SummaryBackgroundSeveral studies have shown that diabetes confers a higher relative risk of vascular mortality among women than among men, but whether this increased relative risk in women exists across age groups and within defined levels of other risk factors is uncertain. We aimed to determine whether differences in established risk factors, such as blood pressure, BMI, smoking, and cholesterol, explain the higher relative risks of vascular mortality among women than among men.MethodsIn our meta-analysis, we obtained individual participant-level data from studies included in the Prospective Studies Collaboration and the Asia Pacific Cohort Studies Collaboration that had obtained baseline information on age, sex, diabetes, total cholesterol, blood pressure, tobacco use, height, and weight. Data on causes of death were obtained from medical death certificates. We used Cox regression models to assess the relevance of diabetes (any type) to occlusive vascular mortality (ischaemic heart disease, ischaemic stroke, or other atherosclerotic deaths) by age, sex, and other major vascular risk factors, and to assess whether the associations of blood pressure, total cholesterol, and body-mass index (BMI) to occlusive vascular mortality are modified by diabetes.ResultsIndividual participant-level data were analysed from 980 793 adults. During 9·8 million person-years of follow-up, among participants aged between 35 and 89 years, 19 686 (25·6%) of 76 965 deaths were attributed to occlusive vascular disease. After controlling for major vascular risk factors, diabetes roughly doubled occlusive vascular mortality risk among men (death rate ratio [RR] 2·10, 95% CI 1·97–2·24) and tripled risk among women (3·00, 2·71–3·33; χ2 test for heterogeneity p<0·0001). For both sexes combined, the occlusive vascular death RRs were higher in younger individuals (aged 35–59 years: 2·60, 2·30–2·94) than in older individuals (aged 70–89 years: 2·01, 1·85–2·19; p=0·0001 for trend across age groups), and, across age groups, the death RRs were higher among women than among men. Therefore, women aged 35–59 years had the highest death RR across all age and sex groups (5·55, 4·15–7·44). However, since underlying confounder-adjusted occlusive vascular mortality rates at any age were higher in men than in women, the adjusted absolute excess occlusive vascular mortality associated with diabetes was similar for men and women. At ages 35–59 years, the excess absolute risk was 0·05% (95% CI 0·03–0·07) per year in women compared with 0·08% (0·05–0·10) per year in men; the corresponding excess at ages 70–89 years was 1·08% (0·84–1·32) per year in women and 0·91% (0·77–1·05) per year in men. Total cholesterol, blood pressure, and BMI each showed continuous log-linear associations with occlusive vascular mortality that were similar among individuals with and without diabetes across both sexes.InterpretationIndependent of other major vascular risk factors, diabetes substantially increased vascular risk in both men and women. Lifestyle changes to reduce smoking...

Background and ObjectivesThe aim of this study is to investigate canagliflozin as an initial therapy in type 2 diabetes mellitus and to explore the effects on metabolic parameters in relation to effects on glycemic control.Subjects and MethodsTreatment-naïve subjects with type 2 diabetes mellitus received canagliflozin 50–100 mg/day monotherapy. At 3 months, levels of glycemic and non-glycemic parameters were compared with those at baseline (n = 39). As a comparator, our previous data of baseline glycosylated hemoglobin (HbA1c)-matched treatment-naïve subjects with ipragliflozin 25–50 mg monotherapy (n = 27) were employed.ResultsSignificant reductions in HbA1c (from 9.96 to 8.33%), fasting blood glucose (−23.9%), homeostasis model assessment-R (HOMA-R, −33.5%), body mass index (−1.8%), and uric acid (UA, −5.2%) levels and significant increases in homeostasis model assessment-B (HOMA-B, 30.1%) levels were observed. Approximately one third of the subjects experienced certain adverse events. Similar results were obtained with ipragliflozin. Baseline levels of HbA1c, triglycerides, non-high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) were chosen as significant contributing factors for the changes in HbA1c levels with canagliflzoin, while only baseline HbA1c levels were selected as such a factor with ipragliflozin. Significant positive correlations between the changes in HbA1c and changes in non-HDL-C (R = 0.3954) or between changes in HbA1c and changes in LDL-C (R = 0.4317) were observed with canagliflozin. With ipragliflozin, no such correlations were noted. No correlations between the changes in HbA1c and changes in body mass index were seen with both drugs.ConclusionsThese results suggest that (1) canagliflozin appears to offer clinically beneficial outcomes as an initial therapy in subjects with type 2 diabetes mellitus, although with certain adverse events. (2) Atherogenic cholesterols including non-HDL-C and LDL-C could be involved in the glycemic efficacy of canagliflozin. This was not the case with ipragliflozin. (3) Unexpectedly, weight reductions with canagliflozin are not associated with its glycemic efficacy.

These results suggest that ipragliflozin has good glycemic efficacy as an initial therapy in subjects with T2DM, although certain adverse events or tolerability issues are concerned. It improves insulin sensitivity and may restore the impaired beta-cell function. However body weight reduction with ipragliflozin is not associated with its glycemic efficacy.

ObjectivesThe aim of this study was to investigate the relations between the changes in body weight and those of glycemic and non-glycemic parameters in drug-naïve subjects with type 2 diabetes mellitus (T2DM) treated with canagliflozin monotherapy.MethodsSubjects received 50–100 mg/day canagliflozin monotherapy for 3 months (n = 36), and were then divided into two groups: (1) those who lost weight [changes in (Δ)BMI ≤ − 0.45, p < 0.00001: Group L(ost), n = 20); and (2) those who did not lose weight [ΔBMI > − 0.45, p = non-significant: Group N(eutral), n = 16]. At 3 months, the levels of glycemic and non-glycemic parameters were compared with those at baseline.ResultsSignificant reductions of BMI levels (− 2.1%, p < 0.00001) were observed for the overall subjects. At baseline, fasting blood glucose (FBG) and HbA1c levels were significantly higher, and homeostasis model assessment-B (HOMA-B) levels were significantly lower in Group N versus Group L. Similar reductions of HbA1c (Group L: 9.54 ± 2.58% to 7.54 ± 1.27%, p < 0.05; Group N: 11.23 ± 2.27% to 9.19 ± 1.64%, p < 0.0002) and homeostasis model assessment-R (HOMA-R; Group L: − 32.3%, p < 0.005; Group N: − 36.5%, p < 0.02) levels were seen in these two groups. However, other parameters showed distinct regulatory patterns. (1) Group L: significant reductions in uric acid (UA) levels (− 6.9%, p < 0.02) were observed. Significant correlations between the changes in FBG and HOMA-R (R = 0.458, p < 0.05) were seen. (2) Group N: significant increases in HOMA-B (+ 69.4%, p < 0.007) and reductions in free fatty acid (FFA; − 25.8%, p < 0.02) levels were observed. Significant negative or positive correlations between the changes in (Δ)FBG and ΔHOMA-B (R = − 0.557, p < 0.03), and between ΔFBG and ΔHOMA-R (R = 0.458, p < 0.05) were seen.ConclusionsThese results indicate that (1) body weight changes with canagliflozin were not associated with its glycemic efficacy; and (2) distinct glucose-lowering pathways may exist with canagliflozin, reducing insulin resistance in those who lose weight and enhancing β-cell function, as well as reducing insulin resistance, possibly via the decreased FFA levels, in those who do not lose weight.

Objectives:The aim of this project is to compare the effect of canagliflozin monotherapy on metabolic parameters between responders and nonresponders with this drug. This study is a prospective, unblinded, observational study.Subjects and Methods:Drug-naïve patients with type 2 diabetes mellitus received only 50–100 mg/day canagliflozin for 3 months (n = 39). They were divided into two groups according to the novel “A1c index” to assess glycemic efficacies; responders (n = 24) and nonresponders (n = 15).Results:At baseline, glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) were significantly higher and homeostatic model assessment (HOMA)-B and body mass index (BMI) were significantly lower in responders. In both groups, similar, significant reductions of BMI (−1.9% with responder and −1.8% with nonresponder) and HOMA-R (−35.8% for responder and –31.5% for nonresponder) were observed. However, differences were seen with other parameters as follows: 1) responders: significant reductions of HbA1c (10.95%–8.44%), FBG (−29.6%) or free fatty acid (FFA) (−16.2%), and significant increases of HOMA-B (79.7%) were observed. 2) Nonresponders: significant reductions of serum uric acid (UA) (−8.6%) levels were seen. Significant correlations were observed between the baseline levels of serum UA and those of HOMA-B (R = 0.7259). However, this link became uncorrelated with the treatment with canagliflozin.Conclusions:These results suggest that (1) responders with canagliflozin have lower BMI and beta-cell function. Reductions of body weight with canagliflozin were not associated with its glycemic efficacy, (2) reduced FFA levels and enhanced insulin sensitivity/beta-cell function could be a potential mechanism of good glycemic efficacy of canagliflozin, and (3) serum UA might be involved in modulating beta-cell function during canagliflozin treatment.