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Introduction There is controversy over whether SGLT2 inhibitors have efficacy in high-risk patients with heart failure (HF) and ejection fraction (EF) >60% with or without type 2 diabetes (T2D). The VERTIS CV trial studied a population of patients with T2D and atherosclerotic cardiovascular disease (ASCVD), 23% of whom had a history of HF. In VERTIS CV, ertugliflozin (ERTU) significantly reduced the risk of first and total hospitalisation for heart failure (HHF) vs placebo (PBO). Whether efficacy in the VERTIS CV population is consistent across the spectrum of pre-trial EF, particularly among those with EF >60%, is unknown. Purpose These post hoc analyses explored the effects of ERTU (5 mg; 15 mg) vs PBO on time to first and total HHF among patients in VERTIS CV across the spectrum of pre-trial EF. Methods As prospectively planned, the 2 ERTU dose groups were combined for all analyses vs PBO. Treatment effects of ERTU vs PBO on the risk of first and total HHF were analysed using adjusted Cox models for first and Andersen-Gill models for total (i.e., first + recurrent) events. Data on pre-trial EF were abstracted from the medical record at trial entry. Multiplicative interaction terms (EF × treatment arm) were used to determine if the efficacy of ERTU was modified by pre-trial EF. Results In VERTIS CV, 8246 patients were randomised to ERTU 5 or 15 mg or PBO (mean follow up 3.5 years). Overall, 5006 patients had pre-trial EF data available; 959 had EF ≤45%, 2860 had EF >45–60%, and 1187 had EF >60%. In the overall population, the event rate for first HHF was lower with ERTU vs PBO (hazard ratio [HR] 0.70; 95% CI 0.54–0.90). The findings were generally consistent across pre-trial EF (P-interaction = 0.26; Figure), including patients with pre-trial EF >60% (HR 0.72; 95% CI 0.34–1.55). In the overall population, event rate for total HHF was lower with ERTU vs PBO (HR 0.70; 95% CI 0.56–0.87). A significant interaction was observed between pre-trial EF and treatment arm for the risk of total HHF events (P-interaction = 0.02), with a greater magnitude of risk reduction in patients with a low pre-trial EF (≤45%; HR 0.39; 95% CI 0.26–0.57). However, the 95% CIs for the HR for total HHF for those with EF >45–60% and >60% nearly entirely or entirely contained the 95% CI of the overall population, respectively (Figure). Conclusion In the VERTIS CV trial of patients with T2D and ASCVD, the efficacy of ERTU in preventing first HHF was generally comparable across the spectrum of pre-trial EF. The trend for greater benefit at lower EF was statistically significant for total HHF events. Findings for patients with EF >45–60% and >60% appeared quantitively consistent with the overall findings for both first and total HHF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

Introduction We analysed data from the VERTIS CV trial that investigated the CV and kidney safety and efficacy of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin (ERTU) vs placebo (PBO) to assess the impact of metformin (MET) use at baseline (BL). These analyses are timely because the recent ESC guidelines recommendation to use SGLT2 inhibitor or GLP-1 RAs as initial glucose-lowering therapy in patients with type 2 diabetes (T2D) with or at high risk for atherosclerotic cardiovascular disease (ASCVD) has been questioned because outcome trials of these drug classes included a large proportion of patients with MET as background therapy, yet MET was not used at BL in approximately 25% of patients in each trial. Purpose These analyses determined cardiorenal endpoints of VERTIS CV according to use of BL MET to assess for evidence of treatment effect modification for ERTU by BL MET use, adjusting for the probability (propensity) of BL MET use. Methods VERTIS CV was an international, double-blind, PBO-controlled trial of 2 doses of ERTU (5 mg; 15 mg) vs PBO in patients with T2DM and ASCVD. As prospectively planned, the 2 ERTU dose groups were combined for all analyses vs PBO. Differences in risk of CV and kidney outcomes between ERTU and PBO across subgroups by BL MET use were conducted using Cox proportional hazards model along with propensity adjustment using inverse probability for treatment weighting to account for differences in patient mix between those with and without BL MET influenced by individual BL characteristics and risk factors. Treatment (categorical), BL MET use (categorical) and the interaction term between treatment and BL MET use subgroup (no or yes) were used in each model to assess effect modification by BL MET use. Hazard ratio and 95% CI are presented along with Pinteraction for evaluation of treatment effect modification by BL MET use. Results In VERTIS CV, 8246 patients were randomised to ERTU 5 mg, 15 mg or PBO. Of these, 6286 (76%) patients used MET (alone or with other glucose-lowering agents [GLA]) at BL. Differences in BL characteristics by BL MET use subgroup (no or yes) included a higher mean UACR (204.4 vs 129.8 mg/g), more patients with eGFR 0.05). Conclusions In VERTIS CV, there was no evidence for effect modification by BL MET use on the effects of ERTU on cardiorenal outcomes in patients with T2D and ASCVD. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

Introduction Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce risk of hospitalisation for heart failure (HHF) in outcome trials, but the biological mediators underlying the therapeutic benefit are not well established. Purpose To identify potential biological mediators through which ertugliflozin reduces risk of HHF. Methods In VERTIS CV, 8246 patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomised to ertugliflozin 5 or 15 mg (observations pooled as prospectively planned) or placebo. Cox regression models were used to evaluate the associations between changes in 26 potential mediators with outcomes. Potential mediators were selected based on proposed mechanisms and/or differential change from baseline with SGLT2 inhibitors. Mediation criteria required 1) significant (P100%. Time-dependent models were used to evaluate associations between early (change from baseline for the first post-baseline measurement) and average (weighted average of change from baseline using all post-baseline measurements) changes in covariates with clinical outcomes. Results Over a mean of 3.5 years, the incidence rate of HHF was 0.7 and 1.1 per 100 patient-years with ertugliflozin and placebo, respectively. Among 26 candidate mediators, 9 and 13 met the mediation criteria based on early and average changes, respectively. The 3 covariates with the largest mediating effects of early changes included haematocrit (40%), haemoglobin (27%) and HDL-C (23%) (Table); other significant biomarkers included urine albumin/creatinine ratio, and serum albumin, uric acid, chloride, protein and sodium. The 3 biomarkers with the largest mediating effects in average changes included haemoglobin (63%), albumin (50%) and uric acid (47%) (Table); other significant biomarkers included haematocrit, urine albumin/creatinine ratio, body weight, serum protein and chloride, systolic blood pressure, ALT, BUN, eGFR and heart rate. Conclusions In these analyses from the VERTIS CV trial, potential markers of volume status and haemoconcentration and/or haematopoiesis were the strongest mediators of the effect of ertugliflozin on reducing risk of HHF in the early and average change periods. Other potential mediators included uric acid, lipid markers and kidney parameters. These findings provide insights into potential mechanisms through which ertugliflozin, and potentially the SGLT2 inhibitor class, may prevent HHF. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

Patients with the highest albumin:creatinine ratio within the normal range are at an increased risk for developing microalbuminuria. The mechanistic basis for this is unknown, but may be related to renal inflammation. Our goal was to characterize the urinary excretion of cytokines/chemokines in normoalbuminuric adolescents with Type 1 diabetes to determine whether higher range normoalbuminuria is associated with evidence of renal inflammation.Forty-two urinary cytokines/chemokines were measured in subjects who were screened for the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Urinary cytokines/chemokines were compared across low (n = 50), middle (n = 50) or high (n = 50) albumin:creatinine ratio tertile groups.At baseline, participants in the upper tertile were younger and had shorter diabetes duration compared with the other groups. Other clinical characteristics were similar. Urinary levels of interleukin 6, interleukin 8, platelet-derived growth factor-AA and RANTES differed across albumin:creatinine ratio tertiles, with higher values in patients in the middle and high tertiles compared with the lower tertile (ANCOVA P ≤ 0.01).Within the normal albumin:creatinine ratio range, higher urinary albumin excretion is associated with elevated urinary levels of inflammatory markers. Ultimately, this may provide mechanistic insights into disease pathophysiology and stratify the risk of nephropathy in Type 1 diabetes.

Systematic study of hyperfiltration in diabetic nephropathy has been hindered by the lack of a simple glomerular filtration rate (GFR) measure that is accurate in this range of renal function. Serum cystatin C (GFR(CYSTATIN C) ) reflects long-term trends in GFR in normal or elevated ranges. To test whether it can reflect acute changes, we examined the impact of clamped hyperglycaemia on GFR(CYSTATIN C) and GFR(INULIN) in subjects with Type 1 diabetes.GFR(INULIN) and GFR(CYSTATIN C) were measured in 32 normotensive, normoalbuminuric subjects during clamped euglycaemia and hyperglycaemia. For comparison, GFR(MDRD) was estimated according to the four-variable equation.During clamped euglycaemia, agreement between GFR(CYSTATIN C) and GFR(INULIN) was excellent, with mean bias +1.9 (90% distribution -29 to +31) ml min(-1) 1.73 m(-2), while GFR(MDRD) had mean bias +11.4 (-45 to +51) ml min(-1) 1.73 m(-2). With exposure to clamped hyperglycaemia, the mean increase in GFR(CYSTATIN C) (+17.5 ± 13.5 ml min(-1) 1.73 m(-2) ) reflected that observed with GFR(INULIN) (+15.3 ± 28.1 ml min(-1) 1.73 m(-2), P = 0.74), while GFR(MDRD) demonstrated a mean decline of -4.4 ± 33.6 ml min(-1) 1.73 m(-2) (P = 0.01). In all 24 subjects in whom GFR(INULIN) increased in response to hyperglycaemia, GFR(CYSTATIN C) reflected a concordant change (sensitivity, 100%) while GFR(MDRD) increased in 10/24 (sensitivity, 42%). In the eight remaining subjects, specificity was 25 and 75% for GFR(CYSTATIN C) and GFR(MDRD), respectively.GFR(CYSTATIN C) reflects normal and elevated renal function better than GFR(MDRD) even under the acute influences of hyperglycaemia, suggesting a role for cystatin C in clinical practice and research for the study of early renal function changes in Type 1 diabetes.

A 20-year-old woman attended a 'rave party' where she took the drug 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'). She had used this drug previously without serious adverse effects. On this occasion, while both she and her friends drank a large quantity of water, only she became seriously ill. The initial manifestation was an altered sensorium; several hours later she had a grand mal seizure. In the Emergency Department, the most striking features were the severe degree of hyponatraemia (112 mmol/l) and cerebral oedema. To explain the basis for this life-threatening clinical presentation, an imaginary consultation was sought with Professor McCance. Using both a deductive and a quantitative analysis that involved several medical subspecialties, he illustrated that a simple story of water ingestion and vasopressin release was not sufficient to explain her hyponatraemia. It was only after events in her gastrointestinal tract were analysed that a plausible hypothesis could be constructed.