Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.

BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS: In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).

Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial.

Context: Combination therapy with insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is important for treating type 2 diabetes (T2D). This trial assesses the efficacy and safety of semaglutide, a GLP-1RA, as an add-on to basal insulin. Objective: To demonstrate the superiority of semaglutide vs placebo on glycemic control as an add-on to basal insulin in patients with T2D. Design: Phase 3a, double-blind, placebo-controlled, 30-week trial. Setting: This study included 90 sites in five countries. Patients: We studied 397 patients with uncontrolled T2D receiving stable therapy with basal insulin with or without metformin. Interventions: Subcutaneous semaglutide 0.5 or 1.0 mg once weekly or volume-matched placebo. Main Outcome Measures: Primary endpoint was change in glycated Hb (HbA1c) from baseline to week 30. Confirmatory secondary endpoint was change in body weight from baseline to week 30. Results: At week 30, mean HbA1c reductions [mean baseline value, 8.4% (67.9 mmol/mol)] with semaglutide 0.5 and 1.0 mg were 1.4% (15.8 mmol/mol) and 1.8% (20.2 mmol/mol) vs 0.1% (1.0 mmol/mol) with placebo [estimated treatment difference (ETD) vs placebo, -1.35 (14.8 mmol/mol); 95% CI, -1.61 to -1.10 and ETD, -1.75% (19.2 mmol/mol); 95% CI, -2.01 to -1.50; both P < 0.0001]. Severe or blood glucose-confirmed hypoglycemic episodes were reported in 11 patients (17 events) and 14 patients (25 events) with semaglutide 0.5 and 1.0 mg, respectively, vs seven patients (13 events) with placebo (estimated rate ratio vs placebo, 2.08; 95% CI, 0.67 to 6.51 and estimated rate ratio vs placebo, 2.41; 95% CI, 0.84 to 6.96 for 0.5 and 1.0 mg; both P = nonsignificant). Mean body weight decreased with semaglutide 0.5 and 1.0 mg vs placebo from baseline to end of treatment: 3.7, 6.4, and 1.4 kg (ETD, -2.31; 95% CI, -3.33 to -1.29 and ETD, -5.06; 95% CI, -6.08 to -4.04 kg; both P < 0.0001). Premature treatment discontinuation due to adverse events was higher for semaglutide 0.5 and 1.0 mg vs placebo (4.5%, 6.1%, and 0.8%), mainly due to gastrointestinal disorders. Conclusions: Semaglutide, added to basal insulin, significantly reduced HbA1c and body weight in patients with uncontrolled T2D vs placebo.

Effects of hypoglycaemia on working memory and regional cerebral blood flow in type 1 diabetes: a randomised, crossover trial.

AIMS/HYPOTHESIS: The aim of this randomised, crossover trial was to compare cognitive functioning and associated brain activation patterns during hypoglycaemia (plasma glucose [PG] just below 3.1 mmol/l) and euglycaemia in individuals with type 1 diabetes mellitus. METHODS: In this patient-blinded, crossover study, 26 participants with type 1 diabetes mellitus attended two randomised experimental visits: one hypoglycaemic clamp (PG 2.8 ± 0.2 mmol/l, approximate duration 55 min) and one euglycaemic clamp (PG 5.5 mmol/l ± 10%). PG levels were maintained by hyperinsulinaemic glucose clamping. Cognitive functioning was assessed during hypoglycaemia and euglycaemia conditions using a modified version of the digit symbol substitution test (mDSST) and control DSST (cDSST). Simultaneously, regional cerebral blood flow (rCBF) was measured in pre-specified brain regions by six H215O-positron emission tomographies (PET) per session. RESULTS: Working memory was impaired during hypoglycaemia as indicated by a statistically significantly lower mDSST score (estimated treatment difference [ETD] -0.63 [95% CI -1.13, -0.14], p = 0.014) and a statistically significantly longer response time (ETD 2.86 s [7%] [95% CI 0.67, 5.05], p = 0.013) compared with euglycaemia. During hypoglycaemia, mDSST task performance was associated with increased activity in the frontal lobe regions, superior parietal lobe and thalamus, and decreased activity in the temporal lobe regions (p < 0.05). Working memory activation (mDSST - cDSST) statistically significantly increased blood flow in the striatum during hypoglycaemia (ETD 0.0374% [95% CI 0.0157, 0.0590], p = 0.002). CONCLUSIONS/INTERPRETATION: During hypoglycaemia (mean PG 2.9 mmol/l), working memory performance was impaired. Altered performance was associated with significantly increased blood flow in the striatum, a part of the basal ganglia implicated in regulating motor functions, memory, language and emotion. TRIAL REGISTRATION: NCT01789593, clinicaltrials.gov FUNDING: This study was funded by Novo Nordisk.

The Impact of Nocturnal Hypoglycemia on Sleep in Subjects With Type 2 Diabetes.

OBJECTIVE: The aim of this trial was to investigate the impact of nocturnal hypoglycemia on sleep patterns (assessed by polysomnography) and counterregulatory hormones. RESEARCH DESIGN AND METHODS: In this single-blinded, crossover trial, 26 subjects with type 2 diabetes attended two experimental night visits (one normoglycemic and one hypoglycemic) in randomized order. Plasma glucose (PG) levels were controlled by hyperinsulinemic glucose clamping. On the hypoglycemic night, hypoglycemia was induced after reaching sleep stage N2 by turning off glucose infusion until the PG target of 2.7-2.8 mmol/L was reached and maintained for 15 min. Thereafter, subjects were brought back to normoglycemia for the rest of the night. On the normoglycemic night, PG was maintained at 5.0-7.0 mmol/L throughout the night. RESULTS: During the first 4 h of sleep (0-4 h; after reaching sleep stage N2), no difference between experimental nights was observed in the rate of electroencephalography-identified arousals or awakenings, but the rate of awakenings was 27% lower during 4-8 h and 20% lower during 0-8 h on the hypoglycemic night than on the normoglycemic night (both statistically significant). Total sleep time tended to be longer on the hypoglycemic night (observed means 366 vs. 349 min, P nonsignificant). Statistically significantly higher counterregulatory hormonal responses (adrenaline, growth hormone, and cortisol) to hypoglycemia were observed compared with normoglycemia. CONCLUSIONS: Nocturnal hypoglycemia in patients with type 2 diabetes caused a decrease in awakening response in the 4-8-h period following the event. These findings underscore the risks associated with nocturnal hypoglycemia because nocturnal hypoglycemia potentially affects the patient's ability to wake up and respond with an adequate intake of carbohydrates.

Efficacy and safety of biphasic insulin aspart 70/30 in type 2 diabetes patients of different race or ethnicity (INITIATEplus trial).

OBJECTIVE: To determine if self-titration using biphasic insulin aspart 70/30 (BIAsp 30) had a different impact on efficacy and safety across different racial/ethnic subgroups. RESEARCH DESIGN/METHODS: This was an exploratory, post hoc analysis by race (White vs. Black/African-American) and ethnicity (Hispanic/Latino vs. non-Hispanic/Latino) of data from the INITIATEplus trial. Participants were treated twice-daily with BIAsp 30 over 24 weeks. TRIAL REGISTRATION: NCT00101751. MAIN OUTCOME MEASURES: Efficacy endpoints included reductions in mean glycated hemoglobin (A1C) and fasting plasma glucose (FPG). Safety endpoints included hypoglycemia rates (events/patient-year) and adverse events. Body weight changes were also measured. RESULTS: Glycemic control improved by a similar extent for all demographic groups. Observed mean decreases in A1C ranged from 2.4% to 2.6% after 24 weeks' treatment. Baseline-adjusted mean A1C decreases for White vs. Black/African-American subjects were 2.56% and 2.13% (p < 0.0001), and for Hispanic/Latino vs. non-Hispanic/Latino subjects were 2.45% and 2.42% (p = 0.677), respectively. Final FPG values were similar among all groups (141-146 mg/dL [7.83-8.10 m mol/L]), and baseline-adjusted FPG decreases were not significantly different (p > 0.025) between groups. Hypoglycemia was low for White, Black/African-American, Hispanic/Latino, and non-Hispanic/Latino subjects (0.08, 0.04, 0.03, and 0.07 major events/patient-year, with 0.60, 0.30, 0.37, and 0.52 minor events/patient-year, respectively). Body weight increases were 3.17 and 3.06 kg (White vs. African-American) and 2.69 and 3.19 kg (Hispanic/Latino vs. non-Hispanic/Latino). Final weight-adjusted total daily insulin doses were 0.60 U/kg for Black/African-American subjects vs. 0.78 U/kg for White subjects (p < 0.0001), and 0.71 U/kg for Hispanic/Latino subjects vs. 0.74 U/kg for non-Hispanic/Latino subjects (p = 0.42). LIMITATIONS: The trial was not designed or powered for comparisons across racial or ethnic groups, subjects were not stratified for pre-baseline medication regimens between each race and ethnic group, and unequal subject numbers and baseline A1C disparities existed between the pairs of groups being compared. CONCLUSIONS: Diabetes self-management with BIAsp 30 using an easily followed self-titration algorithm produced low hypoglycemia rates. All subgroups achieved A1C reductions >2.1% and FPG declines >82 mg/dL that were similar across groups, demonstrating that self-titration of BIAsp 30 can successfully be pursued in a primary care setting by patients who had previously failed to meet ADA A1C targets under oral antidiabetes therapy, with race or ethnicity not an obstacle to achieving better glycemic control.

Efficacy and tolerability of self-titrated biphasic insulin aspart 70/30 in patients aged >65 years with type 2 diabetes: an exploratory post hoc subanalysis of the INITIATEplus trial.

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

A(1c) control in a primary care setting: self-titrating an insulin analog pre-mix (INITIATEplus trial).

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

Fixed-dose combination tablet of repaglinide and metformin is bioequivalent to concomitantly administered individual tablets of repaglinide and metformin : randomized, single-blind, three-period crossover study in healthy subjects.

BACKGROUND AND OBJECTIVE: Repaglinide and metformin enhance insulin secretion and decrease hepatic gluconeogenesis, respectively, and are commonly coadministered as separate formulations to treat patients with type 2 diabetes mellitus. A single combination therapy tablet offers increased patient convenience and the subsequent potential for increased therapy compliance. The aim of this randomized, single-blind, three-period crossover study was to determine the bioequivalence of a fixed-dose combination (FDC) tablet of repaglinide/metformin 2 mg/500 mg versus repaglinide 2 mg and metformin 500 mg coadministered as separate formulations. Secondary objectives included a comparison of the dose proportionality of an FDC tablet of repaglinide/metformin 1 mg/500 mg and an FDC tablet of repaglinide/metformin 2 mg/500 mg, as well as the safety and tolerability of repaglinide and metformin in combination tablet therapy. METHODS: Healthy subjects (n = 93, age 18-45 years) were randomized to one of six possible treatment sequences (Williams design) of an FDC tablet of repaglinide/metformin 2 mg/500 mg, repaglinide 2 mg and metformin 500 mg coadministered as separate tablets and an FDC of repaglinide/metformin 1 mg/500 mg. Fifty-five subjects completed the study. Four primary pharmacokinetic endpoints (area under the plasma concentration-time curve [AUC] from time 0 hours to infinity; AUC from time 0 to 24 hours; AUC from time 0 hours to time t [the last time of measurable concentration after dosing]; and the maximum plasma concentration) were used to assess bioequivalence and dose proportionality. The safety and tolerability of repaglinide and metformin in combination tablet therapy were also evaluated. RESULTS: Both repaglinide and metformin in the combination tablet were determined to be bioequivalent to the individual tablets of repaglinide 2 mg and metformin 500 mg, as the limits of the 90% confidence interval of the mean treatment ratio for all pharmacokinetic parameters were contained within the pre-specified interval required for bioequivalence (0.8, 1.25). Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was determined to be dose proportional to an FDC of repaglinide/metformin 1 mg/500 mg for all analysed endpoints. No withdrawals as a result of adverse events occurred during this study. In addition, no clinically relevant abnormalities were found during physical examinations, in vital signs, ECG parameters or clinical laboratory parameters. CONCLUSION: An FDC tablet of repaglinide/metformin 2 mg/500 mg was bioequivalent to individual tablets of repaglinide 2 mg and metformin 500 mg. Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was dose proportional to an FDC tablet of repaglinide/metformin 1 mg/500 mg. Finally, no unexpected safety concerns were noted with repaglinide/metformin combination tablet therapy. Our results suggest that FDC tablets of repaglinide and metformin would provide safety and efficacy comparable to that of repaglinide and metformin administered as separate formulations.

Children's residential exposure to chlorpyrifos: application of CPPAES field measurements of chlorpyrifos and TCPy within MENTOR/SHEDS-Pesticides model.

The comprehensive individual field-measurements on non-dietary exposure collected in the Children's-Post-Pesticide-Application-Exposure-Study (CPPAES) were used within MENTOR/SHEDS-Pesticides, a physically based stochastic human exposure and dose model. In this application, however, the model was run deterministically. The MENTOR/SHEDS-Pesticides employed the CPPAES as input variables to simulate the exposure and the dose profiles for seven children over a 2-week post-application period following a routine residential and professional indoor crack-and-crevice chlorpyrifos application. The input variables were obtained from a personal activity diary, microenvironmental measurements and personal biomonitoring data obtained from CPPAES samples collected from the individual children and in their homes. Simulation results were compared with CPPAES field measured values obtained from the children's homes to assess the utility of the different microenvironmental data collected in CPPAES, i.e. indicator toys and wipe samplers to estimate aggregate exposures that can be result from one or more exposure pathways and routes. The final analyses of the database involved comparisons of the actual data obtained from the individual biomarker samples of a urinary metabolite of chlorpyrifos (TCPy) and the values predicted by MENTOR/SHEDS-Pesticides using the CPPAES-derived variables. Because duplicate diet samples were not part of the CPPAES study design, SHEDs-Pesticides simulated dose profiles did not account for the dietary route. The research provided more confidence in the types of data that can be used in the inhalation and dermal contact modules of MENTOR/SHEDS-Pesticides to predict the pesticide dose received by a child. It was determined that we still need additional understanding about: (1) the types of activities and durations of activities that result in non-dietary ingestion of pesticides and (2) the influence of dietary exposures on the levels of TCPy found in the urine.