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Aim To assess the effects of canagliflozin on the incidence of atrial fibrillation/atrial flutter (AF/AFL) and other key cardiorenal outcomes in a pooled analysis of the CANVAS and CREDENCE trials. Materials and Methods Participants with type 2 diabetes and high risk of cardiovascular disease or chronic kidney disease were included and randomly assigned to canagliflozin or placebo. We explored the effects of canagliflozin on the incidence of first AF/AFL events and AF/AFL-related complications (ischaemic stroke/transient ischaemic attack/hospitalization for heart failure). Major adverse cardiovascular events and a renal-specific outcome by baseline AF/AFL status were analysed using Cox regression models. Results Overall, 354 participants experienced a first AF/AFL event. Canagliflozin had no detectable effect on AF/AFL (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.67-1.02) compared with placebo. Subgroup analysis, however, suggested a possible reduction in AF/AFL in those with no AF/AFL history (HR 0.78, 95% CI 0.62-0.99). Canagliflozin was also associated with a reduction in AF/AFL-related complications (HR 0.74, 95% CI 0.65-0.86). There was no evidence of treatment heterogeneity by baseline AF/AFL history for other key cardiorenal outcomes (all P-interaction > 0.14). Meta-analysis of five sodium-glucose cotransporter-2 (SGLT2) inhibitor trials demonstrated a 19% reduction in AF/AFL events with active treatment (HR 0.81, 95% CI 0.72-0.92). Conclusions Overall, a significant effect of canagliflozin on the incidence of AF/AFL events could not be shown, however, a possible reduction in AF/AFL events in those with no prior history requires further investigation. Meta-analysis suggests SGLT2 inhibition reduces AF/AFL incidence.

Heart failure is prevalent in those with type 2 diabetes and chronic kidney disease, and is associated with significant mortality and morbidity. In the CREDENCE trial, canagliflozin reduced the risk of hospitalization for heart failure (HHF) or cardiovascular (CV) death by 31%. In the current analysis we sought to determine whether the effect of canagliflozin on HHF/CV death differed in subgroups defined by key baseline participant characteristics. Cox regression models were used to estimate hazard ratios and 95% confidence intervals. Canagliflozin was associated with a reduction in the relative risk of HHF/CV death regardless of age, sex, history of heart failure or CV disease, and the use of loop diuretics or glucagon-like peptide-1 receptor agonists (all p(interaction) > .114). The absolute benefit of canagliflozin was greater in those at highest baseline risk, such as those with CV disease (50 fewer events/1000 patients treated over 2.5 years vs. 20 fewer events in those without CV disease) or advanced kidney disease (estimated glomerular filtration rate [eGFR] 30-45 mL/min/1.73m(2): 61 events prevented/1000 patients treated over 2.5 years vs. 23 events in eGFR 60-90 mL/min/1.73m(2)). Canagliflozin consistently reduces the proportional risk of HHF/CV death across a broad range of subgroups with greater absolute benefits in those at highest baseline risk.

Aim To assess whether the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on cardiovascular, kidney and mortality outcomes are consistent with and without concomitant metformin use.Material and methods We conducted a meta-analysis of event-driven, randomized, placebo-controlled SGLT2 inhibitor trials that reported cardiovascular, kidney or mortality outcomes by baseline metformin use. Treatment effects, reported as hazards ratios (HRs) and 95% confidence intervals (CIs), were pooled using random-effects meta-analysis. The main outcomes in this analysis were (i) major adverse cardiovascular events (MACE) and (ii) hospitalization for heart failure (HHF) or cardiovascular death.Results We included six trials of four SGLT2 inhibitors that enrolled a total of 51 743 participants. Baseline metformin use varied from 21% in DAPA-HF to 82% in DECLARE-TIMI 58. SGLT2 inhibitors reduced the risk of MACE, with and without concomitant metformin use (HR 0.93, 95% CI 0.87-1.00 and HR 0.82, 95% CI 0.71-0.86, respectively; P-heterogeneity = 0.14). There were also clear and separate reductions in HHF or cardiovascular death with SGLT2 inhibitors, irrespective of metformin use (HR 0.79, 95% CI 0.73-0.86 and HR 0.74, 95% CI 0.63-0.87, respectively; P-heterogeneity = 0.48), as well as for major kidney outcomes and all-cause mortality (all P-heterogeneity > 0.40).Conclusion Treatment with SGLT2 inhibitors results in clear and consistent reductions in cardiovascular, kidney and mortality outcomes regardless of whether patients are receiving or not receiving metformin.

We compared the healthiness of packaged foods and beverages between selected countries using the Health Star Rating (HSR) nutrient profiling system. Packaged food and beverage data collected 2013-2018 were obtained for Australia, Canada, Chile, China, India, Hong Kong, Mexico, New Zealand, Slovenia, South Africa, the UK, and USA. Each product was assigned to a food or beverage category and mean HSR was calculated overall by category and by country. Median energy density (kJ/100 g), saturated fat (g/100 g), total sugars (g/100 g) and sodium (mg/100 g) contents were calculated. Countries were ranked by mean HSR and median nutrient levels. Mean HSR for all products (n = 394,815) was 2.73 (SD 1.38) out of 5.0 (healthiest profile). The UK, USA, Australia and Canada ranked highest for overall nutrient profile (HSR 2.74-2.83) and India, Hong Kong, China and Chile ranked lowest (HSR 2.27-2.44). Countries with higher overall HSR generally ranked better with respect to nutrient levels. India ranked consistently in the least healthy third for all measures. There is considerable variability in the healthiness of packaged foods and beverages in different countries. The finding that packaged foods and beverages are less healthy in middle-income countries such as China and India suggests that nutrient profiling is an important tool to enable policymakers and industry actors to reformulate products available in the marketplace to reduce the risk of obesity and NCDs among populations.

AIM: The use of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has been limited, primarily because glycemic efficacy is dependent on kidney function. We performed a systematic review and meta-analysis to assess the efficacy and safety of SGLT2 inhibitors in patients with T2DM and CKD, defined as estimated glomerular filtration rate (eGFR) MATERIALS AND METHODS: We searched MEDLINE, EMBASE and the Cochrane Library to August 7, 2018, as well as the websites of the United States, European, and Japanese regulatory authorities to July 27, 2018 for data from randomized controlled trials of SGLT2 inhibitors that included reporting of effects on biomarkers, cardiovascular, renal, or safety outcomes in individuals with T2DM and CKD. Random effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals.RESULTS: Data were obtained from 27 studies with up to 7,363 participants contributing. In patients with T2DM and CKD, SGLT2 inhibitors lowered glycated hemoglobin (-0.29%, 95% CI -0.39 to -0.19), as well as blood pressure, body weight, and albuminuria. SGLT2 inhibition reduced the risk of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (RR 0.81, 95% CI 0.70-0.94) and heart failure (RR 0.61, 95% CI 0.48-0.78), without a clear effect on all-cause mortality (HR 0.86, 95% CI 0.73-1.01). These agents also attenuated the annual decline in eGFR slope (placebo-subtracted difference of 1.35 mL/1.73m2 /year, 95% CI 0.78-1.93) and reduced the risk of the composite renal outcome (HR 0.71, 95% CI 0.53-0.95). There was no evidence of additional risks with SGLT2 inhibition in CKD beyond those already known for the class, although heterogeneity was observed across individual agents for some safety outcomes.CONCLUSION: Currently available data suggest that despite only modest reductions in glycated hemoglobin, SGLT2 inhibitors reduce the risk of cardiovascular and renal outcomes in patients with T2DM and CKD, without clear evidence of additional safety concerns. This article is protected by copyright. All rights reserved.

Aims To determine the reasons for hospitalizations in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program and the effects of the sodium glucose co-transporter 2 inhibitor canagliflozin on hospitalization. Materials and methods A secondary analysis was performed on the CANVAS Program that included 10,142 participants with type 2 diabetes mellitus randomized to canagliflozin or placebo. The primary outcome was total (first plus all recurrent) all-cause hospitalization (ACH). Secondary outcomes were total hospitalizations categorized by the Medical Dictionary for Regulatory Activities hierarchy at the system organ class level, reported by investigators at each center. Outcomes were assessed using negative binomial models. Results Of the 7115 hospitalizations reported, the most common reasons were cardiac disorders (23.7%), infections and infestations (15.0%), and nervous system disorders (9.0%). The rate of total ACH was lower in the canagliflozin group (n=5795) compared to the placebo group (n=4347): 197.9 versus 215.8 participants per 1000 patient-years, respectively (rate ratio [RR] 0.92; 95% confidence interval [CI] 0.86, 0.98). Canagliflozin reduced the rate of total hospitalizations due to cardiac disorders (RR 0.81; 95% CI 0.75, 0.88). There was no significant difference between the canagliflozin and placebo groups in the rates of total hospitalizations due to infections and infestations (RR 0.96; 95% CI 0.86, 1.02) or nervous system disorders (RR 0.96; 95% CI 0.88, 1.05). Conclusions In the CANVAS Program, the most common reasons for hospitalization were cardiac disorders, infections and infestations, and nervous system disorders. Canagliflozin, compared with placebo, reduced the rate of total ACH. This article is protected by copyright. All rights reserved.

Background Patients with type 2 diabetes (T2D) are predisposed to derangements in serum Magnesium (Mg), which may have implications for cardiometabolic events and outcomes. In clinical trials, participants with T2D randomized to sodium‐glucose co‐transporter 2 (SGLT2) inhibitors have shown mild to moderate increases in serum Mg from baseline levels. This post hoc analysis assesses the relation between serum Mg with cardiovascular outcomes in 10,140 participants of the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program. Methods We evaluated the association of baseline serum Mg with the primary composite end point of death from cardiovascular causes, non‐fatal myocardial infarction, and non‐fatal stroke, and tested whether this association is modified by baseline serum Mg. Using mediation analysis, we determined whether change in serum Mg post‐randomization mediates the beneficial effect of canagliflozin on cardiovascular outcomes. Results Mean serum Mg levels at baseline were 0.77 ± 0.09 mmol/L in both canagliflozin group and placebo groups. The canagliflozin group experienced an average increase in serum Mg by 0.07 mmol/L (95% CI, 0.065–0.072 mmol/L; p, In the CANVAS Program, participant baseline serum Mg is not associated with cardiovascular outcomes and does not modify the effect of canagliflozin on cardiovascular outcomes. Canagliflozin‐associated rise in serum Mg levels does not mediate the beneficial effects of canagliflozin on cardiovascular outcomes.

Reduced-sodium, added-potassium salt substitutes have favorable effects on blood pressure, but have not been tested in India. The Salt Substitute in India Study (SSiIS) is a double-blinded, randomized-controlled trial designed to investigate the effects of reduced-sodium, added-potassium salt substitution to replace usual cooking salt use and blood pressure (BP) among hypertensive patients in rural India. The primary objective is to assess effects on systolic blood pressure at 3 months. The secondary objectives are to determine effects on diastolic blood pressure, urinary sodium, and potassium levels, and to determine acceptability of the intervention. Eligible individuals received usual salt (100% sodium chloride) or salt substitute (70% sodium chloride and 30% potassium chloride) to replace all salt required for cooking and seasoning in the household. A total of 502 participants aged ≥18 years with a history of hypertension were successfully recruited and randomized in a 1:1 ratio to intervention or control, between November 2019 and January 2020. Mean blood pressure at baseline was 133.5/83.6 mm Hg and 96% were using one or more blood pressure-lowering medications. The overall mean average 24-hour urinary sodium excretion was 2825 (SD, 1166) mg/L, which corresponds to a urinary salt excretion of 10.4 g/d. Baseline findings suggest sodium intake in this population significantly exceeds World Health Organization recommendations. The SSiIS trial has successfully recruited participants and is well placed to determine whether salt substitution is an effective means of lowering blood pressure for rural Indian patients with hypertension.

Background Several trials have demonstrated protective effects from inhibition of sodium‐glucose cotransporter 2 among patients with type 2 diabetes mellitus. There is uncertainty about the consistency of the cardiovascular benefits achieved across patient subsets. Methods and Results We included 4 large‐scale trials of sodium‐glucose cotransporter 2 inhibition compared with placebo in patients with diabetes mellitus that reported effects on cardiovascular outcomes overall and for participant subgroups defined at baseline by cardiovascular disease, reduced kidney function, and heart failure. Fixed effects models with inverse variance weighting were used to estimate summary hazard ratios and 95% CIs . There were 38 723 patients from 4 trials, with a mean 2.9 years of follow‐up. Of the patients, 22 870 (59%) had cardiovascular disease, 7754 (20%) had reduced kidney function, and 4543 (12%) had heart failure. There were 3828 major adverse cardiac events. There was overall benefit for major adverse cardiac events (0.88; 95% CI , 0.82–0.94; P P interaction >0.252; I 2 P interaction>0.302; I 2 P interaction>0.167; I 2 P interaction>0.354; I 2 =0%). The only difference in effects across subgroups was for stroke, with protection observed among those with reduced kidney function but not those with preserved kidney function ( P interaction=0.020; I 2 =81%). Conclusions Sodium‐glucose cotransporter 2 inhibitors protect against cardiovascular disease and death in diverse subsets of patients with type 2 diabetes mellitus regardless of cardiovascular disease history.

24 hr. urine sodium excretion is generally regarded as the ‘gold’ standard for assessing dietary sodium in population and epidemiological studies. This review examines the percentage of dietary sodium that is excreted in a 24 hr. urine collection. We systematically searched for all studies where a known and constant amount of dietary sodium was ingested for a minimum of 3 days and where sodium excretion in 24 hr. urine collections was measured. Studies with ‘healthy’ adult participants, or participants with health risks such as hypertension, were considered. 5264 unique studies were identified in the search; 392 underwent a full-text review and 35 studies were included. The pooled estimate for the percentage dietary sodium excreted in urine was 92.8% (95% confidence interval 90.7, 95.0) with little to no differences in subgroup analyses. There was high heterogeneity between studies, indicating that caution is required in interpreting the average percentage excretion, however, lack of study methodological rigor is likely to have contributed to the high heterogeneity. Although the generally high variability in sodium intake indicates that results from a single 24 hr. urine collection should not be used to assess an individual’s usual long-term sodium intake, this meta-analysis suggests that it is an appropriate method for assessing average dietary sodium in a healthy population or people with chronic stable health risks.

BACKGROUND Communities in rural Andhra Pradesh may be at increasing risk of diabetes. In the present study we analyzed three cross-sectional studies over 9 years to estimate the changing prevalence of dysglycemia (diabetes and prediabetes). METHODS The 2005 study sampled 4535 individuals from 20 villages, the 2010 study sampled 4024 individuals from 14 villages, and the 2014 project of 62 254 individuals sought to include all adults aged 40-85 years from 54 villages. Blood glucose levels were estimated using a hand-held device in 2005 and 2014 and using HbA1c dried blood spots in 2010. RESULTS In primary analyses restricted to assays based on fasting samples (2005, n = 3243; 2014, n = 749), the prevalence estimates for dysglycemia were 53.7% (95% confidence interval [CI] 51.8%-55.7%) in 2005 and 62.0% (95% CI 58.5%-65.4%) in 2014 (P < 0.001). Over the same period, mean body mass index (BMI) increased from 22.2 to 24.3 kg/m2 (mean difference 2.1 kg/m2 ; 95% CI 2.0-2.2 kg/m2 ; P < 0.001). In secondary analyses using data from all participants (2005, n = 4535; 2010, n = 4024; 2014, n = 62 254), regardless of measurement technique, the estimated prevalence of dysglycemia was 53.9% (95% CI 52.0%-55.9%) in 2005, 50.5% (95% CI 46.1%-54.9%) in 2010, and 41.3% (95% CI 40.9%-41.7%) in 2014 (P < 0.001). CONCLUSIONS The prevalence of dysglycemia was high at every assessment using every measurement method. Dysglycemia in this population is most likely to have risen with the rise in BMI. The decline in prevalence suggested by the secondary analyses was likely due to confounding from the different assessment methods.