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Objective: The cardiorenal benefits of adding sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy for patients on insulin, particularly those on intensive regimens that include short-acting (SA) insulin, have not been explored.Research Design and Methods: In Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomized to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular (CV), renal, metabolic, and safety outcomes with dapagliflozin versus placebo by insulin dose and regimen were studied with Cox regression models.Results: The study included 7,013 insulin users at baseline, with 4,650 (66.3%) patients on regimens including SA insulin. Insulin doses varied, with 2,443 (34.8%) patients receiving <0.5 IU/kg, 2,795 (39.9%) 0.5 to ≤1 IU/kg, and 1,339 (19.1%) >1 IU/kg. Dapagliflozin reduced CV death/hospitalization for heart failure among overall insulin users (hazard ratio [HR] 0.82 [95% CI 0.69-0.97]) and consistently in patients on insulin regimens with or without SA insulin (0.83 [0.67-1.03] and 0.78 [0.57-1.07], respectively, Pinteraction = 0.75). No heterogeneity was observed by insulin dose (Pinteraction = 0.43). The HR for major adverse CV events with dapagliflozin among insulin users (0.84 [0.74-0.97]) was similar irrespective of regimen or dose (Pinteraction = 0.75 and 0.07). Dapagliflozin reduced the rate of adverse renal outcomes overall and consistently across subgroups of insulin users. Decreases in HbA1c, weight, and systolic blood pressure with dapagliflozin were seen regardless of insulin dose or regimen. The known safety profile of dapagliflozin was unchanged in patients on intensive insulin regimens.Conclusions: The benefits and safety of dapagliflozin were maintained in high-risk patients receiving high-dose or intensive insulin regimens including SA insulin.Article Highlights: Limited data exist regarding the cardiorenal, metabolic, and safety outcomes of SGLT2 inhibitors in patients on high-dose or intensive insulin regimens including short-acting insulin. In DECLARE-TIMI 58, 17,160 patients including 7,013 baseline insulin users were randomized to dapagliflozin versus placebo. Outcomes among insulin users by insulin dose and regimen were studied. Our results suggest that use of dapagliflozin by patients with type 2 diabetes managed with insulin, including high-dose or intensive insulin regimens, provided significant cardiovascular, renal, and metabolic benefits, in line with overall trial results. Adverse events associated with dapagliflozin, including hypoglycemia and diabetic ketoacidosis, were rare in this cohort. [ABSTRACT FROM AUTHOR]

Objective: In patients with moderate to severe albuminuric kidney disease, sodium-glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk.Research Design and Methods: In the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and kidney-related death. Other outcomes included incidence of categorical eGFR decline of different thresholds and chronic (6 month to 4 year) or total (baseline to 4 year) eGFR slopes.Results: Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38-0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001).Conclusions: Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Background: Adverse associations of low- and no-calorie sweetened beverages (LNCSB) with cardiometabolic outcomes in observational studies may be explained by reverse causality and residual confounding.Purpose: To address these limitations we used change analyses of repeated measures of intake and substitution analyses to synthesize the association of LNCSB with cardiometabolic outcomes.Data Sources: MEDLINE, Embase, and the Cochrane Library were searched up to 10 June 2021 for prospective cohort studies with ≥1 year of follow-up duration in adults.Study Selection: Outcomes included changes in clinical measures of adiposity, risk of overweight/obesity, metabolic syndrome, type 2 diabetes (T2D), cardiovascular disease, and total mortality.Data Extraction: Two independent reviewers extracted data, assessed study quality, and assessed certainty of evidence using GRADE. Data were pooled with a random-effects model and expressed as mean difference (MD) or risk ratio (RR) and 95% CI.Data Synthesis: A total of 14 cohorts (416,830 participants) met the eligibility criteria. Increase in LNCSB intake was associated with lower weight (5 cohorts, 130,020 participants; MD -0.008 kg/year [95% CI -0.014, -0.002]). Substitution of LNCSB for sugar-sweetened beverages (SSB) was associated with lower weight (three cohorts, 165,579 participants; MD, -0.12 [-0.14, -0.10,] kg/y) and lower incidence of obesity (OB) (one cohort, 15,765 participants; RR 0.88 [95% CI 0.88, 0.89]), coronary heart disease (six cohorts, 233,676 participants; 0.89 [0.81, 0.98]), cardiovascular disease mortality (one cohort, 118,363 participants; 0.95 [0.90, 0.99]), and total mortality (one cohort, 118,363 participants; 0.96 [0.94, 0.98]) with no adverse associations across other outcomes. Substitution of water for SSB showed lower weight (three cohorts, 165,579 participants; MD -0.10 kg/year [-0.13, -0.06]), lower waist circumference (one cohort, 173 participants; -2.71 cm/year [-4.27, -1.15]) and percent body fat (one cohort, 173 participants; -1.51% per year [-2.61, -0.42]), and lower incidence of OB (one cohort, 15,765 participants; RR 0.85 [0.75, 0.97]) and T2D (three cohorts, 281,855 participants; 0.96 [0.94, 0.98]). Substitution of LNCSB for water showed no adverse associations.Limitations: The evidence was low to very low certainty owing to downgrades for imprecision, indirectness, and/or inconsistency.Conclusions: LNCSB were not associated with cardiometabolic harm in analyses that model the exposure as change or substitutions. The available evidence provides some indication that LNCSB in their intended substitution for SSB may be associated with cardiometabolic benefit, comparable with the standard of care, water. [ABSTRACT FROM AUTHOR]

Objective: Heart failure (HF) is an impactful complication of type 2 diabetes mellitus (T2DM). We aimed to develop and validate a risk score for hospitalization for HF (HHF) incorporating biomarkers and clinical factor(s) in patients with T2DM.Research Design and Methods: We derived a risk score for HHF using clinical data, high-sensitivity troponin T (hsTnT), and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) from 6,106 placebo-treated patients with T2DM in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using Cox regression. The strongest indicators of HHF risk were included in the score using integer weights. The score was externally validated in 7,251 placebo-treated patients in DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58). The effect of dapagliflozin on HHF was assessed by risk category in DECLARE-TIMI 58.Results: The strongest indicators of HHF risk were NT-proBNP, prior HF, and hsTnT (each P < 0.001). A risk score using these three variables identified a gradient of HHF risk (P-trend <0.001) in the derivation and validation cohorts, with C-indices of 0.87 (95% CI, 0.84-0.89) and 0.84 (0.81-0.86), respectively. Whereas there was no significant effect of dapagliflozin versus placebo on HHF in the low-risk group (hazard ratio [HR] 0.98 [95% CI 0.50-1.92]), dapagliflozin significantly reduced HHF in the intermediate-, high-, and very-high-risk groups (HR 0.64 [0.43-0.95], 0.63 [0.43-0.94], and 0.72 [0.54-0.96], respectively). Correspondingly, absolute risk reductions (95% CI) increased across these latter 3 groups: 1.0% (0.0-1.9), 3.0% (0.7-5.3), and 4.4% (-0.2 to 8.9) (P-trend <0.001).Conclusions: We developed and validated a risk score for HHF in T2DM that incorporated NT-proBNP, prior HF, and hsTnT. The risk score identifies patients at higher risk of HHF who derive greater absolute benefit from dapagliflozin. [ABSTRACT FROM AUTHOR]

Objective: International guidelines propose prescribing sodium-glucose cotransporter 2 (SGLT2) inhibitors to patients with type 2 diabetes (T2D) as secondary prevention in patients with established atherosclerotic cardiovascular disease (ASCVD) or for primary prevention of cardiovascular events in high-risk patients with multiple risk factors (MRF) for ASCVD. The current analyses expand on the cardiovascular renal and metabolic effects of SGLT2 inhibitors in MRF patients.Research Design and Methods: In DECLARE-TIMI 58, 17,160 patients with T2D and MRF (59.4%) or established ASCVD (40.6%) were randomized to dapagliflozin versus placebo; patients were followed for a median of 4.2 years. The cardiovascular and renal outcomes in the MRF cohort were studied across clinically relevant subgroups for treatment effect and subgroup-based treatment interaction.Results: Among patients with MRF, the reduction with dapagliflozin in risk of cardiovascular death or hospitalization for heart failure (CVD/HHF) (hazard ratio [HR] 0.84, 95% CI 0.67-1.04) and the renal-specific outcome (HR 0.51, 95% CI 0.37-0.69) did not differ from that for patients with ASCVD (Pinteraction 0.99 and 0.72, respectively). The effect on CVD/HHF was entirely driven by a reduction in HHF (HR 0.64, 95% CI 0.46-0.88). The benefits of dapagliflozin on HHF and on the renal-specific outcome, among the subset with MRF, were directionally consistent across clinically relevant subgroups. At 48 months, HbA1c, weight, systolic blood pressure, and urinary albumin-to-creatinine ratio were lower with dapagliflozin versus placebo and estimated glomerular filtration rate was higher (P < 0.001).Conclusions: In patients with T2D and MRF, dapagliflozin reduced the risk of HHF and adverse renal outcomes regardless of baseline characteristics. These analyses support the benefit of dapagliflozin for important outcomes in a broad primary prevention population. [ABSTRACT FROM AUTHOR]

Objective: Data regarding the effects of sodium-glucose cotransporter 2 inhibitors in the elderly (age ≥65 years) and very elderly (age ≥75 years) are limited.Research Design and Methods: The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 assessed cardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. Efficacy and safety outcomes were studied within age subgroups for treatment effect and age-based treatment interaction.Results: Of the 17,160 patients, 9,253 were <65 years of age, 6,811 ≥65 to <75 years, and 1,096 ≥75 years. Dapagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure consistently, with a hazard ratio (HR) of 0.88 (95% CI 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.5277). Overall, dapagliflozin did not significantly decrease the rates of major adverse cardiovascular events, with HR 0.93 (95% CI 0.81, 1.08), 0.97 (0.83, 1.13), and 0.84 (0.61, 1.15) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.7352). The relative risk reduction for the secondary prespecified cardiorenal composite outcome ranged from 18% to 28% in the different age-groups with no heterogeneity. Major hypoglycemia was less frequent with dapagliflozin versus placebo, with HR 0.97 (95% CI 0.58, 1.64), 0.50 (0.29, 0.84), and 0.68 (0.29, 1.57) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.2107). Safety outcomes, including fractures, volume depletion, cancer, urinary tract infections, and amputations were balanced with dapagliflozin versus placebo, and acute kidney injury was reduced, all regardless of age. Genital infections that were serious or led to discontinuation of the study drug and diabetic ketoacidosis were uncommon, yet more frequent with dapagliflozin versus placebo, without heterogeneity (interaction P values 0.1058 and 0.8433, respectively).Conclusions: The overall efficacy and safety of dapagliflozin are consistent regardless of age. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of inclisiran by diabetes status.Research Design and Methods: ORION-1 (ClinicalTrials.gov, NCT02597127) randomized 501 subjects with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents and high LDL cholesterol (LDL-C), despite maximally tolerated LDL-C-lowering therapies, to one or two doses of placebo or inclisiran. Levels of lipids and proprotein convertase subtilisin/kexin type 9 (PCSK9) at baseline and day 180 were compared.Results: Inclisiran was associated with marked declines in LDL-C (median -28% to -52%, P < 0.0001 and -28% to -55%, P < 0.005 for all doses in the without- and with-diabetes groups, respectively) and PCSK9. The inclisiran-treated groups also had lower apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) but higher HDL cholesterol. Inclisiran had an adverse profile similar to that of placebo, and adverse events were proportionally balanced in the baseline with- and without-diabetes groups.Conclusions: PCSK9-targeted siRNA-driven strategies may provide a novel therapeutic option for managing dyslipidemia in the presence and absence of diabetes. [ABSTRACT FROM AUTHOR]

The article offers information on how public health matters for both COVID-19 and diabetes. Topics include the containment of COVID-19 by physical distancing and wearing face masks has varied widely between countries, regions within countries, and groups in each region, and the people with diabetes are among the groups affected more than the general population.

In December 2008, the U.S. Food and Drug Administration issued guidance to the pharmaceutical industry setting new expectations for the development of antidiabetes drugs for type 2 diabetes. This guidance expanded the scope and cost of research necessary for approval of such drugs by mandating long-term cardiovascular outcomes trials (CVOTs) for safety. Since 2008, 9 CVOTs have been reported, 13 are under way, and 4 have been terminated. Reassuringly, each of the completed trials demonstrated the noninferiority of their respective drugs to placebo for their primary cardiovascular (CV) composite end point. Notably, four additionally provided evidence of CV benefit in the form of significant decreases in the primary CV composite end point, two suggested reductions in CV death, and three suggested reductions in all-cause mortality. Although these trials have yielded much valuable information, whether that information justifies the investment of time and resources is controversial. In June 2016, a Diabetes Care Editors' Expert Forum convened to review the processes and challenges of CVOTs, discuss the benefits and limitations of their current designs, and weigh the merits of modifications that might improve the efficiency and clinical value of future trials. Discussion and analysis continued with the CVOT trial results released in June 2017 at the American Diabetes Association's Scientific Sessions and in September 2017 at the European Association for the Study of Diabetes scientific meeting. This article summarizes the discussion and findings to date. [ABSTRACT FROM AUTHOR]