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Aim: To assess the association between urinary albumin‐to‐creatinine ratio (UACR) categories within the normal range with mortality and adverse cardiovascular outcomes. Materials and Methods: PubMed and Embase were systematically searched for real‐world evidence studies. Studies were manually evaluated according to predefined eligibility criteria. We included prospective and retrospective cohort studies of the association between UACR categories <30 mg/g and cardiovascular outcomes or mortality. Published information regarding study design, participants, UACR categorization, statistical methods, and results was manually collected. Two UACR categorization approaches were defined: a two‐category (UACR <10 mg/g vs. 10‐30 mg/g) and a three‐category division (UACR <5 mg/g vs. 5‐10 and 10‐30 mg/g). A random effects meta‐analysis was performed on studies eligible for the meta‐analysis. Results: In total, 22 manuscripts were identified for the systematic review, 15 of which were eligible for the meta‐analysis. The results suggest an association between elevated UACR within the normal to mildly increased range and higher risks of all‐cause mortality, cardiovascular death, and coronary heart disease, particularly in the range of 10‐30 mg/g. Compared with UACR <10 mg/g, the hazard ratio [HR (95% confidence interval, CI)] for UACR between 10 and 30 mg/g was 1.41 (1.15, 1.74) for all‐cause mortality and 1.56 (1.23, 1.98) for coronary heart disease. Compared with UACR <5 mg/g, the risk of cardiovascular mortality for UACR between 10 and 30 mg/g was more than twofold [HR (95% CI): 2.12 (1.61, 2.80)]. Intermediate UACR (5‐10 mg/g) was also associated with a higher risk of all‐cause mortality [HR (95% CI): 1.14 (1.05, 1.24)] and cardiovascular mortality [HR (95% CI): 1.50 (1.14, 1.99)]. Conclusions: We propose considering higher UACR within the normoalbuminuric range as a prognostic factor for cardiovascular morbidity and mortality. Our findings underscore the clinical significance of even mild increases in albuminuria. [ABSTRACT FROM AUTHOR]

Objective This study aimed to test whether mildly elevated bilirubin levels in preterm infants are associated with increased signal intensity (SI) on magnetic resonance imaging (MRI) of the basal ganglia (BG). Study Design MRI was performed at term equivalent age in 55 postpreterm infants using a neonatal MRI 1-T scanner. SI of the BG was correlated with mild hyperbilirubinemia. Results BG MRI SI was significantly increased in infants with mild hyperbilirubinemia on T1-weighted image (T1; p = 0.0393) and T2-weighted image (T2; p = 0.0309). We found no effect of gestational age or sepsis on BG MRI intensity; however, there was a significant effect of acidosis on T1 (p = 0.0223) but not on T2 (p = 0.2316). Infants with combined hyperbilirubinemia and acidosis had the most significant increase in SI on both T1 and T2 respectively (p = 0.0072 and 0.0195, respectively). Conclusion We found a positive association between increased BG MRI SI and mildly elevated bilirubin levels. The effect was greatly strengthened when hyperbilirubinemia was associated with acidosis. Key Points Excessive bilirubin is neurotoxic to the neonatal brain. It is deposited in the BG. BG MRI SI is increased with bilirubin deposition. The premature brain is more vulnerable to bilirubin associated MRI changes. [ABSTRACT FROM AUTHOR]

Following propensity-score matching, there were 6477 patients in each arm; 5431 patients (41.9%) were women and the mean (SD) patient age was 59.8 (10.9) years (Table 1). Patients with T2D, who initiated an SGLT2 inhibitor (empagliflozin or dapagliflozin) in an outpatient setting between August 2015 and December 2020 were propensity-scored matched with patients starting a DPP-4 inhibitor (sitagliptin, linagliptin, vildagliptin or saxagliptin). Risk of hospitalization with sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes lacking evidence of chronic kidney disease: Real-world data Patients with type 2 diabetes (T2D) have a high incidence of hospitalizations that reduce patients' quality of life and are translated into a significant burden on healthcare systems, accompanied by increased costs.[[1]] Randomized controlled trials (RCTs) showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiovascular events, heart failure (HF) hospitalizations, and kidney outcomes in patients with T2D, HF, or chronic kidney disease (CKD).[3] In some of these RCTs, SGLT2 inhibitors also modestly reduced the risk for any hospitalization.[[4], [6], [8], [10]] However, these studies included patients with T2D and high cardiovascular risk,[[4], [6], [11]] or patients with CKD with and without T2D.[[8]] Whether SGLT2 inhibitor use is associated with a lower risk for any hospitalization in a general population of patients with T2D, especially patients without CKD, is unknown. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Background Chronic pain is prevalent but difficult to treat in patients undergoing hemodialysis (HD). Effective and safe analgesics are limited in this patient population. Our aim in this feasibility study was to evaluate the safety of sublingual oil based medical cannabis for pain management in patients undergoing HD. Methods In a prospective randomized, double-blind, cross-over design, patients undergoing HD with chronic pain were assigned to one of three arms: BOL-DP-o-04-WPE whole-plant extract (WPE), BOL-DP-o-04 cannabinoid extraction (API) or placebo. WPE and API contained trans-delta-9-‏tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:6 ratio (1:6, THC:CBD). Patients were treated for 8 weeks, with subsequent 2-week wash out, followed by a cross-over to a different arm. The primary endpoint was safety. Results Eighteen patients were recruited and 15 were randomized. Three did not complete drug titration period due to adverse events (AEs) and one patient died during titration due to sepsis (WPE). Of those who completed at least one treatment period, seven patients were in the WPE arm, five in the API and nine receiving placebo. The most common AEs were sleepiness, which improved after dose reduction or patient adaptation. Most AEs were mild to moderate and resolved spontaneously. Serious AEs considered related to study drug included one episode of accidental overdose (WPE) leading to hallucinations. Liver enzymes were stable during cannabis treatment. Conclusions Short-term medical cannabis use in patients treated with HD was generally well tolerated. The safety data supports further studies to assess the overall risk–benefit of a treatment paradigm utilizing medical cannabis to control pain in this patient population. [ABSTRACT FROM AUTHOR]

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]

Objective: Current guidelines recommend prescribing SGLT2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c.Research Design and Methods: In the Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomly assigned to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population and with dapagliflozin versus placebo in HbA1c subgroups were studied by Cox regression models.Results: In the overall population, higher baseline HbA1c was associated with a higher risk of cardiovascular death or hospitalization for heart failure (HHF); major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and ischemic stroke; and cardiorenal outcomes (adjusted hazard ratios 1.12 [95% CI 1.06-1.19], 1.08 [1.04-1.13], and 1.17 [1.11-1.24] per 1% higher level, respectively). Elevated HbA1c was associated with a greater increased risk for MACE and cardiorenal outcomes in patients with multiple risk factors (MRF) than in established ASCVD (P-interaction = 0.0064 and 0.0093, respectively). Compared with placebo, dapagliflozin decreased the risk of cardiovascular death/HHF, HHF, and cardiorenal outcomes, with no heterogeneity by baseline HbA1c (P-interaction > 0.05).Conclusions: Higher HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c <7%. [ABSTRACT FROM AUTHOR]

Objective: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk.Research Design and Methods: DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death.Results: Baseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to <30 mg/g, 4,030 (23.93%) with 30-300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35-1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, Pinteraction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups (P < 0.05, Pinteraction = 0.480).Conclusions: In DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease. [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]

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. [ABSTRACT FROM AUTHOR]

Aims: To evaluate comprehensively the safety of dapagliflozin in patients with type 2 diabetes (T2DM), with emphasis placed on potential safety concerns related to the sodium‐glucose co‐transporter‐2 inhibitor class. Methods: In the Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58 (DECLARE‐TIMI 58) study, 17 160 patients with T2DM were randomized to dapagliflozin or placebo and followed for a median of 4.2 years. Safety was evaluated in 17 143 patients receiving at least one dose of study drug. Results: Acute kidney injury occurred less frequently with dapagliflozin, and adverse events suggestive of volume depletion were balanced between treatment groups, both irrespective of baseline estimated glomerular filtration rate, blood pressure, diuretic or loop diuretic use (interaction P values >0.05). Fractures and malignancies were balanced between the groups, irrespective of sex, diabetes duration or smoking (interaction P values >0.05) and fewer cases of bladder cancer occurred in the dapagliflozin versus the placebo group. Diabetic ketoacidosis was very rare, but more frequent with dapagliflozin versus placebo (27 vs. 12 patients with events; P = 0.02), yet signs, symptoms and contributing factors were similar in the two groups. Major hypoglycaemia occurred less frequently with dapagliflozin versus placebo, regardless of baseline use of either insulin or sulphonylureas (interaction P values >0.05). There were more adverse events of genital infections leading to discontinuation of study drug in the dapagliflozin versus the placebo group, but serious genital infections were few and balanced between treatment groups. Urinary tract infections, acute pyelonephritis and urosepsis were also balanced between treatment groups. Conclusions: Dapagliflozin was well tolerated. The long duration and large number of patient‐years in DECLARE‐TIMI 58 comprehensively addressed previous safety questions, confirming the robust safety profile of dapagliflozin. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether the cardiovascular and renal benefits observed with dapagliflozin in the DECLARE‐TIMI 58 trial are also observed in patients with short and long‐standing diabetes. Materials and Methods: This post hoc analysis studied the dual primary efficacy endpoints, a composite of cardiovascular death or hospitalization for heart failure (CVD/HHF) and major adverse cardiovascular events (MACE; CVD, myocardial infarction [MI], ischaemic stroke) by diabetes duration. Results: Of the 17 160 patients, 3836 had diabetes duration of ≤5 years, 4731 >5‐10 years, 3952 >10‐15 years, 2433 >15‐20 years and 2206 >20 years. Dapagliflozin reduced the risk of CVD/HHF by a similar amount across diabetes duration subgroups, ranging from HR 0.79 (0.58‐1.06) in patients with diabetes duration of ≤5 years to 0.75 (0.55‐1.03) in those patients with diabetes duration of >20 years (interaction trend P‐value 0.76). Hazard ratios (HRs) for MACE ranged from 1.08 (0.87‐1.35) in patients with diabetes duration of ≤5 years to 0.67 (0.52‐0.86) in those patients with diabetes duration of >20 years (interaction trend P‐value 0.004). This was driven by greater reductions in the risk of MI and ischaemic stroke with dapagliflozin in patients with long‐standing diabetes (interaction trend P‐values 0.019 and 0.015, respectively). The duration‐based MACE heterogeneity was apparent in those with or without a history of prior MI and in those with multiple risk factors. The renal‐specific outcome was reduced with dapagliflozin with HRs ranging from 0.79 (0.47‐1.34) in patients with diabetes duration of ≤5 years to 0.42 (0.25‐0.72) in those patients with diabetes duration of >20 years (interaction trend P‐value 0.084). Conclusions: Dapagliflozin reduced the risk of CVD/HHF consistently, regardless of diabetes duration, whereas the treatment effect for MACE differed by duration subgroups, with significant reductions with dapagliflozin in patients with long‐standing diabetes. [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 assess treatment satisfaction and the effectiveness of a flash glucose monitoring (FGM) system in patients with type 2 diabetes using insulin.Research Design and Methods: A total of 101 patients with type 2 diabetes on multiple daily insulin injections (MDI) for at least 1 year were assigned randomly to the FGM intervention (n = 53) or the standard care (control) group (n = 48) and followed for 10 weeks. Both groups were instructed to adjust their insulin doses in face-to-face and telephone visits. Satisfaction with treatment, quality of life, comfort using FGM, HbA1c, and frequency of hypoglycemic events were evaluated.Results: The intervention group found treatment significantly more flexible (P = 0.019) and would recommend it to their counterparts (P = 0.023). Satisfaction using the FGM system was high. The changes in HbA1c were -0.82% (9 mmol/mol) vs. -0.33% (3.6 mmol/mol) in the intervention and control group, respectively (P = 0.005); in nonprespecified post hoc analysis, 68.6% of the patients in the intervention group had their HbA1c reduced by ≥0.5% (5.5 mmol/mol) compared with 30.2% in the control group (P < 0.001), and 39.2% had their HbA1c reduced by ≥1.0% (10.9 mmol/mol) vs. 18.6% in the control group (P = 0.0023) without an increased frequency of hypoglycemia.Conclusions: FGM tends to improve treatment satisfaction and may lead to amelioration of glycemic control in patients with type 2 diabetes on MDI without increasing the frequency of hypoglycemia. [ABSTRACT FROM AUTHOR]

Hypoglycaemia is a well-known risk associated with the use of sulphonylureas and insulin, often limiting achievement of glycaemic goals. Recognizing the precipitants and recurrence patterns of hypoglycaemic events, particularly major events, is therefore clinically important. The SAVOR-TIMI-53 trial was a cardiovascular outcome study of 16 492 patients allocated to saxagliptin vs placebo added to conventional care for a median of 2.1 years. Hypoglycaemic events were a prespecified outcome in the study and were defined as a symptomatic episode that recovered with carbohydrates or any recorded blood glucose <3.0 mmol/l (<54 mg/ dL). A major event was defined as one that required third-party assistance. Analysis of the features of the first hypoglycaemic event for each patient showed that a precipitant for the event was recognized by fewer than half of the patients, with the precipitant most often being a missed meal. In 40% of patients reporting major hypoglycaemic events, no precipitating factor was recognized, and in >60%, no previous hypoglycaemic event was reported during the timespan of the study, underscoring the lack of predictability of such an event. [ABSTRACT FROM AUTHOR]

Objective: Dipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy.Research Design and Methods: We studied renal outcomes of 16,492 patients with type 2 diabetes, randomized to saxagliptin versus placebo and followed for a median of 2.1 years in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial.Results: At baseline, 9,696 (58.8%) subjects had normoalbuminuria (albumin/creatinine ratio [ACR] <30 mg/g), 4,426 (26.8%) had microalbuminuria (ACR 30-300 mg/g), and 1,638 (9.9%) had macroalbuminuria (ACR >300 mg/g). Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (EOT) (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively). At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was -19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m2 (BSA), -105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and -245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA. Analyzing ACR as a continuous variable showed reduction in ACR with saxagliptin (1 year, P < 0.0001; 2 years, P = 0.0143; and EOT, P = 0.0158). The change in ACR did not correlate with that in HbA1c (r = 0.041, 0.052, and 0.036; 1 year, 2 years, and EOT, respectively). The change in eGFR was similar in the saxagliptin and placebo groups. Safety renal outcomes, including doubling of serum creatinine, initiation of chronic dialysis, renal transplantation, or serum creatinine >6.0 mg/dL, were similar as well.Conclusions: Treatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR. The beneficial effect of saxagliptin on albuminuria could not be explained by its effect on glycemic control. [ABSTRACT FROM AUTHOR]

Objective: To analyze the impact of adding saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study.Research Design and Methods: Patients with type 2 diabetes (n = 16,492) were randomized to saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement <54 mg/dL) or major hypoglycemia (requiring extended assistance) and patient characteristics overall and by treatment allocation were studied.Results: At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P < 0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA1c ≤7.0% and not in those with baseline HbA1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA1c, macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia.Conclusions: The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy. [ABSTRACT FROM AUTHOR]

SGLT2 inhibitors may lead to short term decrease in eGFR, with later stabilization and long-term reduction in the risk for end stage kidney disease. Fast decline (FD) in eGFR can be defined as a reduction of ≥3 ml/min/1.73m2/year and is associated with poor long-term renal prognosis. In this post-hoc analysis we studied the effect of dapagliflozin (dapa) on the risk for FD in the DECLARE-TIMI 58 trial. In DECLARE-TIMI 58, 17,160 patients with T2D and established or increased risk for CVD, with mean baseline eGFR of 85.2 ml/min/1.73m2, were randomized to dapa vs. placebo and followed for a median of 4.2 years. The risk for FD was compared between treatment arms. In the time frame of 0.5 years (after stabilization) to 4 years, the proportion of patients with FD was reduced with dapa vs. placebo (26.8% vs. 37.1% respectively, p<0.0001). This observation was persistent in all subgroups assessed (Table). The mean (SD) reduction in eGFR per year was 6.3 (3.7) vs. 0.0 (2.5) ml/min/1.73m2/year in the FD (N=4,788) vs. non-FD (N=10,224) patients. The proportion of patients with FD during the entire study period (i.e., 0-4 years) was reduced with dapa vs. placebo as well (33.6% vs. 37.0% respectively, p<0.0001). Dapagliflozin reduced the risk for FD in eGFR in a broad population of patients with T2D and either established or increased risk for CVD, but relatively preserved renal function, irrespective of patients' baseline characteristics. Disclosure: I. Raz: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Consultant; Self; AstraZeneca, BOL, CamerEyes Ltd, Concenter BioPharma, DarioHealth, Diabot, Exscopia, GlucoMe, Insuline Medical, Medial EarlySIgn, Orgenesis Inc. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Stock/Shareholder; Self; BOL, CamerEyes Ltd, DarioHealth, Diabot, GlucoMe, Orgenesis Inc. S.D. Wiviott: Consultant; Self; Aegerion Pharmaceuticals, Allergan, Angelmed, Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Boston Clinical Research Institute, Bristol-Myers Squibb, Daiichi Sankyo, Eisai Inc., Eli Lilly and Company, ICON Clinical, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Servier, St. Jude Medical, XOMA Corporation. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Amgen, Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eisai Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi-Aventis. Other Relationship; Self; See other relationships for list. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. J.P. Dwyer: Advisory Panel; Self; Bayer AG, Bird Rock Bio. Consultant; Self; US Food and Drug Administration (FDA). Employee; Self; Vanderbilt University Medical Center. Other Relationship; Self; Akcea Therapeutics, AstraZeneca, CSL Behring, Lexicon Pharmaceuticals, Inc., Praetego, Sanofi. A. Cahn: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. Consultant; Self; GlucoMe, Medial EarlySign. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. E.L. Goodrich: Other Relationship; Self; AstraZeneca. S. Murphy: Research Support; Self; AstraZeneca. Other Relationship; Self; Abbott, Amgen, Aralez, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharma. A. Rozenberg: None. I. Yanuv: None. J. Wilding: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Mundipharma International, Napp Pharmaceuticals, Novo Nordisk A/S, Wilmington Healthcare. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. L.A. Leiter: Advisory Panel; Self; Abbott, Amgen, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Amgen, AstraZeneca, Kowa Pharmaceuticals America, Inc., Medicines Company. Speaker's Bureau; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Medscape, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. D.L. Bhatt: Research Support; Self; Abbott, Afimmune, Amarin Corporation, Amgen, AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Cardax, Chiesi USA, Inc., CSL Behring, Ferring Pharmaceuticals, Fractyl Laboratories, Inc., Idorsia, Ironwood Pharmaceuticals, Ischemix, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PLx Pharma Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis, Synaptic. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp & Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. R.C. Ma: Advisory Panel; Self; AstraZeneca. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Tricida Inc. T. Tankova: Board Member; Self; Amgen, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Sanofi, Servier. M. Fredriksson: Employee; Self; AstraZeneca. I.A. Gause-Nilsson: Employee; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. M.S. Sabatine: Consultant; Self; Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor Pharmaceuticals, Dyrnamix Inc., Esperion Therapeutics, Inc., IFM Therapeutics, Intarcia Therapeutics, Ionis Pharmaceuticals, Inc., Medicines Company, MedImmune, Merck < Co., Inc. Research Support; Self; Amgen, AstraZeneca, Bayer U.S., Daiichi Sankyo, Eisai Inc., Intarcia Therapeutics, Janssen Research and Development, Medicines Company, MedImmune, Merck & Co., Inc., Novartis AG, Pfizer Inc., Quark Pharmaceuticals. O. Mosenzon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Teva Pharmaceutical Industries Ltd. Funding: AstraZeneca [ABSTRACT FROM AUTHOR]

In the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 study 17160 patients (pts) with T2DM were randomized to the SGLT2 inhibitor dapagliflozin (DAPA) or placebo (PBO) for a median follow up of 4.2 years. At baseline 14068 pts used metformin, 7322 sulfonylureas, 2888 DPP-4 inhibitors, 750 GLP-1 receptor agonist (GLP-1 RA) and 7013 insulin. DAPA reduced the composite of CV death and hospitalization for heart failure (CVD/HHF) vs. PBO regardless of baseline glucose lowering agents (GLA), though the effect appeared to be particularly large in the small group of pts with baseline use of GLP-1 RA (Figure). The overall HR for major adverse cardiovascular events (MACE; CVD, myocardial infarction, ischemic stroke) was 0.93 (95% CI 0.84-1.03) with DAPA vs. PBO, with no interaction by non-insulin GLA, yet a tendency toward greater benefit with DAPA vs. PBO was observed in baseline insulin users (Figure). The renal specific outcome (sustained decrease of ≥40% in eGFR to <60 ml/min/1.73m2, new end stage renal disease, or renal death) was overall reduced with DAPA vs. PBO (HR 0.53, 95% CI 0.43-0.66) with no interaction by baseline GLA (p interaction >0.05). The effects of DAPA on CV and renal outcomes were generally consistent regardless of baseline GLA. Use or non-use of metformin did not alter outcomes. Additional studies defining the clinical benefit of combining CV risk reducing GLAs will be helpful. Disclosure: A. Cahn: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. Consultant; Self; GlucoMe, Medial EarlySign. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. S.D. Wiviott: Consultant; Self; Aegerion Pharmaceuticals, Allergan, Angelmed, Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Boston Clinical Research Institute, Bristol-Myers Squibb, Daiichi Sankyo, Eisai Inc., Eli Lilly and Company, ICON Clinical, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Servier, St. Jude Medical, XOMA Corporation. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Amgen, Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eisai Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi-Aventis. Other Relationship; Self; See other relationships for list. O. Mosenzon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Teva Pharmaceutical Industries Ltd. S. Murphy: Research Support; Self; AstraZeneca. Other Relationship; Self; Abbott, Amgen, Aralez, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharma. E.L. Goodrich: Other Relationship; Self; AstraZeneca. I. Yanuv: None. A. Rozenberg: None. J. Wilding: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Mundipharma International, Napp Pharmaceuticals, Novo Nordisk A/S, Wilmington Healthcare. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. L.A. Leiter: Advisory Panel; Self; Abbott, Amgen, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Amgen, AstraZeneca, Kowa Pharmaceuticals America, Inc., Medicines Company. Speaker's Bureau; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Medscape, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. D.L. Bhatt: Research Support; Self; Abbott, Afimmune, Amarin Corporation, Amgen, AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Cardax, Chiesi USA, Inc., CSL Behring, Ferring Pharmaceuticals, Fractyl Laboratories, Inc., Idorsia, Ironwood Pharmaceuticals, Ischemix, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PLx Pharma Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis, Synaptic. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp & Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. L. Litwak: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk Inc., Sanofi. A. Kooy: Advisory Panel; Self; Eli Lilly and Company, Novartis Pharma K.K. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Research Support; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; Daiichi Sankyo, Mundipharma International. I.A. Gause-Nilsson: Employee; Self; AstraZeneca. M. Fredriksson: Employee; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. M.S. Sabatine: Consultant; Self; Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor Pharmaceuticals, Dyrnamix Inc., Esperion Therapeutics, Inc., IFM Therapeutics, Intarcia Therapeutics, Ionis Pharmaceuticals, Inc., Medicines Company, MedImmune, Merck & Co., Inc. Research Support; Self; Amgen, AstraZeneca, Bayer U.S., Daiichi Sankyo, Eisai Inc., Intarcia Therapeutics, Janssen Research and Development, Medicines Company, MedImmune, Merck & Co., Inc., Novartis AG, Pfizer Inc., Quark Pharmaceuticals. I. Raz: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Consultant; Self; AstraZeneca, BOL, CamerEyes Ltd, Concenter BioPharma, DarioHealth, Diabot, Exscopia, GlucoMe, Insuline Medical, Medial EarlySIgn, Orgenesis Inc. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Stock/Shareholder; Self; BOL, CamerEyes Ltd, DarioHealth, Diabot, GlucoMe, Orgenesis Inc. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose co-transporter-2 inhibitors were previously shown to improve renal parameters. In this predefined analysis of DECLARE-TIMI 58, we report the effects of dapagliflozin (dapa) on albuminuria in a broad population of patients with type 2 diabetes (T2DM) and either multiple risk factors (MRF) for or atherosclerotic cardiovascular disease (ASCVD), according to patients' baseline albuminuria status. Methods: We randomized 17,160 patients with T2DM and either MRF 10,186 (59%) or ASCVD 6974 (41%) to dapa 10 mg or placebo in addition to standard of care, including 13,950 (81%) patients on ACEI/ARB. We report urinary albumin-to-creatinine ratio (UACR) change over the median follow-up of 4 years for dapa vs. placebo, according to albuminuria at baseline. Results: At baseline there were 11,644 (69%) patients w/normo-albuminuria (UACR <30 mg/g), 4,030 (24%) w/microalbuminuria (UACR ≥30 to ≤300 mg/g); and 1,169 (7%) w/macroalbuminuria (UACR >300 mg/g). Dapa blunted the increase in UACR over time by -29.0 mg/g (95% CI -44.0, -14.0; P=0.0002). This benefit was observed in patients with normo-, micro-, and macro-albuminuria: 3.2 mg/g (95% CI -6.4 to 0.03; P=0.052), -51.3 mg/g (95% CI -67.6 to -35.1; P<0.0001) and 262.3 mg/g (95% CI -480.7 to -43.9; P=0.019), respectively. Dapa also significantly increased the likelihood that patients improved from micro to normo-albuminuria (hazard ratio [HR] 1.35, 95% CI [1.24, 1.47]; p<.0001) and from macro to micro or normo-albuminuria (HR 1.55, 95% CI [1.34, 1.8]; p<.0001). Dapa decreased the likelihood that patients deteriorated from normo to micro or macroalbuminuria (HR 0.84, 95% CI [0.79, 0.89]; p<.0001). Conclusion: In a broad population of patients with T2DM, long-term treatment with dapagliflozin blunts the rise in urinary albumin excretion, in all stratum of baseline albuminuria. Disclosure: I. Raz: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Consultant; Self; AstraZeneca, BOL, Bristol-Myers Squibb Company, CameraEyes Ltd, DarioHealth, Diabot, Exscopia, GlucoMe Ltd., Insuline Medical, Medial EarlySign, Orgenesis Ltd. Speaker's Bureau; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Stock/Shareholder; Self; BOL, CameraEyes Ltd, DarioHealth, Diabot, GlucoMe Ltd., Orgenesis Ltd. S.D. Wiviott: Consultant; Self; Aegerion Pharmaceuticals, Allergan, Angel Medical Systems, Inc., Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Boston Clinical Research Institute, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Eisai Inc., Eli Lilly and Company, Icon Clinical, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Servier, St. Jude Medical, XOMA Corporation. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Amgen Inc., Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Eisai Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi-Aventis. I. Yanuv: Research Support; Self; AstraZeneca. A. Rozenberg: Research Support; Self; AstraZeneca. T.A. Zelniker: None. A. Cahn: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, GlucoMe Ltd., Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Stock/Shareholder; Self; GlucoMe Ltd. H.L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation. J.P. Dwyer: Consultant; Self; Akcea Therapeutics, AstraZeneca, Bird Rock Bio, Eisai Inc., Goldfinch Bio, Sanofi-Aventis. E. Goodrich: None. D.L. Bhatt: Research Support; Self; Abbott, Amarin Corporation, Amgen Inc., AstraZeneca, Bayer Vital GmbH, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Chiesi USA, Inc., Eisai Inc., Eli Lilly and Company, Ethicon, Inc., FlowCo, Forest Laboratories, Inc., Idorsia, Ironwood Pharmaceuticals, Inc., Ischemix, Medicines Company, Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PLx Pharma, Regeneron Pharmaceuticals, Roche Pharma, Sanofi, Synaptic, Takeda Pharmaceutical Company Limited. L.A. Leiter: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. D.K. McGuire: Consultant; Self; Eisai Co., Ltd., Eli Lilly and Company, Pfizer Inc. Research Support; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. J.P. Wilding: Consultant; Self; Astellas Pharma Europe Ltd., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, NAPP Pharmaceuticals Limited, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company, WebMD. I.A. Gause-Nilsson: Employee; Self; AstraZeneca. M. Fredriksson: Employee; Self; AstraZeneca. P.A. Johansson: None. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. M.S. Sabatine: Consultant; Self; Amgen Inc., AstraZeneca, Bristol-Myers Squibb Company, CVS/Caremark, Dyrnamix, Esperion, Intarcia Therapeutics, Inc., Janssen Research and Development, Medicines Company, MedImmune, Merck & Co., Inc., Novartis. Research Support; Self; Amgen Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eisai Co., Ltd., GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Janssen Research and Development, Medicines Company, MedImmune, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Takeda. O. Mosenzon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. Funding: AstraZeneca [ABSTRACT FROM AUTHOR]

Introduction: Frailty is a known risk factor for many diseases, including COVID-19. However, many frail patients are undiagnosed as the diagnosis can be cumbersome. Alanine transaminase (ALT) is found not only in the liver but also in the muscle tissue, and multiple studies show that frail sarcopenic patients have lower ALT. Frail patients are at increased risk for severe COVID-19. We evaluated the association between pre-infection low ALT and the risk for severe COVID-19., Methods: We collected data regarding all subjects tested for SARS-CoV-2 between 1 March 2020 and 31 December 2021 from a national state-mandatory HMO in Israel, serving more than 1.3 million patients. Clinical and laboratory data were collected, including ALT from the year prior to infection. Severe COVID-19 was defined either as death, ICU admission, or ≥10 hospitalization days. Patients with low ALT (ALT ≤ 10 IU/l) were compared with patients with normal ALT (11-40 IU/l). Patients younger than 18 years with a diagnosis of liver disease and with ALT > 40 IU/l were excluded., Results: During the study period, 58,961 patients tested positive for SARS-CoV-2. The patients in the low ALT group were younger (40.53 vs. 42.73, p < 0.001), less likely to be males (12.3 vs. 38.7%, p < 0.001), and had lower BMI (25.97 vs. 27.15, p < 0.001). The patients in the low ALT group had higher mortality (2.36 vs. 0.57%, p < 0.001), more ICU hospitalizations (0.49 vs. 0.41%, p = 0.47), and more prolonged hospitalizations [2.63% (95% CI 2-3.2%) vs. 0.98% (95% CI 0.86-1.1%) p < 0.001]. In multivariate logistic regression analyses, low ALT was associated with an increased risk of severe COVID-19, with increased mortality (OR 1.88, 95% CI 1.37-2.56) and prolonged hospitalization (OR 1.78, 95% CI 1.33-2.35)., Conclusion: Low ALT level prior to infection is a significant risk factor for morbidity and mortality from COVID-19 infection. Further studies are warranted to address treatment options for this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Genzel, Katz, Safadi, Rozenberg, Milgrom, Jacobs and Shafrir.)

Background: Chronic pain is prevalent but difficult to treat in patients undergoing hemodialysis (HD). Effective and safe analgesics are limited in this patient population. Our aim in this feasibility study was to evaluate the safety of sublingual oil based medical cannabis for pain management in patients undergoing HD., Methods: In a prospective randomized, double-blind, cross-over design, patients undergoing HD with chronic pain were assigned to one of three arms: BOL-DP-o-04-WPE whole-plant extract (WPE), BOL-DP-o-04 cannabinoid extraction (API) or placebo. WPE and API contained trans-delta-9-‏tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:6 ratio (1:6, THC:CBD). Patients were treated for 8 weeks, with subsequent 2-week wash out, followed by a cross-over to a different arm. The primary endpoint was safety., Results: Eighteen patients were recruited and 15 were randomized. Three did not complete drug titration period due to adverse events (AEs) and one patient died during titration due to sepsis (WPE). Of those who completed at least one treatment period, seven patients were in the WPE arm, five in the API and nine receiving placebo. The most common AEs were sleepiness, which improved after dose reduction or patient adaptation. Most AEs were mild to moderate and resolved spontaneously. Serious AEs considered related to study drug included one episode of accidental overdose (WPE) leading to hallucinations. Liver enzymes were stable during cannabis treatment., Conclusions: Short-term medical cannabis use in patients treated with HD was generally well tolerated. The safety data supports further studies to assess the overall risk-benefit of a treatment paradigm utilizing medical cannabis to control pain in this patient population., Competing Interests: N.A. is an employee of BOL Pharma Ltd. N.V. and B.H. are former employees of BOL Pharma Ltd. O.M. is a former employee of BOL; Advisory Board: Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Novartis, AstraZeneca, Bayer, BOL Pharma; Research grant: Novo Nordisk, AstraZeneca; Speakers Bureau: Novo Nordisk, AstraZeneca, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)