Increased serum potassium affects renal outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial

To assess the effect of an angiotensin receptor blocker (ARB) on serum potassium and the effect of a serum potassium change on renal outcomes in patients with type 2 diabetes and nephropathy. We performed a post hoc analysis in patients with type 2 diabetes participating in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Renal outcomes were defined as a composite of doubling of serum creatinine or end-stage renal disease. At month 6, 259 (38.4%) and 73 (10.8%) patients in the losartan group and 151 (22.8%) and 34 (5.1%) patients in the placebo group had serum potassium a parts per thousand yen5.0 mmol/l and a parts per thousand yen5.5 mmol/l, (p <0.001), respectively. Losartan was an independent predictor for serum potassium a parts per thousand yen5.0 mmol/l at month 6 (OR 2.8; 95% CI 2.0-3.9). Serum potassium at month 6 a parts per thousand yen 5.0 mmol/l was in turn associated with increased risk for renal events (HR 1.22; 95% CI 1.00-1.50), independent of other risk factors. Adjustment of the overall treatment effects for serum potassium augmented losartan's renoprotective effect from 21% (6-34%) to 35% (20-48%), suggesting that the renoprotective effects of losartan are offset by its effect on serum potassium. In this study, we found that treatment with the ARB losartan is associated with a high risk of increased serum potassium levels, which is in turn associated with an increased risk of renal outcomes in patients with diabetes and nephropathy. Whether additional management of high serum potassium would further increase the renal protective properties of losartan is an important clinical question

Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomised controlled trial

Objective To compare the effects on proteinuria and blood pressure of addition of dietary sodium restriction or angiotensin receptor blockade at maximum dose, or their combination, in patients with non-diabetic nephropathy receiving background treatment with angiotensin converting enzyme (ACE) inhibition at maximum dose

Improving clinical trial efficiency by biomarker-guided patient selection

Background: In many therapeutic areas, individual patient markers have been identified that are associated with differential treatment response. These markers include both baseline characteristics, as well as short-term changes following treatment. Using such predictive markers to select subjects for inclusion in randomized clinical trials could potentially result in more targeted studies and reduce the number of subjects to recruit. Methods: This study compared three trial designs on the sample size needed to establish treatment efficacy across a range of realistic scenarios. A conventional parallel group design served as the point of reference, while the alternative designs selected subjects on either a baseline characteristic or an early improvement after a short active run-in phase. Data were generated using a model that characterized the effect of treatment on survival as a combination of a primary effect, an interaction with a baseline marker and/or an early marker improvement. A representative scenario derived from empirical data was also evaluated. Results: Simulations showed that an active run-in design could substantially reduce the number of subjects to recruit when improvement during active run-in was a reliable predictor of differential treatment response. In this case, the baseline selection design was also more efficient than the parallel group design, but less efficient than the active run-in design with an equally restricted population. For most scenarios, however, the advantage of the baseline selection design was limited. Conclusions: An active run-in design could substantially reduce the number of subjects to recruit in a randomized clinical trial. However, just as with the baseline selection design, generalizability of results may be limited and implementation could be difficult

Plasma C-Peptide and Risk of Developing Type 2 Diabetes in the General Population

C-peptide measurement may represent a better index of pancreatic β-cell function compared to insulin. While insulin is mainly cleared by liver, C-peptide is mainly metabolized by kidneys. The aim of our study was to evaluate the association between baseline plasma C-peptide level and the development of type 2 diabetes independent of glucose and insulin levels and to examine potential effect-modification by variables related to kidney function. We included 5176 subjects of the Prevention of Renal and Vascular End-Stage Disease study without type 2 diabetes at baseline. C-peptide was measured in plasma with an electrochemiluminescent immunoassay. Cox proportional hazards regression was used to evaluate the association between C-peptide level and type 2 diabetes development. Median C-peptide was 722 (566-935) pmol/L. During a median follow-up of 7.2 (6.0-7.7) years, 289 individuals developed type 2 diabetes. In multivariable-adjusted Cox regression models, we observed a significant positive association of C-peptide with the risk of type 2 diabetes independent of glucose and insulin levels (hazard ratio (HR): 2.35; 95% confidence interval (CI): 1.49-3.70). Moreover, we found significant effect modification by hypertension and albuminuria (p < 0.001 and p = 0.001 for interaction, respectively), with a stronger association in normotensive and normo-albuminuric subjects and absence of an association in subjects with hypertension or albuminuria. In this population-based cohort, elevated C-peptide levels are associated with an increased risk of type 2 diabetes independent of glucose, insulin levels, and clinical risk factors. Elevated C-peptide level was not independently associated with an increased risk of type 2 diabetes in individuals with hypertension or albuminuria

POS-255 EFFECT OF DAPAGLIFLOZIN ON BLOOD PRESSURE IN PATIENTS WITH CKD: A PRE-SPECIFIED ANALYSIS FROM DAPA-CKD

Introduction: Hypertension is common in patients with chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibitors decrease blood pressure in patients with type 2 diabetes, but the consistency and magnitude of blood pressure lowering with dapagliflozin in patients with CKD is unknown. We performed a pre-specified analysis of the DAPA-CKD trial to investigate the effect of dapagliflozin on systolic blood pressure in patients with CKD, with and without type 2 diabetes. Methods: We randomized 4,304 adults with baseline eGFR 25–75 mL/min/1.73m2and urinary albumin-to-creatinine ratio (UACR) 200–5,000 mg/g to either dapagliflozin 10 mg or placebo once daily; median follow-up was 2.4 years. The primary outcome was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or death from a kidney or cardiovascular cause. Change in systolic blood pressure was a pre-specified endpoint. Subgroup analyses were performed according to baseline type 2 diabetes status. Results: Baseline mean (SD) systolic blood pressure was 137.1 mmHg (17.4); in participants with and without type 2 diabetes 139.2 mmHg (17.3) and 132.6 mmHg (16.7), respectively. By week 2, dapagliflozin compared to placebo reduced systolic blood pressure by 3.6 mmHg (95%CI 2.8, 4.4; p\u3c0.001), an effect maintained over the duration of the trial, with similar reductions in patients with and without type 2 diabetes (Table). The reduction in systolic blood pressure with dapagliflozin explained 7.6% (95%CI 1.8, 20.9) of the effect on the primary composite outcome, with similar proportions explained in patients with and without type 2 diabetes. Conclusions: In participants with CKD, dapagliflozin lowered systolic blood pressure with a consistent effect in participants with and without type 2 diabetes. The modest reduction in blood pressure explained a small proportion of the benefit of dapagliflozin on the primary outcome. Conflict of interest Potential conflict of interest: HLH received grant funding and honoraria for consultancy as a member of the steering committee of the DAPA-CKD trial from AstraZeneca. Honoraria for steering committee membership paid to his institution from Janssen, Gilead, Bayer, Chinook, CSL Pharma honoraria for consultancy paid to his institution from Abbvie, Boehringer Ingleheim, Retrophin, Novo Nordisk honoraria for advisory board participation paid to his institution from Janssen, Merck, Mitsubishi Tanabe and Munipharma lecture fees received from AstraZeneca and Mitsubishi Tanabe and grant support received from Boehringer Ingelheim

Cardiorenal protective effects of canagliflozin in CREDENCE according to glucose lowering

Introduction Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain. Research design and methods We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components. Results HbA1c lowering was modified by baseline estimated glomerular filtration rate (eGFR). For baseline eGFR 60-90, 45-59, and 30-44 mL/min/1.73 m 2, overall HbA1c (canagliflozin vs placebo) decreased by -0.24%, -0.14%, and -0.08% respectively and likelihood of >0.5% decrease in HbA1c decreased with ORs of 1.47 (95% CI 1.27 to 1.67), 1.12 (0.94 to 1.33) and 0.99 (0.83 to 1.18), respectively. Adjustment for postbaseline HbA1c marginally attenuated canagliflozin effects on primary and kidney composite outcomes: unadjusted HR 0.67 (95% CI 0.57 to 0.80) and 0.66 (95% CI 0.53 to 0.81); adjusted for week 13 HbA1c, HR 0.71 (95% CI 0.060 to 0.84) and 0.68 (95% CI 0.55 to 0.83). Results adjusted for time-varying HbA1c or HbA1c as a cubic spline were similar and consistent with preserved clinical benefits across a range of excellent and poor glycemic control. Conclusions The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.2

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C-reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women