Novel Therapies for Kidney Disease in People With Diabetes.

CONTEXT: The increasing burden of diabetic kidney disease (DKD) has led to the discovery of novel therapies. OBJECTIVE: This review aims to summarize the results of recent clinical trials that test the efficacy of potential therapies for DKD. METHODS: A systematized narrative review was performed utilizing the PubMed, Embase (Ovid), CINAHL, and Cochrane databases (January 2010 to January 2021). The included trials assessed the efficacy of specific medications using renal endpoints in adult participants with type 1 or 2 diabetes. RESULTS: Fifty-three trials were identified. Large, multinational, and high-powered trials investigating sodium-glucose cotransporter 2 (SGLT2) inhibitors demonstrated improved renal outcomes, even in patients with established DKD. Trials examining incretin-related therapies also showed some improvement in renal outcomes. Additionally, mineralocorticoid receptor antagonists exhibited potential with multiple improved renal outcomes in large trials, including those involving participants with established DKD. Atrasentan, baricitinib, ASP8232, PF-04634817, CCX140-B, atorvastatin, fenofibrate, probucol, doxycycline, vitamin D, omega-3 fatty acids, silymarin, turmeric, total glucosides of paeony, and tripterygium wilfordii Hook F extract were all associated with some improved renal endpoints but need further exploration. While bardoxolone methyl was associated with a decrease in albuminuria, high rates of cardiovascular adverse effects curtailed further exploration into this agent. Selonsertib, allopurinol, praliciguat, palosuran, benfotiamine, and diacerein were not associated with improved renal outcomes. CONCLUSION: Trials have yielded promising results in the search for new therapies to manage DKD. SGLT2 inhibitors and incretin-related therapies have demonstrated benefit and were associated with improved cardiovascular outcomes. Mineralocorticoid receptor antagonists are another class of agents with increasing evidence of benefits.

Effect of Salt Supplementation on Sympathetic Activity and Endothelial Function in Salt-Sensitive Type 2 Diabetes.

CONTEXT: Lower sodium intake is paradoxically associated with higher mortality in type 2 diabetes (T2D). OBJECTIVE: To determine whether sympathetic nervous system (SNS) activation and endothelial dysfunction contribute to these observations, we examined the effect of salt supplementation on these systems in people with T2D with habitual low sodium. We hypothesized that salt supplementation would lower SNS activity and improve endothelial function compared to placebo. DESIGN: We conducted a randomized, double-blinded, placebo-controlled crossover trial. SETTING: The study took place in a tertiary referral diabetes outpatient clinic. PARTICIPANTS: Twenty-two people with T2D with habitual low sodium intake (24-hour urine sodium <150 mmol/24h) were included. INTERVENTION: Salt supplementation (100 mmol NaCl/24h) or placebo for 3 weeks was administered. MAIN OUTCOME MEASURES: The primary outcome of SNS activity and endothelial function was assessed as follows: Microneurography assessed muscle sympathetic nerve activity (MSNA), pulse amplitude tonometry assessed endothelial function via reactive hyperemic index (RHI), and arterial stiffness was assessed via augmentation index (AI). Secondary outcomes included cardiac baroreflex, serum aldosterone, ambulatory blood pressure monitoring (ABPM), heart rate variability (HRV), and salt sensitivity. RESULTS: Compared to placebo, salt supplementation increased MSNA (burst frequency P = .047, burst incidence P = .016); however, RHI (P = .24), AI (P = .201), ABPM (systolic P = .09, diastolic P = .14), and HRV were unaffected. Salt supplementation improved baroreflex (slope P = .026) and lowered aldosterone (P = .004), and in salt-resistant individuals there was a trend toward improved RHI (P = .07). CONCLUSIONS: In people with T2D and low habitual sodium intake, salt supplementation increased SNS activity without altering endothelial function or blood pressure but improved baroreflex function, a predictor of cardiac mortality. Salt-resistant individuals trended toward improved endothelial function with salt supplementation.

Effect of angiotensin II receptor blocker and salt supplementation on short-term blood pressure variability in type 2 diabetes.

High blood pressure variability (BPV) has been associated with increased cardiovascular (CV) risk. The effect of dietary salt and renin-angiotensin-aldosterone system (RAAS) activity on short-term BPV in type 2 diabetes mellitus (T2DM) is not well characterised. We aimed to determine the effect of dietary salt (sodium chloride, NaCl) supplementation on 24-h mean arterial BPV (24hBPV) during angiotensin II receptor blocker (telmisartan) use and to evaluate the effects of age, sex, plasma renin activity (PRA) and serum aldosterone on 24hBPV. In a randomised, double-blind, crossover study, patients with T2DM (n = 28), treated with telmisartan received NaCl (100 mmol/24 h) or placebo capsules during 2 weeks of telmisartan. Following a 6-week washout, the protocol was repeated in reverse. 24hBPV was evaluated as a co-efficient of variation [CV (%) = mean/standard deviation] × 100). Twenty-four hour urinary sodium excretion, ambulatory BP and biochemical tests were performed at each phase. Results were analysed using a linear mixed model to generate predicted values for 24hBPV. Predicted 24hBPV was higher with telmisartan vs baseline (p = 0.01), with a trend towards reduced 24hBPV with salt (p = 0.052). Predicted 24hBPV was lower in females (p = 0.017), increasing age (p = 0.001) and increasing PRA (p = 0.011). In patients with T2DM, predicted 24hBPV increased from baseline with telmisartan, but there was no additional increase in predicted 24hBPV with salt supplementation. This suggests that in the short-term, salt supplementation has no apparent deleterious effects on 24hBPV. Long-term studies are required to evaluate the effect of 24hBPV on CV outcomes in patients with T2DM.

Review of Evidence for Adult Diabetic Ketoacidosis Management Protocols.

BACKGROUND: Diabetic ketoacidosis (DKA) is an endocrine emergency with associated risk of morbidity and mortality. Despite this, DKA management lacks strong evidence due to the absence of large randomised controlled trials (RCTs). OBJECTIVE: To review existing studies investigating inpatient DKA management in adults, focusing on intravenous (IV) fluids; insulin administration; potassium, bicarbonate, and phosphate replacement; and DKA management protocols and impact of DKA resolution rates on outcomes. METHODS: Ovid Medline searches were conducted with limits "all adult" and published between "1973 to current" applied. National consensus statements were also reviewed. Eligibility was determined by two reviewers' assessment of title, abstract, and availability. RESULTS: A total of 85 eligible articles published between 1973 and 2016 were reviewed. The salient findings were (i) Crystalloids are favoured over colloids though evidence is lacking. The preferred crystalloid and hydration rates remain contentious. (ii) IV infusion of regular human insulin is preferred over the subcutaneous route or rapid acting insulin analogues. Administering an initial IV insulin bolus before low-dose insulin infusions obviates the need for supplemental insulin. Consensus-statements recommend fixed weight-based over "sliding scale" insulin infusions although evidence is weak. (iii) Potassium replacement is imperative although no trials compare replacement rates. (iv) Bicarbonate replacement offers no benefit in DKA with pH > 6.9. In severe metabolic acidosis with pH < 6.9, there is lack of both data and consensus regarding bicarbonate administration. (v) There is no evidence that phosphate replacement offers outcome benefits. Guidelines consider replacement appropriate in patients with cardiac dysfunction, anaemia, respiratory depression, or phosphate levels <0.32 mmol/L. (vi) Upon resolution of DKA, subcutaneous insulin is recommended with IV insulin infusions ceased with an overlap of 1-2 h. (vii) DKA resolution rates are often used as end points in studies, despite a lack of evidence that rapid resolution improves outcome. (viii) Implementation of DKA protocols lacks strong evidence for adherence but may lead to improved clinical outcomes. CONCLUSION: There are major deficiencies in evidence for optimal management of DKA. Current practice is guided by weak evidence and consensus opinion. All aspects of DKA management require RCTs to affirm or redirect management and formulate consensus evidence-based practice to improve patient outcomes.

Effects of salt supplementation on the albuminuric response to telmisartan with or without hydrochlorothiazide therapy in hypertensive patients with type 2 diabetes are modulated by habitual dietary salt intake.

OBJECTIVE This prospective randomized double-blind placebo-controlled crossover study examined the effects of sodium chloride (NaCl) supplementation on the antialbuminuric action of telmisartan with or without hydrochlorothiazide (HCT) in hypertensive patients with type 2 diabetes, increased albumin excretion rate (AER), and habitual low dietary salt intake (LDS; <100 mmol sodium/24 h on two of three consecutive occasions) or high dietary salt intake (HDS; >200 mmol sodium/24 h on two of three consecutive occasions). RESEARCH DESIGN AND METHODS Following a washout period, subjects (n = 32) received 40 mg/day telmisartan for 4 weeks followed by 40 mg telmisartan plus 12.5 mg/day HCT for 4 weeks. For the last 2 weeks of each treatment period, patients received either 100 mmol/day NaCl or placebo capsules. After a second washout, the regimen was repeated with supplements in reverse order. AER and ambulatory blood pressure were measured at weeks 0, 4, 8, 14, 18, and 22. RESULTS In LDS, NaCl supplementation reduced the anti-albuminuric effect of telmisartan with or without HCT from 42.3% (placebo) to 9.5% (P = 0.004). By contrast, in HDS, NaCl supplementation did not reduce the AER response to telmisartan with or without HCT (placebo 30.9%, NaCl 28.1%, P = 0.7). Changes in AER were independent of changes in blood pressure. CONCLUSIONS The AER response to telmisartan with or without HCT under habitual low salt intake can be blunted by NaCl supplementation. By contrast, when there is already a suppressed renin angiotensin aldosterone system under habitual high dietary salt intake, the additional NaCl does not alter the AER response.