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Background We compared kidney and cardiorenal protection in patients without type 2 diabetes across urine albumin–creatinine ratio (UACR) levels after initiation on dapagliflozin for the treatment of chronic kidney disease (CKD). Methods OPTIMISE-CKD is an observational study describing dapagliflozin treatment for CKD. Adult patients with CKD without type 2 diabetes were included in the primary analysis. Baseline UACR was grouped as normal/mildly elevated (0–29 mg/g), low (30–200 mg/g) and high (>200 mg/g). Outcomes were estimated glomerular filtration rate (eGFR) trajectories/slopes, cardiorenal complications and all-cause mortality. Results In total, 1480 patients had low (n  = 796) and high (n  = 684) UACR. The two groups were similar at baseline, aged 75 and 74 years, and 42% and 39% female, respectively. After dapagliflozin initiation, an acute eGFR dip of 3 mL/min/1.73 m2 was observed, followed by a flat development in both groups. The eGFR slope [95% confidence interval (CI)] for patients with low UACR was 0.79 mL/min/1.73 m2 per year (–0.59, 2.56), and similar to patients with high UACR [0.40 mL/min/1.73 m2 per year (–0.46, 1.38)]. Risks of cardiorenal complications and all-cause mortality were similar, with adjusted hazard ratios of 0.89 (95% CI 0.66, 1.19) and 1.10 (95% CI 0.63, 1.92), respectively. Analogous results were found in those with normal/mildly elevated UACR. Conclusions Dapagliflozin in patients without type 2 diabetes for the treatment of CKD demonstrated similar kidney protection, cardiorenal and all-cause mortality risk across UACR levels. This suggests that the efficacy of dapagliflozin found in clinical trials expands to real-world patients with CKD, regardless of albuminuria levels. [ABSTRACT FROM AUTHOR]

Background: Type-2 diabetes (T2D), chronic kidney disease, and heart failure (HF) share epidemiological and pathophysiological features. Although their prevalence was described, there is limited contemporary, high-resolution, epidemiological data regarding the overlap among them. We aimed to describe the epidemiological intersections between T2D, HF, and kidney dysfunction in an entire database, overall and by age and sex. Methods: This is a cross-sectional analysis of adults ≥ 25 years, registered in 2019 at Maccabi Healthcare Services, a large healthcare maintenance organization in Israel. Collected data included sex, age, presence of T2D or HF, and last estimated glomerular filtration rate (eGFR) in the past two years. Subjects with T2D, HF, or eGFR < 60 mL/min/1.73 m2 were defined as within the diabetes-cardio-renal (DCR) spectrum. Results: Overall, 1,389,604 subjects (52.2% females) were included; 445,477 (32.1%) were 25– < 40 years, 468,273 (33.7%) were 40– < 55 years, and 475,854 (34.2%) were ≥ 55 years old. eGFR measurements were available in 74.7% of the participants and in over 97% of those with T2D or HF. eGFR availability increased in older age groups. There were 140,636 (10.1%) patients with T2D, 54,187 (3.9%) with eGFR < 60 mL/min/1.73m2, and 11,605 (0.84%) with HF. Overall, 12.6% had at least one condition within the DCR spectrum, 2.0% had at least two, and 0.23% had all three. Cardiorenal syndrome (both HF and eGFR < 60 mL/min/1.73m2) was prevalent in 0.40% of the entire population and in 2.3% of those with T2D. In patients with both HF and T2D, 55.2% had eGFR < 60 mL/min/1.73m2 and 15.8% had eGFR < 30 mL/min/1.73m2. Amongst those within the DCR spectrum, T2D was prominent in younger participants, but was gradually replaced by HF and eGFR < 60 mL/min/1.73m2 with increasing age. The congruence between all three conditions increased with age. Conclusions: This large, broad-based study provides a contemporary, high-resolution prevalence of the DCR spectrum and its components. The results highlight differences in dominance and degree of congruence between T2D, HF, and kidney dysfunction across ages. [ABSTRACT FROM AUTHOR]

Aims: To examine heart failure (HF) and chronic kidney disease (CKD) risks reduction associated with sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2i) compared to other glucose‐lowering drugs (oGLD) in the early stage of type 2 diabetes patients without established cardiovascular or renal diseases (CVRD‐free T2D). Materials and Methods: We performed an observational cohort study using a Japanese hospital claims registry, Medical Data Vision. CVRD‐free T2D patients were identified between 1 April 2014 and 30 September 2018. SGLT‐2i and oGLD new users (and dipeptidyl peptidase 4 inhibitors [DPP‐4i] separately) were subjected to 1:1 propensity‐score matching analysis. Hazard ratios (HRs) of cardiorenal disease (HF and/or CKD), HF, CKD, stroke, myocardial infarction (MI), and all‐cause mortality, were estimated using unadjusted Cox regression. Results: A total of 108 362 CVRD‐free patients including 54 181 SGLT‐2i and 54 181 oGLD users were matched. Baseline characteristics were well balanced (mean age 59.1 years, 63% male, and follow‐up 1.50 years [162 970 patient‐years]). Compared to oGLD group, SGLT‐2i group had lower risk of cardiorenal disease, HF, CKD, stroke, and all‐cause mortality with HRs (95% confidence intervals) 0.55 (0.49‐0.61), 0.73 (0.61‐0.87), 0.45 (0.39‐0.52), 0.69 (0.59‐0.81), and 0.52 (0.46‐0.58), respectively, while no difference in MI. These were consistent in 1:1 propensity‐score matching analysis between SGLT‐2i and DPP‐4i users (n = 17 232 in each group). Conclusions: In Japanese CVRD‐free T2D patients, SGLT‐2i initiation was associated with lower risk of cardiorenal diseases, stroke, and all‐cause mortality compared to oGLD, suggesting preventive effect of SGLT‐2i treatment in the early stage of T2D patients without CVRD manifestation. [ABSTRACT FROM AUTHOR]

Aims: To examine heart failure (HF) and chronic kidney disease (CKD) risks reduction associated with sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2i) compared to other glucose‐lowering drugs (oGLD) in the early stage of type 2 diabetes patients without established cardiovascular or renal diseases (CVRD‐free T2D). Materials and Methods: We performed an observational cohort study using a Japanese hospital claims registry, Medical Data Vision. CVRD‐free T2D patients were identified between 1 April 2014 and 30 September 2018. SGLT‐2i and oGLD new users (and dipeptidyl peptidase 4 inhibitors [DPP‐4i] separately) were subjected to 1:1 propensity‐score matching analysis. Hazard ratios (HRs) of cardiorenal disease (HF and/or CKD), HF, CKD, stroke, myocardial infarction (MI), and all‐cause mortality, were estimated using unadjusted Cox regression. Results: A total of 108 362 CVRD‐free patients including 54 181 SGLT‐2i and 54 181 oGLD users were matched. Baseline characteristics were well balanced (mean age 59.1 years, 63% male, and follow‐up 1.50 years [162 970 patient‐years]). Compared to oGLD group, SGLT‐2i group had lower risk of cardiorenal disease, HF, CKD, stroke, and all‐cause mortality with HRs (95% confidence intervals) 0.55 (0.49‐0.61), 0.73 (0.61‐0.87), 0.45 (0.39‐0.52), 0.69 (0.59‐0.81), and 0.52 (0.46‐0.58), respectively, while no difference in MI. These were consistent in 1:1 propensity‐score matching analysis between SGLT‐2i and DPP‐4i users (n = 17 232 in each group). Conclusions: In Japanese CVRD‐free T2D patients, SGLT‐2i initiation was associated with lower risk of cardiorenal diseases, stroke, and all‐cause mortality compared to oGLD, suggesting preventive effect of SGLT‐2i treatment in the early stage of T2D patients without CVRD manifestation. [ABSTRACT FROM AUTHOR]

There are limited data on cardiovascular efficacy and safety of type 2 diabetes therapies in Japan, where treatments are characterized by lower metformin use and higher dipeptidyl peptidase‐4 inhibitor (DPP4i) use versus other countries. We investigated the cardiovascular outcomes in Japanese patients with type 2 diabetes initiating sodium–glucose cotransporter 2 inhibitors (SGLT2i) matched 1:1 to patients initiating other glucose‐lowering drugs (33,890 patients/group) or DPP4i (9,876 patients/group). SGLT2i initiation was associated with lower risks (hazard ratio of in‐hospital death [death] 0.56, 95% confidence interval [CI] 0.47–0.67; hospitalization for heart failure 0.75, 95% CI 0.64–0.89; composite of hospitalization for heart failure or death 0.65, 95% CI 0.58–0.74 and stroke 0.66, 95% CI 0.52–0.84 versus other glucose‐lowering drugs and lower risks of death 0.52, 95% CI 0.36–0.73) and composite of hospitalization for heart failure or death (0.65, 95% CI 0.51–0.83) versus DPP4i. In conclusion, SGLT2i initiators had lower risks of cardiovascular events versus other glucose‐lowering drug initiators and, uniquely, versus DPP4i initiators in Japanese real‐world practice. [ABSTRACT FROM AUTHOR]

Aims: To investigate cardiovascular (CV) safety and event rates for dapagliflozin versus other glucose‐lowering drugs (GLDs) in a real‐world type 2 diabetes population after applying the main inclusion criteria and outcomes from the DECLARE‐TIMI 58 study. Methods: Patients with new initiation of dapagliflozin and/or other GLDs were identified in Swedish nationwide healthcare registries for the period 2013 to 2016. Patients were included if they met the main DECLARE‐TIMI 58 inclusion criteria: age ≥40 years and established CV disease or presence of multiple‐risk factors, e.g. men aged ≥55 years and women aged ≥60 years with hypertension or dyslipidaemia. Propensity scores for the likelihood of dapagliflozin initiation were calculated, then 1:3 matching was carried out. DECLARE‐TIMI 58 outcomes were hospitalization for heart failure (HHF) or CV‐specific mortality, and major adverse CV events (MACE; CV‐specific mortality, myocardial infarction, or stroke). Cox survival models were used to estimate hazard ratios (HRs). Results: After matching, a total of 28 408 new‐users of dapagliflozin and/or other GLDs were identified, forming the population for the present study (henceforth referred to as the DECLARE‐like cohort. The mean age of this cohort was 66 years, and 34% had established CV disease. Dapagliflozin was associated with 21% lower risk of HHF or CV mortality versus other GLDs (HR 0.79, 95% confidence interval [CI] 0.69‐0.92) and had no significant association with MACE (HR 0.90, 95% CI 0.79‐1.03). HHF and CV mortality risks, separately, were lower at HR 0.79 (95% CI 0.67‐0.93) and HR 0.75 (95% CI 0.57‐0.97), respectively. Non‐significant associations were seen for myocardial infarction and stroke: HR 0.91 (95% CI 0.74‐1.11) and HR 1.06 (95% CI 0.87‐1.30), respectively. Conclusion: In a real‐world population similar to those included in the DECLARE‐TIMI 58 study, dapagliflozin was safe with regard to CV outcomes and resulted in lower event rates of HHF and CV mortality versus other GLDs. [ABSTRACT FROM AUTHOR]

Objectives To compare short-term cardiovascular (CV) outcome in type 2 diabetes (T2D) patients without ischaemic heart disease (IHD), with IHD but no prior myocardial infarction (MI), and those with prior MI; and assess the impact on risk of age when initiating first-time glucose-lowering drug (GLD). Design Cohort study linking morbidity, mortality and medication data from Swedish national registries. Participants First-time users of GLD during 2007-2016. Outcomes Predicted cumulative incidence for the CV outcome (MI, stroke and CV mortality) was estimated. A Cox model was developed where age at GLD start and CV risk was modelled. Results 260 070 first-time GLD users were included, 221 226 (85%) had no IHD, 16 294 (6%) had stable IHD--prior MI and 22 550 (9%) had IHD+MI. T2D patients without IHD had a lower risk of CV outcome compared with the IHD populations (±prior MI), (3-year incidence 4.78% vs 5.85% and 8.04%). The difference in CV outcome was primarily driven by a relative greater MI risk among the IHD patients. For T2D patients without IHD, an almost linear association between age at start of GLD and relative risk was observed, whereas in IHD patients, the younger (<60 years) patients had a relative greater risk compared with older patients. Conclusions T2D patients without IHD had a lower risk of the CV outcome compared with the T2D populations with IHD, primarily driven by a greater risk of MI. For T2D patients without IHD, an almost linear association between age at start of GLD and relative risk was observed, whereas in IHD patients, the younger patients had a relative greater risk compared with older patients. Our findings suggest that intense risk prevention should be the key strategy in the management of T2D patients, especially for younger patients. [ABSTRACT FROM AUTHOR]

The multinational, observational CVD‐REAL study recently showed that initiation of sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2i) was associated with significantly lower rates of death and heart failure vs other glucose‐lowering drugs (oGLDs). This sub‐analysis of the CVD‐REAL study sought to determine the association between initiation of SGLT‐2i vs oGLDs and rates of myocardial infarction (MI) and stroke. Medical records, claims and national registers from the USA, Sweden, Norway and Denmark were used to identify patients with T2D who newly initiated treatment with SGLT‐2i (canagliflozin, dapagliflozin or empagliflozin) or oGLDs. A non‐parsimonious propensity score was developed within each country to predict initiation of SGLT‐2i, and patients were matched 1:1 in the treatment groups. Pooled hazard ratios (HRs) and 95% CIs were generated using Cox regression models. Overall, 205 160 patients were included. In the intent‐to‐treat analysis, over 188 551 and 188 678 person‐years of follow‐up (MI and stroke, respectively), there were 1077 MI and 968 stroke events. Initiation of SGLT‐2i vs oGLD was associated with a modestly lower risk of MI and stroke (MI: HR, 0.85; 95%CI, 0.72‐1.00; P = .05; Stroke: HR, 0.83; 95% CI, 0.71‐0.97; P = .02). These findings complement the results of the cardiovascular outcomes trials, and offer additional reassurance with regard to the cardiovascular effects of SGLT‐2i, specifically as it relates to ischaemic events. [ABSTRACT FROM AUTHOR]

Background There are few data on risk factors for stroke during long-term follow-up of healthy individuals. Aims We aimed to investigate the long-term predictive impact on stroke risk of baseline variables including hemodynamic variables measured at rest and during exercise in middle-aged, healthy men. Methods We performed a prospective cohort study of 2014 healthy Norwegian men aged 40–59 years, recruited during the period 1972–1975 and followed until 2007. Participants underwent a comprehensive clinical assessment at baseline, including a bicycle exercise test. Data on stroke, transient ischemic attack, and death were collected on all participants from follow-up visits, medical records, and the National Cause of Death Registry. We used Cox regression for analysis and estimated hazard ratios with 95% confidence intervals, adjusting for traditional risk factors and hemodynamic variables measured at rest and during exercise. Results During 35 years’ follow-up, 316 participants (16%) had stroke, of which 287 (91%) were ischemic and 29 (9%) were hemorrhagic. Age (hazard ratio 2.70 per increase in one standard deviation, 95% confidence interval 2.13–3.43), resting systolic blood pressure (hazard ratio 1.24, 95% confidence interval 1.11–1.39), body mass index (hazard ratio 1.14, 95% confidence interval 1.02–1.29), and atrioventricular conduction time (hazard ratio 1.11, 95% confidence interval 1.03–1.19) were significantly associated with long-term risk of stroke, as were maximal systolic blood pressure and heart rate during exercise (hazard ratio 1.28, 95% confidence interval 1.13–1.46, and hazard ratio 0.86, 95% confidence interval 0.74–0.99, respectively). Conclusions Hemodynamic variables at rest and during exercise testing add to the predictive value of clinical variables in healthy, middle-aged men, and should be included in the assessment of long-term risk of stroke, when available. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The global diabetes epidemic affects countries differently. We aimed to describe trends in the incidence and prevalence of type 2 diabetes mellitus requiring glucose-lowering treatment, together with associated life expectancy and risks of significant clinical complications. Methods: Data on patients with type 2 diabetes who filled a prescription for any glucose-lowering drug (GLD) during the period 2006-2013 were extracted from the Swedish Prescribed Drug Register, Cause of Death Register and Swedish National Patient Register. Results: In 2013, the prevalence of GLD-treated type 2 diabetes was 4.4% ( n = 352,436) and the incidence was 399 per 100,000 population ( n = 30,620). During 2006-2013, the prevalence increased by 61% while the incidence remained relatively stable; the prevalence of cardiovascular disease (CVD, 34% in 2013) and microvascular disease (16% in 2013) was also stable. Insulin use increased by 29% while sulfonylurea use declined by 55%. Compared with the general population, patients with type 2 diabetes had increased risk of myocardial infarction, stroke and all-cause mortality, with age-standardised risks of ∼1.7-, 1.5- and 1.3-fold, respectively. These risks declined over time. Life-years lost due to diabetes was most pronounced at younger ages and improved in women over time from 2006 to 2013. Conclusions/interpretation: The prevalence of type 2 diabetes requiring GLD treatment in Sweden increased substantially in recent years, while the incidence remained stable. Use of sulfonylurea declined while insulin use increased. The high prevalence of diabetes-related comorbidities, increased risk of complications and life-years lost highlights the need for optimised and new preventive strategies in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background and Objectives: Statin-induced changes in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) are unrelated. Many patients initiated on statins experience a paradoxical decrease in HDL-C. The aim of this study was to evaluate the association between a decrease in HDL-C and risk of major adverse cardiovascular events (MACE). Methods: Data from 15,357 primary care patients initiated on statins during 2004-2009 were linked with data from mandatory national hospital, drug-dispensing, and cause-of-death registers, and were grouped according to HDL-C change: decreased ≥0.1 mmol/L, unchanged ±0.1 or ≥0.1 mmol/L increased. To evaluate the association between decrease in HDL-C and risk of MACE, a sample of propensity score-matched patients from the decreased and unchanged groups was created, using the latter group as reference. MACE was defined as myocardial infarction, unstable angina pectoris, ischaemic stroke, or cardiovascular mortality. Cox proportional hazards models were used to estimate relative risks. Results: HDL-C decreased in 20 %, was unchanged in 58%, and increased in 22 % of patients initiated on statin treatment (96 % treated with simvastatin). The propensity score-matched sample comprised 5950 patients with mean baseline HDL-C and LDL-C of 1.69 and 4.53 mmol/L, respectively. HDL-C decrease was associated with 56 % higher MACE risk (hazard ratio 1.56; 95 % confidence interval 1.12-2.16; p < 0.01) compared with the unchanged HDL-C group. Conclusions: Paradoxical statin-induced reduction in HDL-C was relatively common and was associated with increased risk of MACE. [ABSTRACT FROM AUTHOR]

Objectives. Inflammation and increased blood viscosity are associated with increased risk of cardiovascular mortality. Erythrocyte sedimentation rate (ESR) and hematocrit both influence blood viscosity whereas the first also is a marker of inflammation. We aimed to investigate ESR, hematocrit and the interaction between them as predictors of cardiovascular mortality during 26 years follow-up among healthy middle aged men. Design. Four hundred and eighty eight men aged 40–59 were extensively examined in 1972–1975 and followed over a period of 26 years. Risk estimation was made in Cox proportional hazards and adjusted for age, smoking, systolic blood pressure, total serum cholesterol, and physical fitness. Results. A 2.44-fold (95% CI 1.37–4.35) adjusted risk of cardiovascular mortality was found in the highest quartile of hematocrit compared to the lowest. Among the 265 men who had an ESR <6 mm/h (median), the adjusted risk of cardiovascular mortality was 3.05-fold (95% CI 1.49–6.23) in the highest quartile of hematocrit compared to the lowest. This association was not observed among the 223 men with ESR <6 mm/h. Conclusion. Elevated hematocrit is independently associated with increased long-term risk of cardiovascular mortality in men with high ESR. Our data suggest that the combination of inflammation and blood viscosity may improve the prediction of cardiovascular risk. [ABSTRACT FROM AUTHOR]

The article presents comment on the study regarding the lower risk of death in associated with sodium–glucose cotransporter 2 inhibitors (SGLT2i) compared with insulin treatment in a broad population with type 2 diabetes. It examines the different issues in the study and recognizes the risks of biases in the treatments. The authors argue that observational studies can provide relevant new knowledge about the efficacy of different treatments in real clinical setting.

Background: It is widely accepted that exercise capacity in healthy individuals is limited by the cardiac function, while the respiratory system is considered oversized. Although there is physiological, age-related decline in both lung function and physical capacity, the association between decline in lung function and decline in exercise capacity is little studied. Therefore, we examined the longitudinal association between lung function indices and exercise capacity, assessed by the total amount of work performed on a standardized incremental test, in a cohort of middle-aged men.Methods: A total of 745 men between 40 and 59 years were examined using spirometry and standardized bicycle exercise ECG test within "The Oslo Ischemia Study," at two time points: once during 1972-1975, and again, approximately 16 years later, during 1989-1990. The subjects exercise capacity was assessed as physical fitness i.e. the total bicycle work (in Joules) at all workloads divided by bodyweight (in kg).Results: Higher FEV1, FVC and PEF values related to higher physical fitness at both baseline and follow-up (all p values < 0.05). Higher explanatory values were found at follow-up than baseline for FEV1 (r2 = 0.16 vs. r2 = 0.03), FVC (r2 = 0.14 vs. r2 = 0.03) and PEF (r2 = 0.13 vs. r2 = 0.02). No significant correlations were found between decline in physical fitness and declines in FEV1, FVC or PEF.Conclusions: A weak association between lung function indices and exercise capacity, assessed through physical fitness, was found in middle-aged, healthy men. This association was strengthened with increasing age, suggesting a larger role for lung function in limiting exercise capacity among elderly subjects. However, decline in physical fitness over time was not related to decline in lung function. [ABSTRACT FROM AUTHOR]