGC, despite a lower hypoglycaemia rate than in previous IIT trials. Our findings support the continued use of CGC.

Clinical Features and Outcome in Children with Severe Plasmodium falciparum Malaria: A Meta-Analysis

BackgroundAlthough global malaria mortality is declining, estimates may not reflect better inpatient management of severe malaria (SM) where reported case fatality rates (CFRs) vary from 1–25%.MethodsA meta-analysis of prospective studies of SM was conducted to examine i) whether hypothesized differences between clinical features and outcome in Melanesian compared with African or Asian children really exist, and ii) to explore temporal changes in overall and complication-specific CFRs. The proportions of different SM complications and, overall and complication-specific CFRs were incorporated into the meta-analysis. Adjustments were made for study-level covariates including geographic region, SM definition, artemisinin treatment, median age of participants and time period.FindingsSixty-five studies were included. Substantial heterogeneity (I 2>80%) was demonstrated for most outcomes. SM definition contributed to between-study heterogeneity in proportions of cerebral malaria (CM), metabolic acidosis (MA), severe anemia and overall CFR, whilst geographic region was a significant moderator in for CM and hypoglycemia (HG) rates. Compared with their African counterparts, Melanesian children had lower rates of HG (10% [CI95 7–13%] versus 1% [0–3%], P<0.05), lower overall CFR (2% [0–4%] versus 7% [6–9%], P<0.05) and lower CM-specific CFR (8% [0–17%] versus 19% [16–21%], P<0.05). There was no temporal trend for overall CFR and CM-specific CFR but declining HG- and MA- specific CFRs were observed.InterpretationThese data highlight that recent estimates of declining global malaria mortality are not replicated by improved outcomes for children hospitalized with SM. Significant geographic differences in the complication rates and subsequent CFRs exist and provide the first robust confirmation of lower CFRs in Melanesian children, perhaps due to less frequent HG.

Liraglutide Versus Sitagliptin in a 24-week, Multicenter, Open-label, Randomized, Parallel-group Study in Japanese Type 2 Diabetes Mellitus Patients Responding Inadequately to a Sulfonylurea and/or One or Two Other Oral Antidiabetic Drugs (JDDM 33).

OBJECTIVELiraglutide (glucagon-like peptide-1 [GLP-1] receptor agonist) and sitagliptin (dipeptidyl peptidase-4 inhibitor) are approved in Japan for treating type 2 diabetes mellitus (T2DM). We compared the efficacy and safety of adding liraglutide or sitagliptin to a sulfonylurea in Japanese T2DM patients.METHODSPatients aged 18 to <80 years with hemoglobin A1c (HbA1c; National Glycohemoglobin Standardization Program [NGSP]) of 6.9–9.4%, body mass index ≤35 kg/m2, and treatment with a sulfonylurea and/or one or two non-sulfonylurea oral antidiabetic drugs for greater than or equal to eight weeks before enrollment were eligible. Patients were randomized in an open-label manner to either 0.9 mg/day liraglutide (n = 50) or 50–100 mg/day sitagliptin (n = 49) and were treated for 24 weeks. Non-sulfonylureas were discontinued before randomization. Patients using other oral antidiabetic drugs started sulfonylurea treatment. The primary endpoint was the change in HbA1c from baseline to Week 24.RESULTSHbA1c decreased in both groups, and the reduction was significantly greater throughout in the liraglutide group except for Week 24 (0.59 ± 0.80 vs. 0.24 ± 0.94%; P = 0.0525). Fasting plasma glucose (FPG) decreased significantly in the liraglutide group compared with the sitagliptin group (−21.15 ± 31.22 vs. +0.46 ± 39.39 mg/dL; P = 0.0014). Homeostasis model assessment of β cell function and C-peptide increased significantly in the liraglutide group but not in the sitagliptin group. Hypoglycemic symptoms and adverse events occurred in four and nine patients, respectively, in the liraglutide group, and in two and five patients, respectively, in the sitagliptin group.CONCLUSIONTreatment with liraglutide or sitagliptin together with a sulfonylurea improved HbA1c in Japanese T2DM patients in primary care. Both drugs were associated with low rates of adverse events and hypoglycemia. The improvement in β cell function probably contributed to the improvement in glycemic control in the liraglutide group.

Evaluation of blood glucose control in ICU patients with Space GlucoseControl: a European study

Regardless of the ongoing debate on optimum target ranges, glycaemia control (GC) remains an important therapeutic goal in critically ill patients. Dozens of different insulin protocols for ICUs have been developed with different complexity, effectiveness, blood glucose (BG) variability and safety. Although comparison of existing protocols is difficult due to significant differences in processes and outcome measures, computerized clinical decision support systems generally achieved better GC with consistently lower hypoglycaemia rates than that achieved with paper-based protocols [1]. The enhanced Model Predictive Control (eMPC) algorithm, developed by the CLINICIP group, is the effective clinically proven protocol, which has been successfully tested at multiple institutions on medical and surgical patients with different nutritional protocols [2,3]. The eMPC models the behaviour of glucose and insulin in ICU patients with a variable sample interval based on the accuracy of the BG prediction. It has been integrated in the B.Braun Space GlucoseControl (SGC) system, which allows direct data communication between pumps and Space Control with the incorporated eMPC algorithm. Although SGC is already clinically used in dozens of ICUs worldwide, there are few only published experiences with its use [4].

Dapagliflozin as Monotherapy in Drug-Naive Asian Patients With Type 2 Diabetes Mellitus: A Randomized, Blinded, Prospective Phase III Study

ObjectiveDapagliflozin is a highly selective, orally active inhibitor of renal sodium-glucose cotransporter 2 that reduces hyperglycemia by increasing urinary glucose excretion. The goal of this study was to evaluate dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise. MethodsIn this Phase III, multicenter, parallel-group, double-blind study, drug-naive patients with glycosylated hemoglobin (HbA1c) levels ≥7.0% to ≤10.5% (≥53–≤91 mmol/mol) were randomized (by using an interactive voice response system) to receive placebo (n = 132), dapagliflozin 5 mg (n = 128), or dapagliflozin 10 mg (n = 133). The primary end point was mean change from baseline in HbA1c level at week 24 (last-observation-carried-forward). Secondary end points included changes in fasting plasma glucose, 2-hour postprandial glucose, body weight, and other glycemic parameters. ResultsBaseline characteristics were balanced across groups. Most patients (89%) were Chinese, median disease duration was 0.2 year, and mean HbA1c level was 8.26%. Most patients (87%) completed the study. At week 24, mean reductions in HbA1c were −0.29% for placebo versus −1.04% and −1.11% for dapagliflozin 5 and 10 mg, respectively (P < 0.0001 for both doses). Changes in fasting plasma glucose were 2.5, −25.1, and –31.6 mg/dL (0.14, −1.39, and −1.75 mmol/L) for placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg. Changes in 2-hour postprandial glucose were 1.1, −46.8, and −54.9 mg/dL (0.06, −2.60, and −3.05 mmol/L). Reductions in body weight were −0.27, −1.64, and −2.25 kg. Proportions of patients achieving HbA1c levels <7.0% (53 mmol/mol) were 21.3%, 42.6%, and 49.8%. Adverse events (AEs) occurred in 63.6%, 61.7%, and 60.9% of patients, and serious AEs occurred in 1.5%, 3.9%, and 3.0% of patients. No deaths occurred. Hypoglycemia was uncommon (1.5%, 0.8%, and 0.8%); no hypoglycemic event led to discontinuation. Genital infections occurred in 0.8%, 3.1%, and 4.5% of patients and urinary tract infections in 3.0%, 3.9%, and 5.3% of patients. No AEs of renal infection or pyelonephritis were reported. No changes in renal function or AEs of renal failure occurred. ConclusionsCompared with placebo, dapagliflozin 5 and 10 mg demonstrated clinically and statistically significant improvements in HbA1c levels after 24 weeks of treatment. Dose-dependent, statistically significant reductions in fasting plasma glucose, postprandial glucose, and weight were also observed for both doses compared with placebo. AEs and serious AEs were balanced across groups, with low rates of hypoglycemia and no increase in renal events. Genital infections and urinary tract infections were more common with dapagliflozin. Dapagliflozin as monotherapy in these drug-naive Asian patients was well tolerated, significantly improving glycemic control with the additional benefit of weight loss.