Development and first-stage validation of a digital version of the Digit Symbol Substitution test for use in assessing cognitive function in older people with diabetes.

AIMS: To describe the development and report the first-stage validation of a digital version of the digit symbol substitution test (DSST), for assessment of cognitive function in older people with diabetes. MATERIALS AND METHODS: A multidisciplinary team of experts was convened to conceptualize and build a digital version of the DSST and develop a machine-learning (ML) algorithm to analyse the inputs. One hundred individuals with type 2 diabetes (aged ≥ 60 years) were invited to participate in a one-time meeting in which both the digital and the pencil-and-paper (P&P) versions of the DSST were administered. Information pertaining to demographics, laboratory measurements, and diabetes indices was collected. The correlation between the digital and P&P versions of the test was determined. Additionally, as part of the validation process, the performance of the digital version in people with and without known risk factors for cognitive impairment was analysed. RESULTS: The ML model yielded an overall accuracy of 89.1%. A strong correlation was found between the P&P and digital versions (r = 0.76, p < 0.001) of the DSST, as well as between the ML model and the manual reading of the digital DSST (r = 0.99, p < 0.001). CONCLUSIONS: This study describes the development of and provides first-stage validation data for a newly developed digital cognitive assessment tool that may be used for screening and surveillance of cognitive function in older people with diabetes. More studies are needed to further validate this tool, especially when self-administered and in different clinical settings.

A polygenic risk score predicts atrial fibrillation in cardiovascular disease.

AIMS: Interest in targeted screening programmes for atrial fibrillation (AF) has increased, yet the role of genetics in identifying patients at highest risk of developing AF is unclear. METHODS AND RESULTS: A total of 36,662 subjects without prior AF were analyzed from four TIMI trials. Subjects were divided into quintiles using a validated polygenic risk score (PRS) for AF. Clinical risk for AF was calculated using the CHARGE-AF model. Kaplan-Meier event rates, adjusted hazard ratios (HRs), C-indices, and net reclassification improvement were used to determine if the addition of the PRS improved prediction compared with clinical risk and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Over 2.3 years, 1018 new AF cases developed. AF PRS predicted a significant risk gradient for AF with a 40% increased risk per 1-SD increase in PRS [HR: 1.40 (1.32-1.49); P < 0.001]. Those with high AF PRS (top 20%) were more than two-fold more likely to develop AF [HR 2.45 (1.99-3.03), P < 0.001] compared with low PRS (bottom 20%). Furthermore, PRS provided an additional gradient of risk stratification on top of the CHARGE-AF clinical risk score, ranging from a 3-year incidence of 1.3% in patients with low clinical and genetic risk to 8.7% in patients with high clinical and genetic risk. The subgroup of patients with high clinical risk, high PRS, and elevated NT-proBNP had an AF risk of 16.7% over 3 years. The C-index with the CHARGE-AF clinical risk score alone was 0.65, which improved to 0.67 (P < 0.001) with the addition of NT-proBNP, and increased further to 0.70 (P < 0.001) with the addition of the PRS. CONCLUSION: In patients with cardiovascular conditions, AF PRS is a strong independent predictor of incident AF that provides complementary predictive value when added to a validated clinical risk score and NT-proBNP.

Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People With Type 2 Diabetes: A Meta-Analysis of Individual Participant Data From Randomized, Controlled Trials.

BACKGROUND: Hyperkalemia increases risk of cardiac arrhythmias and death and limits the use of renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, which improve clinical outcomes in people with chronic kidney disease or systolic heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiorenal events in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease. However, their effect on hyperkalemia has not been systematically evaluated. METHODS: A meta-analysis was conducted using individual participant data from randomized, double-blind, placebo-controlled clinical outcome trials with SGLT2 inhibitors in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease in whom serum potassium levels were routinely measured. The primary outcome was time to serious hyperkalemia, defined as central laboratory-determined serum potassium ≥6.0 mmol/L, with other outcomes including investigator-reported hyperkalemia events and hypokalemia (serum potassium ≤3.5 mmol/L). Cox regression analyses were performed to estimate treatment effects from each trial with hazards ratios and corresponding 95% CIs pooled with random-effects models to obtain summary treatment effects, overall and across key subgroups. RESULTS: Results from 6 trials were included comprising 49 875 participants assessing 4 SGLT2 inhibitors. Of these, 1754 participants developed serious hyperkalemia, and an additional 1119 investigator-reported hyperkalemia events were recorded. SGLT2 inhibitors reduced the risk of serious hyperkalemia (hazard ratio, 0.84 [95% CI, 0.76-0.93]), an effect consistent across studies (Pheterogeneity=0.71). The incidence of investigator-reported hyperkalemia was also lower with SGLT2 inhibitors (hazard ratio, 0.80 [95% CI, 0.68-0.93]; Pheterogeneity=0.21). Reductions in serious hyperkalemia were observed across a range of subgroups, including baseline kidney function, history of heart failure, and use of renin-angiotensin-aldosterone system inhibitor, diuretic, and mineralocorticoid receptor antagonist. SGLT2 inhibitors did not increase the risk of hypokalemia (hazard ratio, 1.04 [95% CI, 0.94-1.15]; Pheterogeneity=0.42). CONCLUSIONS: SGLT2 inhibitors reduce the risk of serious hyperkalemia in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease without increasing the risk of hypokalemia.

Efficacy and Safety of Dapagliflozin in Type 2 Diabetes According to Baseline Blood Pressure: Observations From DECLARE-TIMI 58 Trial.

BACKGROUND: Dapagliflozin improved heart failure and kidney outcomes in patients with type 2 diabetes (T2DM) with or at high risk for atherosclerotic cardiovascular disease in the DECLARE-TIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58). Here, the aim was to analyze the efficacy and safety of dapagliflozin stratified according to baseline systolic blood pressure (SBP). METHODS: The DECLARE-TIMI 58 trial randomly assigned patients with T2DM and either previous atherosclerotic cardiovascular disease or atherosclerotic cardiovascular disease risk factors to dapagliflozin or placebo. Patients were categorized by baseline SBP levels: <120, 120 to 129, 130 to 139, 140 to 159, and ≥160 mm Hg (normal, elevated, stage 1, stage 2, and severe hypertension, respectively). Efficacy outcomes of interest were hospitalization for heart failure and a renal-specific composite outcome (sustained decrease in estimated glomerular filtration rate by 40%, progression to end-stage renal disease, or renal death). Safety outcomes included symptoms of volume depletion, lower extremity amputations, and acute kidney injury. RESULTS: The trial comprised 17 160 patients; mean age, 64.0±6.8 years; 37.4% women; median duration of T2DM, 11 years; 40.6% with prevalent cardiovascular disease. Overall, dapagliflozin reduced SBP by 2.4 mm Hg (95% CI, 1.9-2.9; P<0.0001) compared with placebo at 48 months. The beneficial effects of dapagliflozin on hospitalization for heart failure and renal outcomes were consistent across all baseline SBP categories, with no evidence of modification of treatment effect (Pinteractions=0.28 and 0.52, respectively). Among normotensive patients, the hazard ratios were 0.66 (95% CI, 0.42-1.05) and 0.39 (95% CI, 0.19-0.78), respectively, for hospitalization for heart failure and the renal-specific outcome. Events of volume depletion, amputation, and acute kidney injury did not differ with dapagliflozin overall or within any baseline SBP group. CONCLUSIONS: In patients with T2DM with or at high atherosclerotic cardiovascular disease risk, dapagliflozin reduced risk for hospitalization for heart failure and renal outcomes regardless of baseline SBP, with no difference in adverse events of interest at any level of baseline SBP. These results indicate that dapagliflozin provides cardiorenal benefits in patients with T2DM at high atherosclerotic cardiovascular disease risk independent of baseline blood pressure. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01730534.

Curalin supplement for patients with type 2 diabetes mellitus.

OBJECTIVE: To examine the efficacy and safety of Curalin supplement in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adult patients with type 2 diabetes were randomized 1:1 to receive Curalin supplement or placebo. The primary endpoint was HbA1c decrease at 1 month. The secondary endpoint was a decrease in HbA1c by more than 0.5% and 1% and a change in 7 daily blood glucose measurements. A satisfaction questionnaire was used as an exploratory endpoint. Safety variables and adverse events were assessed. RESULTS: After 1 month of intervention, HbA1c was reduced by 0.94% in the Curalin arm versus 0.4% in the placebo arm (P = 0.008). 72% of Curalin patients had decreased HbA1c levels >0.5% versus 35% in the placebo arm (P < 0.05). The Treatment Satisfaction Questionnaire indicated that Curalin arm patients reported higher overall satisfaction. CONCLUSIONS: Curalin treatment significantly reduced HbA1c over a 1-month period and was well-tolerated.

Obesity and effects of dapagliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus in the DECLARE-TIMI 58 trial.

AIMS: We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: DECLARE-TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to <25), overweight (25 to <30), moderately obese (30 to <35), severely obese (35 to <40), and very-severely obese (≥40). Outcomes analysed were CV death, hospitalization for heart failure (HHF), renal-specific composite outcome, and atrial fibrillation or flutter (AF/AFL). Of 17 134 patients, 9.0% had a normal BMI, 31.5% were overweight, 32.4% were moderately, 17.2% severely, and 9.8% were very-severely obese. Higher BMI was associated with a higher adjusted risk of HHF and AF/AFL (hazard ratio 1.30 and 1.28, respectively, per 5 kg/m2; P < 0.001 for all). Dapagliflozin reduced body weight by similar relative amounts consistently across BMI categories (percent difference: -1.9 to -2.4%). Although relative risk reductions in CV and renal-specific composite outcomes with dapagliflozin did not significantly differ across the range of BMI (P for interaction ≥0.20 for all outcomes), obese patients (BMI ≥ 30 kg/m2) tended to derive greater absolute risk reduction in HHF and AF/AFL (P for interaction 0.02 and 0.09, respectively) than non-obese patients. CONCLUSIONS: In DECLARE-TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534.

Drug Therapies for Diabetes.

The treatment of type 2 diabetes (T2D) necessitates a multifaceted approach that combines behavioral and pharmacological interventions to mitigate complications and sustain a high quality of life. Treatment encompasses the management of glucose levels, weight, cardiovascular risk factors, comorbidities, and associated complications through medication and lifestyle adjustments. Metformin, a standard in diabetes management, continues to serve as the primary, first-line oral treatment across all age groups due to its efficacy, versatility in combination therapy, and cost-effectiveness. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) offer notable benefits for HbA1c and weight reduction, with significant cardiovascular benefits. Sodium-glucose cotransporter inhibitors (SGLT-2i) lower glucose levels independently of insulin while conferring notable benefits for cardiovascular, renal, and heart-failure outcomes. Combined therapies emphasizing early and sustained glycemic control are promising options for diabetes management. As insulin therapy remains pivotal, metformin and non-insulin agents such as GLP-1 RA and SGLT-2i offer compelling options. Notably, exciting novel treatments like the dual GLP-1/ glucose-dependent insulinotropic polypeptide (GIP) agonist show promise for substantially reducing glycated hemoglobin and body weight. This comprehensive review highlights the evolving landscape of pharmacotherapy in diabetes, the drugs currently available for treating diabetes, their effectiveness and efficacy, the impact on target organs, and side effects. This work also provides insights that can support the customization of treatment strategies.

Obesity in late adolescence and incident type 1 diabetes in young adulthood.

AIMS/HYPOTHESIS: Studies in children have reported an association between increased BMI and risk for developing type 1 diabetes, but evidence in late adolescence is limited. We studied the association between BMI in late adolescence and incident type 1 diabetes in young adulthood. METHODS: All Israeli adolescents, ages 16-19 years, undergoing medical evaluation in preparation for mandatory military conscription between January 1996 and December 2016 were included for analysis unless they had a history of dysglycaemia. Data were linked with information about adult onset of type 1 diabetes in the Israeli National Diabetes Registry. Weight and height were measured at study entry. Cox proportional models were applied, with BMI being analysed both as a categorical and as a continuous variable. RESULTS: There were 777 incident cases of type 1 diabetes during 15,819,750 person-years (mean age at diagnosis 25.2±3.9 years). BMI was associated with incident type 1 diabetes. In a multivariable model adjusted for age, sex and sociodemographic variables, the HRs for type 1 diabetes were 1.05 (95% CI 0.87, 1.27) for the 50th-74th BMI percentiles, 1.41 (95% CI 1.11, 1.78) for the 75th-84th BMI percentiles, 1.54 (95% CI 1.23, 1.94) for adolescents who were overweight (85th-94th percentiles), and 2.05 (95% CI 1.58, 2.66) for adolescents with obesity (≥95th percentile) (reference group: 5th-49th BMI percentiles). One increment in BMI SD was associated with a 25% greater risk for incidence of type 1 diabetes (HR 1.25, 95% CI 1.17, 1.32). CONCLUSIONS: Excessively high BMI in otherwise healthy adolescents is associated with increased risk for incident type 1 diabetes in early adulthood.

Clinical Application of a Novel Genetic Risk Score for Ischemic Stroke in Patients With Cardiometabolic Disease.

BACKGROUND: Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease. METHODS: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors. RESULTS: In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke (P trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04-1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81-1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHA2DS2-VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA2DS2-VASc score of 3. CONCLUSIONS: Across a broad spectrum of subjects with cardiometabolic disease, a 32-single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA2DS2-VASc scores, the GRS identified patients with risk comparable to those with higher CHA2DS2-VASc scores.

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.

BACKGROUND: The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined. METHODS: We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause. RESULTS: We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001). CONCLUSIONS: In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).

Machine learning based study of longitudinal HbA1c trends and their association with all-cause mortality: Analyses from a National Diabetes Registry.

OBJECTIVE: The association of long-term HbA1c variability with mortality has been previously suggested. However, the significance of HbA1c variability and trends in different age and HbA1c categories is unclear. RESEARCH DESIGN AND METHODS: Data on patients with diabetes listed in the Israeli National Diabetes Registry during years 2012-2016 (observation period) were collected. Patients with >4 HbA1c measurements, type 1 diabetes, eGFR < 30mg/ml/min, persistent HbA1c < 6% or malignancy were excluded. Utilizing machine learning methods, patients were classified into clusters according to their HbA1c trend (increasing, stable, decreasing). Mortality risk during 2017-2019 was calculated in subgroups defined by age (35-54, 55-69, 70-89 years) and last HbA1c (≤7% and >7%) at end of observation period. Models were adjusted for demographic, clinical and laboratory measurements including HbA1c, standard deviation (SD) of HbA1c and HbA1c trend. RESULTS: This historical cohort study included 293,314 patients. Increased HbA1c variability (high SD) during the observation period was an independent predictor of mortality in patients aged more than 55 years (p < 0.01). The HbA1c trend was another independent predictor of mortality. Patients with a decreasing versus stable HbA1c trend had a greater mortality risk; this association persisted in all age groups in patients with HbA1c > 7% at the end of the observation period (p = 0.02 in age 35-54; p < 0.01 in aged >55). Patients with an increasing versus stable HbA1c trend had a greater mortality risk only in the elderly group (>70), yet in both HbA1c categories (p < 0.01). CONCLUSIONS: HbA1c variability and trend are important determinants of mortality risk and should be considered when adjusting glycaemic targets.

The efficacy and safety of dapagliflozin in women and men with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Women remain underrepresented in clinical trials and those with type 2 diabetes mellitus are at high risk for cardiovascular (CV) events. The sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin reduces the risk of CV death or heart failure hospitalisations in individuals with type 2 diabetes. Here, we performed a pre-specified analysis to examine whether sex modifies these effects. METHODS: The DECLARE-TIMI 58 trial randomised 17,160 patients with type 2 diabetes with or at risk for atherosclerotic disease to dapagliflozin or placebo (median follow-up 4.2 years). The dual efficacy outcomes were CV death or heart failure hospitalisations, and major adverse cardiovascular events (MACE; CV death, myocardial infarction or ischaemic stroke). The renal-specific composite outcome was a sustained ≥40% drop in eGFR to <60 ml min-1 [1.73 m]-2, new end-stage renal disease or renal death. Cox models were run separately by sex with treatment-by-sex interaction testing for each outcome. RESULTS: At baseline, women (n = 6422, 37.4%) had higher HbA1c, longer type 2 diabetes duration, and were on fewer glucose-lowering medications. There was no evidence of modification of the effect of dapagliflozin by sex for (1) CV death or heart failure hospitalisations: women (3.8% vs 4.5%; HR 0.84, 95% CI 0.66, 1.07) and men (5.3% vs 6.4%; HR 0.83, 95% CI 0.71, 0.96; pinteraction = 0.90); (2) MACE: women (6.3% vs 6.8%; HR 0.93, 95% CI 0.77, 1.12) and men (10.0% vs 10.7%; HR 0.93, 95% CI 0.83, 1.05; pinteraction = 0.99); or (3) renal-specific composite: women (1.4% vs 2.8%; HR 0.50, 95% CI 0.35, 0.70) and men (1.5% vs 2.5%; HR 0.55, 95% CI 0.42, 0.73; pinteraction = 0.64). The overall safety profile of dapagliflozin was similar for women and men. CONCLUSIONS/INTERPRETATION: Dapagliflozin offers comparable CV and renal benefits and a comparable safety profile in women and men. FUNDING: AstraZeneca. TRIAL REGISTRATION: clinicaltrials.gov NCT01730534.

Effect of Dapagliflozin on Atrial Fibrillation in Patients With Type 2 Diabetes Mellitus: Insights From the DECLARE-TIMI 58 Trial.

BACKGROUND: Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes mellitus and its related comorbidities, including hypertension, obesity, and heart failure (HF). SGLT2 (sodium-glucose cotransporter 2) inhibitors have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling, and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes mellitus. We therefore investigated whether SGLT2 inhibitors could also reduce the risk of AF/AFL. METHODS: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) studied the efficacy and safety of the SGLT2 inhibitor dapagliflozin versus placebo in 17 160 patients with type 2 diabetes mellitus and either multiple risk factors for atherosclerotic cardiovascular disease (n=10 186) or known atherosclerotic cardiovascular disease (n=6974). We explored the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using MedDRA preferred terms ("atrial fibrillation," "atrial flutter"). RESULTS: Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events; 7.8 versus 9.6 events per 1000 patient-years; hazard ratio [HR], 0.81 [95% CI, 0.68-0.95]; P=0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (previous AF/AFL: HR, 0.79 [95% CI, 0.58-1.09]; no AF/AFL: HR, 0.81 [95% CI, 0.67-0.98]; P for interaction 0.89). Similarly, presence of atherosclerotic cardiovascular disease (HR, 0.83 [95% CI, 0.66-1.04]) versus multiple risk factors (HR, 0.78 [95% CI, 0.62-0.99]; P for interaction 0.72) or a history of HF (HF: HR, 0.78 [95% CI, 0.55-1.11]; No HF: HR, 0.81 [95% CI, 0.68-0.97]; P for interaction 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, glycated hemoglobin A1c, body mass index, blood pressure, or estimated glomerular filtration rate (all P for interaction >0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio, 0.77 [95% CI, 0.64-0.92]; P=0.005). CONCLUSIONS: Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with type 2 diabetes mellitus. This effect was consistent regardless of the patient's previous history of AF, atherosclerotic cardiovascular disease, or HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01730534.

Dapagliflozin and Cardiac, Kidney, and Limb Outcomes in Patients With and Without Peripheral Artery Disease in DECLARE-TIMI 58.

BACKGROUND: Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular complications. The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk for hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes mellitus. An increased risk of amputation has been observed with canagliflozin in 1 previous trial. We examined cardiovascular and kidney efficacy and the risk of limb-related events in patients with and without PAD in an exploratory analysis. METHODS: A total of 17 160 patients with type 2 diabetes mellitus, including 1025 (6%) with PAD, were randomized. Key efficacy outcomes were MACE (cardiovascular [CV] death, myocardial infarction, stroke), CV death/HHF, and progression of kidney disease. Amputations, peripheral revascularization, and limb ischemic adverse events were site-reported and categorized by a blinded reviewer. RESULTS: Patients in the placebo arm with PAD versus those without tended to have higher adjusted risk of CV death, myocardial infarction, or stroke (adjusted hazard ratio [HR], 1.23 [95% CI, 0.97-1.56], P=0.094) and significantly higher adjusted risk of CV death/HHF (adjusted HR, 1.60 [95% CI, 1.21-2.12], P=0.0010) and progression of kidney disease (adjusted HR, 1.51 [95% CI, 1.13 - 2.03], P=0.0058), and limb adverse events (adjusted HR, 8.37, P<0.001). The relative risk reductions with dapagliflozin for CV death/HHF (HR, 0.86, PAD; HR, 0.82, no-PAD; P-interaction=0.79) and progression of kidney disease (HR, 0.78, PAD; HR, 0.76, no-PAD; P-interaction=0.84) were consistent regardless of PAD. There were 560 patients who had at least 1 limb ischemic event, 454 patients with at least 1 peripheral revascularization, and 236 patients with at least 1 amputation, with a total of 407 amputations reported. Overall, there were no significant differences in any limb outcome with dapagliflozin versus placebo including limb ischemic adverse events (HR, 1.07 [95% CI, 0.90-1.26]) and amputation (HR, 1.09 [95% CI, 0.84-1.40]), with no significant interactions by a history of PAD versus not (P-interactions=0.30 and 0.093, respectively). CONCLUSIONS: Patients with versus without PAD are at a higher risk of CV death of CV death, HHF, and kidney outcomes, and have a consistent benefits for CV death/HHF and progression of kidney disease with dapagliflozin. Patients with PAD had a higher risk of limb events, with no consistent pattern of incremental risk observed with dapagliflozin. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01730534.

From glucose lowering agents to disease/diabetes modifying drugs: a "SIMPLE" approach for the treatment of type 2 diabetes.

During the last decade we experienced a surge in the number of glucose lowering agents that can be used to treat patients with type 2 diabetes. Especially important are the discoveries that sodium glucose co-transporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve patients' cardiovascular and renal outcomes. Accordingly, various medical associations have updated their guidelines for the treatment of diabetes in this new era. Though not agreeing on every issue, these position-statements generally share a detailed and often complex workflow that may be too complicated for the busy and overworked primary care setting, where the majority of patients with type 2 diabetes are managed in many countries. Other guidelines, generally those from the cardiology associations focus primarily on the population of patients with high risk for or pre-existing cardiovascular disease, which represent only the minority of patients with type 2 diabetes. We believe that we should re-define SGLT2i and GLP-1 RA as diabetes/disease modifying drugs (DMDs) given the recent evidence of their cardiovascular and renal benefits. Based on this definition we have designed a SIMPLE approach in order to assist primary care teams in selecting the most appropriate therapy for their patients. We believe that most subjects newly diagnosed with type 2 diabetes should initiate early combination therapy with metformin and a prognosis changing DMD. The decision whether to use GLP-1 RA or SGLT2i should be made based on specific patient's risk factors and preferences. Importantly, DMDs are known to have a generally safe side-effect profile, with lower risk for hypoglycemia and weight gain, further promoting their wider usage. Early combination therapy with DMDs may improve the multiple pathophysiological abnormalities responsible for type 2 diabetes and its complications, thus resulting in the greatest long term benefits.

NAFLD in type 2 diabetes mellitus: Still many challenging questions.

Epidemiologic data consistently show that in patients with type 2 diabetes (T2DM) the prevalence of non-alcoholic fatty liver disease (NAFLD), including advanced fibrosis, is double compared to the general population, and it associates with high risk of liver-related morbidity (advanced fibrosis, hepatocellular carcinoma) and mortality, but also with other systemic consequences, such as cardiovascular (CV) disease, chronic kidney disease, and overall mortality. There are still many answers that need to be clarified regarding NAFLD in T2DM, including deciphering the complex pathogenetic mechanisms, the intertwined relationships with the extrahepatic organs and tissues (mainly heart, kidneys, adipose tissue, gut), the prognostic value of NAFLD for CV risk stratification, and more importantly, what would be the most appropriate screening algorithm, diagnostic method and therapeutic approach. We advocate here for proactive action, in order to identify NAFLD in a timely manner, and suggest a simple algorithm to be used in clinical practice, based on risk stratification and on experts' opinions. We discuss the current therapeutic options for NAFLD in T2DM, for which a multifactorial approach is needed, that concomitantly addresses the liver and the cardio-reno-metabolic disturbances.

Five years into the Israeli National Diabetes Program - are we on the right track?

Diabetes mellitus poses major public health and economic challenges which necessitate national-level intervention. The ultimate goal of the Israel National Diabetes Program is to ensure that all people with diabetes, or at high risk of developing diabetes, will live well and have access to high-quality services that meet their individual needs. The integrated National Diabetes Program in Israel was established in 2014. Prevailing needs were identified and working groups assigned to delineate deficiencies and propose mode of action. Program leaders summarized and prioritized the needs, and identified main targets of action for the preliminary years. The program was achieved by a combined approach: top-bottom, having the Director General of the Ministry of Health (MoH) personally involved, and bottom-up, by routine meetings with representatives of the health organizations, clinical experts, patient representatives and other stakeholders. Main achievements during the first five years of the program included setting up a novel funding mechanism for diabetes prevention, substantiating the field of diabetes education in Israel, designing the infrastructure of diabetic foot care in Israel, updating the national health-budget allocation formula with incentives to improve provision of services, and promoting a mandatory system for judgemental labelling of food products. The program is in progress with ongoing monitoring, evaluation and improvement with particular emphasis on translational learning. Although there is much to be done, diabetes care in Israel has taken an enormous step forward in the past five years.

Haemoglobin A1c is a predictor of COVID-19 severity in patients with diabetes.

AIM: Poor outcomes of coronavirus disease 2019 (COVID-19) have been linked to diabetes, but its relation to pre-infection glycaemic control is still unclear. MATERIALS AND METHODS: To address this question, we report here the association between pre-infection Haemoglobin A1c (HbA1c) levels and COVID-19 severity as assessed by need for hospitalization in a cohort of 2068 patients with diabetes tested for COVID-19 in Leumit Health Services (LHSs), Israel, between 1 February and 30 April 2020. Using the LHS-integrated electronic medical records system, we were able to collect a large amount of clinical information including age, sex, socio-economic status, weight, height, body mass index, HbA1c, prior diagnosis of ischaemic heart disease, depression/anxiety, schizophrenia, dementia, hypertension, cerebrovascular accident, congestive heart failure, smoking, and chronic lung disease. RESULTS: Of the patients included in the cohort, 183 (8.85%) were diagnosed with COVID-19 and 46 were admitted to hospital. More hospitalized patients were female, came from higher socio-economic background and had a higher baseline HbA1c. A prior diagnosis of cerebrovascular accident and chronic lung disease conferred an increased risk of hospitalization but not obesity or smoking status. In a multivariate analysis, controlling for multiple prior clinical conditions, the only parameter associated with a significantly increased risk for hospitalization was HbA1c ≥ 9%. CONCLUSION: Using pre-infection glycaemic control data, we identify HbA1c as a clear predictor of COVID-19 severity. Pre-infection risk stratification is crucial to successfully manage this disease, efficiently allocate resources, and minimize the economic and social burden associated with an undiscriminating approach.

The relationship between inpatient hyperglycaemia and mortality is modified by baseline glycaemic status.

AIMS: There is a well-established association between inpatient hyperglycaemia and mortality. However, evidence is inconsistent regarding whether this association is differential among those with and without type 2 diabetes mellitus (T2DM). Most studies are based on convenience samples or are unable to adjust for comorbidities. We examined whether the association between hyperglycaemia and 30-day mortality was modified by baseline glycaemic status. MATERIALS AND METHODS: This was a retrospective cohort study of 174,671 eligible hospitalized individuals between 2012 and 2015. Thirty-day mortality was assessed during the first inpatient stay up to 30 days post discharge. The adjusted association between hyperglycaemia and mortality was assessed with logistic regression models. Then, four interaction terms were entered into the model to assess if the association between hyperglycaemia and mortality differed by baseline glycaemic status. RESULTS: The multivariate model demonstrated a 2.18-fold risk of mortality associated with hyperglycaemia (odds ratio [OR] [95%CI]: 2.19 [2.08-2.31]). Adding the interaction terms between hyperglycaemia and baseline glycaemic status the ORs of 30-day mortality were 1.41 (1.25-1.60) in non-T2DM status, 1.32 (1.16-1.51) in pre-diabetes status and 1.30 (1.04-1.62) in unscreened status, as compared to T2DM status with hyperglycaemia. CONCLUSIONS: Hyperglycaemia is positively associated with mortality and both those without and with controlled T2DM are at highest risk. These findings may help medical staff identify potential increased risk of mortality upon hospital entry and discharge, and direct further research to assess how hyperglycaemia control and proactive deterioration prevention throughout the entire inpatient stay may prevent adverse outcomes.

Cardiorenal outcomes with dapagliflozin by baseline glucose-lowering agents: Post hoc analyses from DECLARE-TIMI 58.

AIM: To assess the associations between baseline glucose-lowering agents (GLAs) and cardiorenal outcomes with dapagliflozin versus placebo in the DECLARE-TIMI 58 study. MATERIALS AND METHODS: DECLARE-TIMI 58 assessed the cardiorenal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. This post hoc analysis elaborates the efficacy and safety outcomes by baseline GLA for treatment effect and GLA-based treatment interaction. RESULTS: At baseline, 14 068 patients (82.0%) used metformin, 7322 (42.7%) sulphonylureas, 2888 (16.8%) dipeptidyl peptidase-4 inhibitors, 750 (4.4%) glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and 7013 (40.9%) insulin. Dapagliflozin reduced the composite of cardiovascular death (CVD) and hospitalization for heart failure (HHF) versus placebo regardless of baseline GLA, with greater benefit in the small group of patients with baseline use of GLP-1 RAs (HR [95% CI] 0.37 [0.18, 0.78] vs. 0.86 [0.75, 0.98] in GLP-1 RA users vs. non-users, Pinteraction = .03). The overall HR for major adverse cardiovascular events (CVD, myocardial infarction or ischaemic stroke) was 0.93 (95% CI 0.84, 1.03) with dapagliflozin versus placebo, with no interaction by baseline GLA (Pinteraction > .05). The renal-specific outcome was reduced with dapagliflozin versus placebo in the overall cohort (HR [95%CI] 0.53[0.43-0.66]), with no interaction by baseline GLA (Pinteraction > .05). All of these outcomes were similar in those with versus those without baseline metformin use. CONCLUSIONS: The effects of dapagliflozin on cardiorenal outcomes were generally consistent regardless of baseline GLA, with consistent benefits regardless of baseline metformin use. The potential clinical benefit of combining sodium-glucose co-transporter-2 inhibitors with GLP-1 RAs, given some evidence of cardiovascular risk reduction with both classes, should be explored further.