Change In HbA Research Articles

Results of semaglutide in patients older than 70 years, a real-world study of efficacy and safety.

The aim of this study is to investigate the use of once-weekly semaglutide in a real population of patients with type 2 diabetes mellitus (T2DM) over 70 years in two Spanish hospitals. An observational, retrospective, and multicenter clinical study was designed. It included 60 patients with T2DM, with a mean age of 76.5 years, 63.3% women, and a mean of 15.5 years of evolution of T2DM, all managed in the outpatient clinical setting. The primary endpoint was the change in HbA<inf>1c</inf> from baseline to the end of the study. The secondary endpoints included changes in body weight and the proportion of patients achieving HbA<inf>1c</inf> <7.0% and body weight loss >5%. After 12 months of follow-up, the reductions in HbA<inf>1c</inf> were -0.61±0.9% (P<0.0001) in the total cohort. Body weight reductions were -8.2±5.3 kg (P<0.0001). Overall, 67% reached the objective of an HbA<inf>1c</inf> level of <7%, and 73% achieved a weight loss of ≥5%. In routine clinical practice in Spain, the use of semaglutide once a week was associated with statistically significant and clinically relevant improvements in HbA<inf>1c</inf> and body weight in adults aged over 70 years with T2DM, without notable adverse effects, which supports real-world use.

A Real-World Study in Patients with Type 2 Diabetes Treated with Gliclazide Modified Release during Fasting in Gulf Cooperation Council Countries: An Analysis from the International DIA-RAMADAN Study

Introduction: The safety and effectiveness of gliclazide modified release (MR) in patients with type 2 diabetes mellitus (T2DM) who fasted during Ramadan were previously published. Here, we carried out a regional analysis among patients living in Gulf Cooperation Council (GCC) countries. Patients and Methods: DIA-RAMADAN was a real-world, observational, international, noncomparative study conducted in nine countries that included >1200 T2DM adults receiving gliclazide MR for at least 90 days before inclusion. The study comprised 2 visits: at inclusion, 6–8 weeks before the start of Ramadan (V0) and 4–6 weeks after the end of Ramadan (V1). The primary endpoint was the proportion of patients reporting ≥1 symptomatic hypoglycemic event as collected using a patient diary. Changes in HbA1c, fasting plasma glucose (FPG), and weight were also analyzed. This manuscript represents data collected in GCC countries (Kuwait, Saudi Arabia, and United Arab Emirates). Results: Data from 161 patients were analyzed: mean (SD) age 56.8 (10.6) years, 30.4% women, body mass index 29.1 (3.7) kg/m2, T2DM disease duration 6.7 (3.3) years, baseline HbA1c 7.9% (0.8). The proportions of patients reporting ≥1 symptomatic hypoglycemic event or confirmed hypoglycemia during Ramadan were 4.3% and 0.6%, respectively. No cases of severe hypoglycemia were reported. Significant reductions in main variables were observed before the start of Ramadan (V0) and 4–6 weeks after the end of Ramadan (V1): HbA1c (from 7.9 [0.8] to 7.6 [0.7]%; p value <0.001), FPG (from 143.5 [24.3] to 137.9 [25.2] mg/dL; p value = 0.031), and weight (from 79.0 [73.0–86.0] to 78.0 [72.0–85.0] kg; p value = 0.018). Conclusions: These real-world data indicate that patients with T2DM treated with gliclazide MR during Ramadan in the selected GCC countries have a low risk of hypoglycemia and maintain glycemic control and weight while fasting.

Impact of Androgen Deprivation Therapy on Non-Alcoholic Fatty Liver Disease in Patients with Prostate Cancer: A CT Evaluation

Purpose: The aim of this study was to investigate the influence of androgen deprivation therapy (ADT) on the progression of non-alcoholic fatty liver disease (NAFLD) in patients with prostate cancer (PCa) by evaluation of hepatic steatosis on computed tomography (CT). Methods: The study included 77 PCa patients who underwent abdominal CT at baseline and after 6 months of ADT. The degree of hepatic steatosis was evaluated according to the attenuation value for liver parenchyma (CT_LP), the attenuation ratio for liver and spleen (LS_ratio), and the difference in attenuation between LS (LS_dif). The associations between these 3 indices and various metabolic syndrome-related factors were analyzed. Results: The number of NAFLD patients increased from 9 (11.6%) at baseline to 16 (20.7%) after ADT. The CT_LP, LS_ratio, and LS_dif values were significantly lower after ADT than before (p < 0.05). There were significant correlations between the percent change in CT_LP and the percent change in HbA_1c, between the percent change in LS_ratio and the percent change in abdominal circumference, and between the percent change in LS_dif and the percent change in BMI. Conclusions: Six months of ADT was associated with significant progression of NAFLD in PCa patients. This progression was strongly correlated with changes in HbA_1c, abdominal circumference, and BMI.

SAT-139 Clinical Impact of Oral Semaglutide Compared with Sitagliptin in T2D on Metformin ± Sulfonylurea: The Pioneer 3 Trial

Long-term effects, safety and tolerability of oral semaglutide (SEMA; a GLP-1 receptor agonist [GLP-1RA]) vs sitagliptin (SITA) as add-on to metformin ± sulfonylurea was investigated in patients (pts) with T2D in a 78-week, double-blind, double-dummy trial. Pts were randomized to once daily oral SEMA 3 mg (N=466), 7 mg (N=466) or 14 mg (N=465), or SITA 100 mg (N=467). Primary endpoint was change in HbA1c, confirmatory secondary endpoint was change in body weight, both from baseline to week 26. Two estimands were defined (‘treatment policy [TPol] estimand’: treatment effect regardless of trial product discontinuation and rescue medication use; ‘trial product estimand’: treatment effect assuming on trial product without rescue medication use) in all randomized pts. Confirmatory testing was based on the TPol estimand; within each dose level, non-inferiority for the primary endpoint (non-inferiority margin: 0.3%) had to be confirmed before testing superiority for the primary and confirmatory secondary endpoints. Estimated week 26 HbA1c reductions with 7 and 14 mg were –1.0% and –1.3%, vs –0.8% with SITA, and were superior (TPol estimand; estimated treatment difference vs SITA [ETD; 95% CI]: –0.3% [–0.4, –0.1]; –0.5% [–0.6, –0.4]; both P<0.001). Non-inferiority of 3 mg vs SITA was not confirmed (ETD: 0.2% [0.1, 0.3]; P=0.09); HbA1c reductions favored SITA (P=0.008). Similar results were obtained with the trial product estimand at week 26 (ETD: –0.3% [–0.4, –0.2]; –0.6% [–0.7, –0.5] for 7 and 14 mg; both P<0.001 favoring oral SEMA; 0.2% [0.1, 0.4] for 3 mg; P<0.001 favoring SITA). At week 78, HbA1c reductions with 14 mg were statistically significantly greater vs SITA for both estimands; there was no statistically significant difference with 3 mg (both estimands) or 7 mg (TPol estimand). All oral SEMA doses significantly lowered body weight vs SITA at week 26 for the TPol estimand (ETD: –0.6 kg [–1.1, –0.1]; –1.6 kg [–2.0, –1.1]; –2.5 kg [–3.0, –2.0] for 3, 7 and 14 mg; all P<0.02), confirming superiority of 7 and 14 mg (3 mg superiority not tested), and the trial product estimand (ETD: –0.5 kg [–1.0, –0.1]; –1.5 kg [–2.0, –1.1]; –2.6 kg [–3.1, –2.1] for 3, 7 and 14 mg; all P<0.03). Week 78 body weight reductions were also statistically significant, favoring oral SEMA (all doses, both estimands). Adverse events (AEs) occurred similarly across treatment arms. The most common AE with oral SEMA was transient mild/moderate nausea, affecting 7.5–15.7% of pts. Serious AEs were reported by 13.7%, 10.1% and 9.5% of pts for 3, 7 and 14 mg, and 12.4% for SITA. AEs led to premature trial product discontinuation in 5.6%, 5.8% and 11.6% of pts for 3, 7 and 14 mg, and 5.2% for SITA, mainly due to gastrointestinal AEs. In conclusion, oral semaglutide 7 and 14 mg provided statistically superior HbA1c and body weight reductions at week 26 compared with SITA 100 mg (TPol estimand). Safety and tolerability were consistent with other GLP-1RAs.

Slope of change in HbA1c from baseline with empagliflozin compared with sitagliptin or glimepiride in patients with type 2 diabetes.

SummaryAimsTo analyse the effect of baseline glycated haemoglobin (HbA1c) on the reduction in HbA1c with empagliflozin compared with sitagliptin or glimepiride in patients with type 2 diabetes.Materials and methodsUsing regression analyses of individual patient data from two Phase III studies, we compared the change in HbA1c according to a unit change in baseline HbA1c (the slope) with empagliflozin 10 mg or 25 mg vs sitagliptin (monotherapy) after 24 weeks, and with empagliflozin 25 mg vs glimepiride (as add‐on to metformin) after 52 weeks.ResultsSteeper slopes of HbA1c decline were observed with empagliflozin 10 or 25 mg vs sitagliptin monotherapy at week 24. Regression analysis showed slopes of −0.59 (95% CI −0.70, −0.47), −0.49 (95% CI −0.62, −0.37) and −0.29 (95% CI −0.42, −0.15) for empagliflozin 10 mg, empagliflozin 25 mg and sitagliptin, respectively (P < .001 and P < .05 for empagliflozin 10 mg and empagliflozin 25 mg, respectively, vs sitagliptin). Similarly, a steeper slope of HbA1c decline was observed with empagliflozin 25 mg vs glimepiride as add‐on to metformin at week 52. Regression analysis showed slopes of − 0.52 (95% CI −0.59, −0.44) and −0.32 (95% CI −0.39, −0.25) for empagliflozin 25 mg and glimepiride, respectively (P < .001 for empagliflozin 25 mg vs glimepiride).ConclusionsIncremental reductions in HbA1c with increasing baseline HbA1c are greater with empagliflozin compared with sitagliptin or glimepiride in patients with type 2 diabetes.

Changes in HbA1c and circulating and adipose tissue androgen levels in overweight‐obese women with polycystic ovary syndrome in response to electroacupuncture

SummaryAimInsulin sensitivity is ~40% lower in women with polycystic ovary syndrome (PCOS) than in controls. We tested the hypothesis that 5 weeks of electroacupuncture treatment improves glucose regulation and androgen levels in overweight/obese women with PCOS.Material and MethodsSeventeen women with PCOS, aged 18 to 38 years, with a body mass index (BMI) ≥25 kg/m2 and diagnosed with PCOS were included in this experimental and feasibility study and subjected to five weeks of electroacupuncture treatments three times/week. The primary outcome was changes in whole‐body glucose homeostasis measured by euglycemic hyperinsulinemic clamp before and after the intervention. Secondary outcome were changes in HbA1c, circulating catecholamines, adipocyte size and adipose tissue expression of sex steroids and nerve growth factor (NGF).ResultsNo significant change in glucose homeostasis was observed, but HbA1c decreased by 9.5% (p = 0.004), circulating testosterone decreased by 22% (p = 0.0007) and dihydrotestosterone decreased by 12% (p = 0.007). The two vagal activity markers of plasma serotonin levels and the dopamine metabolite homovanillic acid decreased by 21% (p = 0.027) and 20% (p = 0.011), respectively. Adipose tissue concentrations of testosterone decreased by 18% (p = 0.049), and androstenedione decreased by 13% (p = 0.035), and mature NGF/proNGF ratio, a marker of sympathetic activity, increased (p = 0.04). These changes occurred without changes in anthropometrics.ConclusionFive weeks of electroacupuncture treatment improves HbA1c and circulating and adipose tissue androgens in women with PCOS. This effect is mediated, at least in part, via modulation of vagal activity and adipose tissue sympathetic activity. Based on these findings, we have recently initiated a randomized controlled study (NTC02647827).

Assessing the Effect of Personalized Diabetes Risk Assessments During Ophthalmologic Visits on Glycemic Control: A Randomized Clinical Trial.

Optimization of glycemic control is critical to reduce the number of diabetes mellitus-related complications, but long-term success is challenging. Although vision loss is among the greatest fears of individuals with diabetes, comprehensive personalized diabetes education and risk assessments are not consistently used in ophthalmologic settings. To determine whether the point-of-care measurement of hemoglobin A(1c) (HbA(1c)) and personalized diabetes risk assessments performed during retinal ophthalmologic visits improve glycemic control as assessed by HbA(1c) level. Ophthalmologist office-based randomized, multicenter clinical trial in which investigators from 42 sites were randomly assigned to provide either a study-prescribed augmented diabetes assessment and education or the usual care. Adults with type 1 or 2 diabetes enrolled into 2 cohorts: those with a more-frequent-than-annual follow-up (502 control participants and 488 intervention participants) and those with an annual follow-up (368 control participants and 388 intervention participants). Enrollment was from April 2011 through January 2013. Point-of-care measurements of HbA1c, blood pressure, and retinopathy severity; an individualized estimate of the risk of retinopathy progression derived from the findings from ophthalmologic visits; structured comparison and review of past and current clinical findings; and structured education with immediate assessment and feedback regarding participant's understanding. These interventions were performed at enrollment and at routine ophthalmic follow-up visits scheduled at least 12 weeks apart. Mean change in HbA(1c) level from baseline to 1-year follow-up. Secondary outcomes included body mass index, blood pressure, and responses to diabetes self-management practices and attitudes surveys. In the cohort with more-frequent-than-annual follow-ups, the mean (SD) change in HbA(1c) level at 1 year was -0.1% (1.5%) in the control group and -0.3% (1.4%) in the intervention group (adjusted mean difference, -0.09% [95% CI, -0.29% to 0.12%]; P = .35). In the cohort with annual follow-ups, the mean (SD) change in HbA(1c) level was 0.0% (1.1%) in the control group and -0.1% (1.6%) in the intervention group (mean difference, -0.05% [95% CI, -0.27% to 0.18%]; P = .63). Results were similar for all secondary outcomes. Long-term optimization of glycemic control is not achieved by a majority of individuals with diabetes. The addition of personalized education and risk assessment during retinal ophthalmologic visits did not result in a reduction in HbA(1c) level compared with usual care over 1 year. These data suggest that optimizing glycemic control remains a substantive challenge requiring interventional paradigms other than those examined in our study. clinicaltrials.gov Identifier:NCT01323348.

Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: the KORA S4/F4 study.

The role of biomarkers of subclinical inflammation in the early deterioration of glycaemia before type 2 diabetes is largely unknown. We hypothesised that increased levels of circulating proinflammatory biomarkers and decreased circulating adiponectin would be associated with 7 year increases of HbA(1c) in non-diabetic individuals. This study was based on individuals who participated in the prospective Cooperative Health Research in the Region of Augsburg (KORA) S4 survey (1999-2001) and the 7 year follow-up KORA F4 (2006-2008) survey. Individuals with type 2 diabetes at baseline or with a diagnosis of diabetes in the period between both surveys were excluded, which left a sample of 850 men and women. Multivariable linear regression analyses were performed to assess associations among baseline values of leucocyte count and levels of acute-phase proteins (high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA] and fibrinogen), IL-6 and adiponectin with changes in HbA1c between baseline and follow-up. A high leucocyte count and high hsCRP, SAA and IL-6 levels were positively associated with changes in HbA(1c) after adjusting for age, sex, lifestyle factors and baseline HbA(1c). In contrast, the adiponectin level was inversely associated with changes in HbA(1c) (p value between <0.0001 and 0.020). The associations of leucocyte count and levels of hsCRP and SAA with HbA(1c) changes remained significant after additional adjustment for waist circumference and circulating lipids at baseline and for the 7 year change in waist circumference (p value between 0.004 and 0.045). An elevated leucocyte count and elevated hsCRP and SAA were associated with early deterioration of glycaemia before the diagnosis of type 2 diabetes. These associations were largely independent of baseline abdominal adiposity and increases in waist circumference.

Effects of advanced carbohydrate counting in patients with Type 1 diabetes: a systematic review

Advanced carbohydrate counting, a systematic method for insulin bolus calculation, is recommended in the management of type 1 diabetes. The aim of this systematic review was to summarize all available evidence from randomized and observational studies of the effects of advanced carbohydrate counting on glycaemic control (HbA(1c)), psychosocial measures, weight and hypoglycaemic events in patients of all age groups with type 1 diabetes on a basal-bolus insulin regimen. An electronic search of Scopus, MEDLINE and The Cochrane Library conducted in January 2013 identified 27 relevant articles. Six were randomized controlled trials and 21 were observational studies. Large heterogeneity existed across studies with regard to study design and patient populations. Reporting of statistical measures was insufficient to serve as a basis for a meta-analysis. Overall, the studies demonstrated a positive trend in change in HbA(1c) after introduction of advanced carbohydrate counting. Reductions in HbA(1c) ranged from 0.0 to 13 mmol/mol (0.0-1.2%). Most psychosocial measures improved; however, only few improvements were considered clinically relevant. Both weight gain and reduction were registered, but most studies found no significant weight changes. The majority of studies assessing the incidence of hypoglycaemic events found a significant reduction in the event rate and none reported an increase in the incidence. In summary, the currently available literature does not provide sufficient evidence to definitively determine the effects of advanced carbohydrate counting on HbA(1c), psychosocial measures, weight or hypoglycaemic events. Nevertheless, the method still appears preferable to other insulin dosing procedures, which justifies continued use and inclusion of advanced carbohydrate counting in clinical guidelines.

Effect of large doses of parenteral vitamin D on glycaemic control and calcium/phosphate metabolism in patients with stable type 2 diabetes mellitus: a randomised, placebo-controlled, prospective pilot study

Vitamin D (D₃) status is reported to correlate negatively with insulin production and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). However, few placebo-controlled intervention data are available. We aimed to assess the effect of large doses of parenteral D3 on glycosylated haemoglobin (HbA(₁c)) and estimates of insulin action (homeostasis model assessment insulin resistance: HOMA-IR) in patients with stable T2DM. We performed a prospective, randomised, double-blind, placebo-controlled pilot study at a single university care setting in Switzerland. Fifty-five patients of both genders with T2DM of more than 10 years were enrolled and randomised to either 300,000 IU D₃ or placebo, intramuscularly. The primary endpoint was the intergroup difference in HbA(₁c) levels. Secondary endpoints were: changes in insulin sensitivity, albuminuria, calcium/phosphate metabolism, activity of the renin-aldosterone axis and changes in 24-hour ambulatory blood pressure values. After 6 months of D₃ supply, there was a significant intergroup difference in the change in HbA(₁c) levels (relative change [mean ± standard deviation] +2.9% ± 1.5% in the D₃ group vs +6.9% ± 2.1% the in placebo group, p = 0.041) as HOMA-IR decreased by 12.8% ± 5.6% in the D₃ group and increased by 10% ± 5.4% in the placebo group (intergroup difference, p = 0.032). Twenty-four-hour urinary albumin excretion decreased in the D₃ group from 200 ± 41 to 126 ± 39, p = 0.021). There was no significant intergroup difference for the other secondary endpoints. D₃ improved insulin sensitivity (based on HOMA-IR) and affected the course of HbA(₁c) positively compared with placebo in patients with T2DM.

RETRACTED: The impact of anxiety and depression on patients within a large type 1 diabetes insulin pump population. An observational study

Continuous subcutaneous insulin infusion (CSII) is generally successful for patients with type 1 diabetes in improving glycaemic control, alleviating the burden of hypoglycaemia and improving the quality of life. There is however, a cohort of patients who fail to thrive on pump therapy and psychological factors or "brittleness" have been posited as a cause for this. We aimed to assess the extent and spectrum of psychological illness in a population of pump patients. We analysed the patient data and records of 350 patients with type 1 diabetes who formed the insulin pump patient population from a large teaching hospital and compared them with an age and sex matched reference population of patients with type 1 diabetes. We quantified the prevalence of anxiety and depression before and after the initiation of pump therapy and looked to see whether this had implications for changes in glycaemic control and hypoglycaemia reduction. Mental health problems amongst patients selected for CSII occur significantly more frequently than in a matched population with type 1 diabetes (51% vs 40%, P<0.05). Depression and anxiety were more prevalent in the CSII group. Of those with mental health problems, there is a tendency to do less well in terms of improvements in glycaemic control as indicated by changes in HbA(1c) and hypoglycaemia reduction--the latter most notable in patients with co-existent depression. The incidence and prevalence of mental health problems in individuals with diabetes is greater than that of the general population. In patients who are selected to go onto insulin pump therapy, the incidence is again greater. We have shown that in those with psychological illness, they tend to do less well in terms of improving their overall diabetes control. These results suggest that CSII may not be a suitable route of therapy alone for all of those who would fulfill the traditional criteria and suggest that psychological assessment, therapy and intervention may be an altogether more appropriate or alternative or adjunctive course of action in supporting their diabetes self management. The wider implication is that all the patients with diabetes should be regularly assessed for psychological problems and that there needs to be greater psychology/psychiatric support available to intensive diabetes clinics, especially as part of a pre-pump pathway.

Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial

Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve glycaemia in patients with type 2 diabetes by enhancing urinary glucose excretion. We compared the efficacy and safety of canagliflozin, an SGLT2 inhibitor, with glimepiride in patients with type 2 diabetes inadequately controlled with metformin. We undertook this 52 week, randomised, double-blind, active-controlled, phase 3 non-inferiority trial at 157 centres in 19 countries between Aug 28, 2009, and Dec 21, 2011. Patients aged 18-80 years with type 2 diabetes and glycated haemoglobin A1c (HbA1c) of 7·0-9·5% on stable metformin were randomly assigned (1:1:1) by computer-generated random sequence via an interactive voice or web response system to receive canagliflozin 100 mg or 300 mg, or glimepiride (up-titrated to 6 mg or 8 mg per day) orally once daily. Patients, study investigators, and local sponsor personnel were masked to treatment. The primary endpoint was change in HbA1c from baseline to week 52, with a non-inferiority margin of 0·3% for the comparison of each canagliflozin dose with glimepiride. If non-inferiority was shown, we assessed superiority on the basis of an upper bound of the 95% CI for the difference of each canagliflozin dose versus glimepiride of less than 0·0%. Analysis was done in a modified intention-to-treat population, including all randomised patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00968812. 1450 of 1452 randomised patients received at least one dose of glimepiride (n=482), canagliflozin 100 mg (n=483), or canagliflozin 300 mg (n=485). For lowering of HbA1c at 52 weeks, canagliflozin 100 mg was non-inferior to glimepiride (least-squares mean difference -0·01% [95% CI -0·11 to 0·09]), and canagliflozin 300 mg was superior to glimepiride (-0·12% [-0·22 to -0·02]). 39 (8%) patients had serious adverse events in the glimepiride group versus 24 (5%) in the canagliflozin 100 mg group and 26 (5%) in the 300 mg group. In the canagliflozin 100 mg and 300 mg groups versus the glimepiride group, we recorded a greater number of genital mycotic infections (women: 26 [11%] and 34 [14%] vs five [2%]; men: 17 [7%] and 20 [8%] vs three [1%]), urinary tract infections (31 [6%] for both canagliflozin doses vs 22 [5%]), and osmotic diuresis-related events (pollakiuria: 12 [3%] for both doses vs one [<1%]; polyuria: four [<1%] for both doses vs two [<1%]). Canagliflozin provides greater HbA1c reduction than does glimepiride, and is well tolerated in patients with type 2 diabetes receiving metformin. These findings support the use of canagliflozin as a viable treatment option for patients who do not achieve sufficient glycaemic control with metformin therapy. Janssen Research & Development, LLC.

Efficacy and safety of insulin degludec three times a week versus insulin glargine once a day in insulin-naive patients with type 2 diabetes: results of two phase 3, 26 week, randomised, open-label, treat-to-target, non-inferiority trials

Results of an exploratory phase 2 study showed that insulin degludec, a basal insulin with an action profile of longer than 42 h, provided similar glycaemic control when injected three times a week (IDeg 3TW) to once-daily insulin glargine (IGlar OD). To provide further evidence, we did two phase 3 trials to compare the efficacy and safety of IDeg 3TW with IGlar OD in insulin-naive patients with type 2 diabetes. In two 26 week, randomised, open-label, parallel group, non-inferiority trials IDeg was injected Monday, Wednesday, and Friday before breakfast (IDeg 3TW(AM)) in the AM trial (94 sites in seven countries) or with the evening meal (IDeg 3TW(PM)) in the PM trial (89 sites in seven countries), and compared with IGlar OD. Adults with type 2 diabetes (HbA(1c) 7.0-10.0%; body-mass index ≤45 kg/m(2)) were randomly allocated (1:1) without stratification by a central interactive response system to IDeg 3TW or IGlar OD. Both groups continued taking metformin with or without dipeptidyl peptidase-4 inhibitors. Insulin was titrated to achieve a prebreakfast self-monitored blood glucose (SMBG) concentration of between 3.9 and less than 5.0 mmol/L. The primary outcome was non-inferiority of IDeg 3TW compared with IGlar OD, as assessed by change in HbA(1c) from baseline to 26 weeks (non-inferiority limit of 0.4%) by ANOVA in an intent-to-treat analysis (full analysis set). These trials are registered with ClinicalTrials.gov, numbers NCT01068678 and NCT01076647. We recruited 460 patients for the AM trial (IDeg 3TW(AM), n=230; IGlar OD, n=230) and 467 patients for the PM trial (IDeg 3TW(PM), n=233; IGlar OD, n=234). After 26 weeks, mean HbA decreased by 0.9% (IDeg 3TW(AM)) and 1.3% (IGlar OD) in the AM trial, and by 1.1% (IDeg 3TW(PM)) and 1.4% (IGlar OD) in the PM trial. Non-inferiority was not confirmed in either trial (estimated treatment difference [IDeg 3TW(AM)-IGlar OD] 0.34%, 95% CI 0.18-0.51; [IDeg 3TW(PM)-IGlar OD] 0.26%, 0.11-0.41). Across the two trials, rates of confirmed hypoglycaemia (SMBG <3.1 mmol/L or severe [needing assistance]) ranged from 1.0 to 1.6 episodes per patient-year and were similar for IDeg 3TW(AM) and IGlar OD (estimated rate ratio [ERR] 1.04, 95% CI 0.69-1.55), but higher for IDeg 3TW(PM) than for IGlar OD (ERR 1.58, 1.03-2.43). The rate of nocturnal confirmed hypoglycaemia was higher for IDeg 3TW(AM) than for IGlar OD (ERR 2.12, 1.08-4.16); we noted no significant difference between IDeg 3TW(PM) and IGlar OD (ERR 0.60, 0.21-1.69). The inferior glycaemic control and increased risk of hypoglycaemia with IDeg 3TW compared with IGlar OD do not support a three-times-weekly dosing regimen. Novo Nordisk.

Effects of Mitiglinide, a Short-Acting Insulin Secretagogue, on Daily Glycemic Variability and Oxidative Stress Markers in Japanese Patients with Type 2 Diabetes Mellitus

The objective of this study was to clarify the effects of mitiglinide on daily glycemic variability and oxidative stress markers in outpatients with type 2 diabetes mellitus that is insufficiently controlled by diet and/or non-insulin secretagogues. We enrolled 24 patients with type 2 diabetes whose glycemic control had been suboptimal [i.e. glycosylated hemoglobin (HbA(1c)) ≥ 6.9 %]. The patients were treated with mitiglinide 10 mg three times daily for 16 weeks. If their glycemic control was not improved at week 8, the dose of mitiglinide was increased to 20 mg three times daily. Daily glycemic variability was assessed by 7-point self-monitoring of blood glucose for 2 days, and standard deviation (SD), M value, and mean of daily differences(MODD) were calculated. Oxidative stress was assessed by oxidized low-density lipoprotein, pentosidine,urinary 8-iso-prostaglandin F2 alpha, and urinary 8-hydroxydeoxy guanosine. After 16 weeks of mitiglinide treatment, the HbA(1c) level was significantly decreased (mean ± SD,7.4 ± 0.7 to 6.8 ± 0.5 %, P < 0.0001). Postprandial glucose excursion and glycemic variability were also significantly improved after mitiglinide treatment (all P < 0.05). The reductions in SD, M value, and MODD were 17, 50,and 48 %, respectively. There was a significant positive correlation between the change in HbA(1c) and change in SD during the study (r = 0.454, P = 0.03). There were no significant changes in oxidative stress markers. The present study supports the notion that mitiglinide improves postprandial glucose excursion and HbA(1c) level in patients with type 2 diabetes. In addition,we demonstrated that mitiglinide also effectively improves daily glycemic variability. The effect of mitiglinide on oxidative stress needs further investigation.

Antihyperglycemic, antihyperlipidemic, anti-inflammatory and adenosine deaminase&amp;ndash;lowering effects of garlic in patients with type 2 diabetes mellitus with obesity

IntroductionType 2 diabetes mellitus is a chronic disorder characterized by chronic hyperglycemia, with long term macrovascular and microvascular complications. The treatment is lifestyle management, exercise, weight control, and antihyperglycemic drugs such as sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, and meglitinide. Recently, a direct association between high levels of C-reactive protein and serum adenosine deaminase levels in patients with uncontrolled diabetes with long-term complications has been seen. This study was conducted to assess the antihyperglycemic, lipid-lowering, anti-inflammatory, and improving glycemic control of garlic in type 2 diabetes patients with obesity.Materials and methodsThis was an open-label, prospective, comparative study, conducted on 60 patients having type 2 diabetes mellitus and obesity. The patients were divided into two groups of 30 each, of either sex. Group 1 was given metformin tablets, 500 mg twice a day (BD)/three times a day (TDS), after meals, and group 2 was given metformin tablets, 500 mg BD/TDS, after meals, along with garlic (Allium sativum) capsules, 250 mg BD. Patients were routinely investigated for fasting and postprandial blood glucose, glycosylated hemoglobin (HbA1c), serum adenosine deaminase levels and lipid profile (serum cholesterol, high-density lipoprotein cholesterol, triglycerides and low-density lipoprotein cholesterol) at the start of the study. Patients were followed up for 12 weeks, with monitoring of fasting and postprandial blood glucose at 2 week intervals, and monitoring of the other parameters at the end of study. Data obtained at the end of the study was statistically analyzed using Student’s t test.ResultsIt was observed that both metformin alone and metformin with garlic reduced fasting blood glucose and postprandial blood glucose significantly, with a greater percentage reduction with metformin plus garlic; however, change in HbA1c levels was not significant. A fall in total cholesterol, triglyceride, and low-density lipoprotein and an increase in high-density lipoprotein were more pronounced in patients treated with metformin plus garlic. Similarly, a fall in C-reactive protein and adenosine deaminase levels was greater in patients taking metformin with garlic than in patients taking only metformin.ConclusionGarlic has been shown to have antihyperglycemic and lipid-lowering properties. The additional lowering of C-reactive protein and serum adenosine deaminase levels with garlic suggests that garlic can be a valuable agent in providing good glycemic control and the prevention of long-term complications.

Taspoglutide, a once‐weekly glucagon‐like peptide 1 analogue, vs. insulin glargine titrated to target in patients with Type 2 diabetes: an open‐label randomized trial

To compare the efficacy and safety of once-weekly taspoglutide with insulin glargine in patients with advanced Type 2 diabetes failing metformin and sulphonylurea combination therapy. This open-label, parallel-group, multi-centre trial randomized 1049 patients continuing metformin 1:1:1 to taspoglutide 10 mg once weekly, taspoglutide 20 mg once weekly or insulin glargine once daily with forced titration to fasting plasma glucose ≤ 6.1 mmol/l. Sulphonylureas were discontinued before randomization. The primary endpoint was change in HbA(1c) after 24 weeks. After 24 weeks, least-square mean changes from baseline in HbA(1c) in patients receiving taspoglutide 10 mg [-8 mmol/mol (se 1)] [-0.77% (se 0.05)] or taspoglutide 20 mg [-11 mmol/mol (se 1)] [-0.98% (se 0.05)] were non-inferior to insulin glargine [-9 mmol/mol (se 1)] [-0.84% (se 0.05)]; treatment difference of 0.07% (95% CI -0.06 to 0.21) and -0.14% (95% CI -0.28 to -0.01), for taspoglutide 10 and 20 mg, respectively, vs. insulin glargine. Taspoglutide was associated with more adverse events (mainly gastrointestinal) and significantly less hypoglycaemia than insulin glargine. Compared with insulin glargine, taspoglutide provided non-inferior HbA(1c) reductions associated with less hypoglycaemia, but more gastrointestinal adverse events.

Volume of supervised exercise training impacts glycaemic control in patients with type 2 diabetes: a systematic review with meta-regression analysis

Supervised exercise programmes improve glycaemic control in type 2 diabetes, but training characteristics associated with reduction in HbA(1c) remain unclear. We conducted a systematic review with meta-regression analysis of randomised clinical trials (RCTs) assessing the association between intensity and volume of exercise training (aerobic, resistance or combined) and HbA(1c) changes in patients with type 2 diabetes. Five electronic databases were searched (1980-2012) to retrieve RCTs of at least 12weeks' duration, consisting of supervised exercise training vs no intervention, that reported HbA(1c) changes and exercise characteristics. Two independent reviewers conducted study selection and data extraction. Twenty-six RCTs (2,253 patients) met the inclusion criteria. In multivariate analysis, baseline HbA(1c) and exercise frequency explained nearly 58% of between-study variance. Baseline HbA(1c) was inversely correlated with HbA(1c) reductions after the three types of exercise training. In aerobic training, exercise volume (represented by frequency of sessions) was associated with changes in HbA(1c) (weighted r = -0.64), while no variables were correlated with glycaemic control induced by resistance training. In combined training, weekly volume of resistance exercise explained heterogeneity in multivariate analysis and was associated with changes in HbA(1c) levels (weighted r = -0.70). Reduction in HbA(1c) is associated with exercise frequency in supervised aerobic training, and with weekly volume of resistance exercise in supervised combined training. Therefore, exercise volume is a major determinant of glycaemic control in patients with type 2 diabetes.

Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study

Glucagon-like peptide-1 receptor agonists exenatide and liraglutide have been shown to improve glycaemic control and reduce bodyweight in patients with type 2 diabetes. We compared the efficacy and safety of exenatide once weekly with liraglutide once daily in patients with type 2 diabetes. We did a 26 week, open-label, randomised, parallel-group study at 105 sites in 19 countries between Jan 11, 2010, and Jan 17, 2011. Patients aged 18 years or older with type 2 diabetes treated with lifestyle modification and oral antihyperglycaemic drugs were randomly assigned (1:1), via a computer-generated randomisation sequence with a voice response system, to receive injections of once-daily liraglutide (1·8 mg) or once-weekly exenatide (2 mg). Participants and investigators were not masked to treatment assignment. The primary endpoint was change in glycated haemoglobin (HbA(1c)) from baseline to week 26. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01029886. Of 912 randomised patients, 911 were included in the intention-to-treat analysis (450 liraglutide, 461 exenatide). The least-squares mean change in HbA(1c) was greater in patients in the liraglutide group (-1·48%, SE 0·05; n=386) than in those in the exenatide group (-1·28%, 0·05; 390) with the treatment difference (0·21%, 95% CI 0·08-0·33) not meeting predefined non-inferiority criteria (upper limit of CI <0·25%). The most common adverse events were nausea (93 [21%] in the liraglutide group vs 43 [9%] in the exenatide group), diarrhoea (59 [13%] vs 28 [6%]), and vomiting 48 [11%] vs 17 [4%]), which occurred less frequently in the exenatide group and with decreasing incidence over time in both groups. 24 (5%) patients allocated to liraglutide and 12 (3%) allocated to exenatide discontinued participation because of adverse events. Both once daily liraglutide and once weekly exenatide led to improvements in glycaemic control, with greater reductions noted with liraglutide. These findings, plus differences in injection frequency and tolerability, could inform therapeutic decisions for treatment of patients with type 2 diabetes. Eli Lilly and Company and Amylin Pharmaceuticals LLC.

A randomized non‐inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with Type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin

To test the hypothesis that glycaemic control achieved when switching sitagliptin to exenatide twice daily plus metformin is non-inferior to adding exenatide twice daily to sitagliptin and metformin. Patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin were randomly assigned to 20 weeks of treatment with twice-daily exenatide plus placebo and metformin (SWITCH, n = 127) or twice-daily exenatide plus sitagliptin and metformin (ADD, n = 128). Non-inferiority (0.4% margin) of SWITCH to ADD treatment, measured by change in HbA(1c) from baseline to week 20, was not shown {between-treatment difference in least-squares mean [95% CI 3 mmol/mol (0.30%)] [0.8-5.8 (0.07-0.53)]}. A greater reduction (P = 0.012) in HbA(1c) [least-squares mean (se)] was experienced by patients in the ADD group {-7 mmol/mol [-0.68%] [0.9 (0.08)]}, compared with those in the SWITCH group {-4 mmol/mol [-0.38%] [1.0 (0.09)]} and a greater proportion (P = 0.027) of patients in the ADD group (41.7%) reached < 7.0% (< 53 mmol/mol) HbA(1c) target, compared with those in the SWITCH group (26.6%) by week 20. Patients in the ADD group experienced greater fasting serum glucose (P = 0.038) and daily mean postprandial self-monitored blood glucose (P = 0.048) reductions, compared with patients in the SWITCH group, by week 20. Patients in both groups experienced a lower incidence of nausea and vomiting compared with previous exenatide studies. Non-inferiority of SWITCH to ADD treatment was not supported by the results of this study. In patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin, adding exenatide provided better glycaemic control than switching to exenatide. These results are consistent with the clinical approach that adding is better than switching to another oral anti-hyperglycaemic medication.

Hemoglobin Interactions with αB Crystallin: A Direct Test of Sensitivity to Protein Instability

As a small stress response protein, human αB crystallin, detects protein destabilization that can alter structure and function to cause self assembly of fibrils or aggregates in diseases of aging. The sensitivity of αB crystallin to protein instability was evaluated using wild-type hemoglobin (HbA) and hemoglobin S (HbS), the glutamate-6-valine mutant that forms elongated, filamentous aggregates in sickling red blood cells. The progressive thermal unfolding and aggregation of HbA and HbS in solution at 37°C, 50°C and 55°C was measured as increased light scattering. UV circular dichroism (UVCD) was used to evaluate conformational changes in HbA and HbS with time at the selected temperatures. The changes in interactions between αB crystallin and HbA or HbS with temperature were analyzed using differential centrifugation and SDS PAGE at 37°C, 50°C and 55°C. After only 5 minutes at the selected temperatures, differences in the aggregation or conformation of HbA and HbS were not observed, but αB crystallin bound approximately 6% and 25% more HbS than HbA at 37°C, and 50°C respectively. The results confirmed (a) the remarkable sensitivity of αB crystallin to structural instabilities at the very earliest stages of thermal unfolding and (b) an ability to distinguish the self assembling mutant form of HbS from the wild type HbA in solution.