An overview of the CANVAS Program and CREDENCE trial: The primary outcomes and key clinical implications for those managing patients with type 2 diabetes.

AIMS: To provide an overview of the primary outcomes and key clinical implications of the CANVAS Program and CREDENCE trial, which were event-driven, double-blind randomized controlled trials that established the efficacy and safety of canagliflozin in those with type 2 diabetes (T2D) and high cardiovascular risk (CV) or albuminuric chronic kidney disease (CKD). METHODS AND RESULTS: The CANVAS programme (CANVAS and CANVAS-R trials) randomized 10 142 people with T2D and high CV risk to canagliflozin or placebo and followed them for a median of 126 weeks. The primary efficacy outcome was met, with canagliflozin treatment associated with a 14% reduction in major adverse CV events (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.75 to 0.97; p < 0.001) as compared to placebo. The CREDENCE trial randomized 4401 individuals with T2D and albuminuric CKD to canagliflozin or placebo and followed them for 109 weeks. The CREDENCE trial also met its primary endpoint; canagliflozin treatment was associated with a 30% reduction in the composite of kidney failure, sustained doubling of serum creatinine level, or death from kidney or CV causes (HR 0.70, 95% CI 0.59 to 0.82; p < 0.001). Substantial reductions in hospitalization for heart failure (CANVAS: HR 0.67, 95% CI 0.52 to 0.87; CREDENCE: HR 0.61, 95% CI 0.47 to 0.80) and other key CV and kidney outcomes were also identified. Relative clinical benefits were consistent across subgroups defined by baseline age, sex, kidney function and history of CV disease but absolute benefits were greatest in those at highest baseline risk. Total serious adverse events were less common with canagliflozin treatment. Concerns about amputation and fracture risk observed in the CANVAS Program were not seen in CREDENCE and appear to have been spurious chance findings. CONCLUSION: Canagliflozin reduced important CV, kidney and mortality outcomes in those with T2D and high CV risk or CKD across diverse patient groups, with a good safety profile. Taken together with the other sodium-glucose cotransporter-2 inhibitor CV and renal outcomes trials, these landmark findings have changed the treatment landscape for patients worldwide.

Cardio-metabolic pathophysiology in mild glucocorticoid excess: Potential implications for management of adrenal incidentaloma.

Adrenal adenomas are incidentally identified in up to 5% of computer tomography scans performed for unrelated indications. A proportion of these adrenal incidentalomas are found to autonomously secrete cortisol based on definitions in current guidelines. Epidemiological studies suggest that chronic exposure to mild glucocorticoid excess from adrenal incidentalomas is associated with significantly increased cardiometabolic risk. However, current management guidelines adopt a conservative approach as no large prospective randomized studies have demonstrated that these patients benefit from surgery. This narrative review examines the epidemiological and mechanistic studies related to three common clinical settings of mild glucocorticoid excess to gain further insight into the potential benefits of treating patients with adrenal incidentaloma and possible autonomous cortisol secretion.

The impact of assisted reproductive technology and ovulation induction on breech presentation: A whole of population-based cohort study.

AIMS: Multiple studies have suggested a likely association between breech presentation and assisted reproductive technology (ART) for conception. The aims were to determine whether conception via in vitro fertilisation (IVF) and ovulation induction (OI) is associated with fetal malpresentation at birth and to ascertain what mediating factors most significantly contribute to fetal malpresentation. METHODS: This whole-population-based cohort study included 355 990 singleton pregnancies born in Queensland, Australia, between July 2012 and July 2018. Multinomial logistic regression models estimated the adjusted odds of breech, transverse/shoulder and face/brow malpresentations in pregnancies conceived via spontaneous conception, OI (OI group) and IVF with or without intracytoplasmic sperm injection (ART group). RESULTS: After adjustment for potential confounding factors, breech presentation occurred approximately 20% more often in singleton pregnancies conceived via both ART (adjusted odds ratio: 1.20, 95% confidence interval: 1.10-1.30, P < 0.001) and OI (1.21, 95% confidence interval: 1.04-1.39, P < 0.05). No significant associations were observed between the three modes of conception and transverse/shoulder or face/brow presentations. Low birthweight was found to be the most significant mediating factor for breech presentation in pregnancies conceived via ART and OI. CONCLUSIONS: Similar levels of increased odds of breech presentation are present in pregnancies conceived via OI and ART, suggesting a shared underlying mechanism for the aetiology of breech presentation. For women who are considering or have conceived via these methods, counselling with respect to this increased risk is recommended.

Dietary sodium intake and cortisol measurements.

OBJECTIVES: To assess the influence of a dietary sodium intake intervention on cortisol measurements within the general population. DESIGN: Cross-over intervention. PATIENTS: Six hundred thirty adults without known Cushing syndrome, cardiovascular or renal disease completed a restricted dietary sodium diet (10 mmol/d, 230 mg/d) followed by cross-over to a liberalized dietary sodium diet (200 mmol/d, 4600 mg/d). Twenty-four-hour urine collection and biochemical investigations were performed at the end of each dietary intervention. RESULTS: Mean 24-hour urinary free cortisol increased with liberalized sodium intake when compared with restricted sodium intake (178.0 ± 89.7 vs 121.3 ± 65.6 nmol/d, P < .001). Nearly all participants (84%) had an increase in the urinary free cortisol following liberalized sodium intake. This translated to a substantial difference in the proportion of participants exceeding categorical thresholds of urinary cortisol on liberalized vs restricted sodium intake: 62% vs 27% for 138 nmol/d (50 mcg/d), 46% vs 17% for 166 nmol/d (60 mcg/d), 32% vs 10% for 193 nmol/d (70 mcg/d), 23% vs 6% for 221 nmol/d (80 mcg/d), 17% vs 4% for 248 nmol/d (90 mcg/d). In parallel, there was a small decrease in morning total serum cortisol with liberalized sodium intake (303.0 ± 117.3 vs 326.4 ± 162.5 nmol/L, P < .001). CONCLUSIONS: Increased dietary sodium intake increases urinary free cortisol excretion and may increase the risk for false-positive results. Variations in dietary sodium intake may influence the interpretations of cortisol measurements performed to evaluate for hypercortisolism.

Relationship between urinary sodium-to-potassium ratio and ambulatory blood pressure in patients with diabetes mellitus.

Previous studies investigating the relationship between sodium intake and blood pressure have mostly relied on dietary recall and clinic blood pressure measurement. In this cross-sectional study, we aimed to investigate the relationship between 24 hour urinary sodium and potassium excretion, and their ratio, with 24 hour ambulatory blood pressure parameters including nocturnal blood pressure dipping in patients with type 1 and 2 diabetes. We report that in 116 patients with diabetes, systolic blood pressure was significantly predicted by the time of day, age, the interaction between dipping status with time, and 24 hour urinary sodium-to-potassium ratio (R2  = 0.83) with a relative contribution of 53%, 21%, 20% and 6%, respectively. However, there was no interaction between urinary sodium-to-potassium ratio and dipping status.

Short-term dietary salt supplementation blunts telmisartan induced increases in plasma renin activity in hypertensive patients with type 2 diabetes mellitus.

Current guidelines recommend low dietary salt intake (LDS) in patients with diabetes to reduce blood pressure (BP). However, low salt intake has been associated with higher mortality rates in people with diabetes. Our aim is to examine the effect of angiotensin II receptor blocker (ARB), telmisartan, with and without dietary sodium chloride (NaCl) supplementation, on BP [mean arterial pressure (MAP)], plasma renin activity (PRA), serum aldosterone level and estimated glomerular filtration rate (eGFR) in hypertensive patients with type 2 diabetes. In a randomized, double-blind, placebo-controlled study (RCT), 28 patients with type 2 diabetes, treated with telmisartan (40 mg daily), received 2 weeks of placebo or NaCl capsules (100 mmol/24 h). Following a 6-week washout, the protocol was repeated in reverse. Twenty-four-hour urinary sodium excretion (24hUNa), ambulatory BP (ABP) monitoring and blood tests were performed before and after each study phase. The telmisartan-associated increase in PRA was blunted by approximately 50% during salt supplementation compared with placebo; median PRA was 2.3 µg/l/h with placebo compared with 1.7 µg/l/h with salt (P<0.001). A trend towards blunting of ARB induced increases in serum aldosterone was also demonstrated. Salt supplementation significantly reduced the MAP lowering effects of telmisartan (P<0.05). The present study demonstrates that salt supplementation blunts the telmisartan induced increase in PRA in patients with type 2 diabetes.

Cardiovascular Risk Markers in Adults With Adrenal Incidentaloma and Mild Autonomous Cortisol Secretion.

CONTEXT: Many adrenal adenomas exhibit mild autonomous cortisol secretion (MACS). Although MACS is associated with increased cardiovascular mortality, the underlying mechanisms are not fully defined. OBJECTIVE: To investigate mechanisms that may link MACS and cardiovascular mortality in adults with adrenal adenoma. DESIGN: Cross-sectional study. PATIENTS: Twenty adults with adrenal adenoma and MACS and 20 controls with nonfunctioning adrenal adenoma. METHODS: Reactive hyperemia index (RHI) was measured by peripheral artery tonometry and 24-hour ambulatory blood pressure monitoring (24h AMBP) was performed. Indices of insulin secretion and sensitivity were estimated by measuring glucose and insulin fasting and following a mixed meal. MAIN OUTCOME MEASURE: The primary outcome was the difference in RHI between participants with MACS vs nonfunctioning adrenal adenoma. RESULTS: The average cortisol after 1-mg dexamethasone and urinary free cortisol were higher in patients with MACS. There was no significant difference in fasting RHI (2.0 [interquartile range (IQR) 1.6-2.4] vs 2.0 [IQR 1.7-2.2, P = .72), but postprandial RHI was higher in patients with MACS (2.2 [1.8-2.7] vs 1.8 [1.5-2.2], P = .04). 24-hour ambulatory blood pressure monitoring and Matsuda index were not significantly different in the groups. Fasting glucose and glucose area under the curve after the mixed meal were higher and insulinogenic index was lower in participants with MACS. CONCLUSION: Adults with adrenal adenoma and MACS do not have fasting endothelial dysfunction and postprandial endothelial function may be better. These patients have fasting and postprandial hyperglycemia with lower insulin secretion, which may underlie the association between MACS and increased cardiovascular mortality.

The Performance of Freestyle Libre Pro Flash Continuous Glucose Monitoring in Hospitalized Patients Treated with an Intravenous Insulin Infusion for Acute Prednisolone-Induced Hyperglycemia.

Few studies have evaluated the performance of flash glucose monitoring in hospitalized patients requiring intravenous insulin therapy. In this prospective study, an intravenous insulin infusion was adjusted hourly using flash glucose monitoring in hospitalized adults with prednisolone-associated hyperglycemia. The difference in paired point of care (POC) and flash glucose measurements and risk of severe hyper- or hypoglycemia (assessed by Clarke error grid analysis) were assessed. Glucose concentration measured by flash glucose monitoring was lower than POC glucose (mean difference 1.5 mmol/L [27 mg/dL], p < 0.001); however, mean POC glucose was within the target range (9.1 ± 4.1 mmol/L [164 ± 72 mg/dL]) and 97.8% of glucose measurements were within Zone A and B on error grid analysis. Flash glucose monitoring could be used in combination with POC glucose monitoring to minimize the frequency of finger prick blood glucose levels in hospitalized patients prescribed an intravenous insulin infusion.

Clinical determinants of insulin requirements during treatment of prednisolone-induced hyperglycaemia.

AIMS: The optimal treatment of prednisolone-associated hyperglycaemia is unclear, but guidelines recommend using a body weight-based daily insulin dose. This study evaluated how clinical variables were associated with insulin requirements in hospitalised patients with prednisolone-associated hyperglycaemia. METHODS: In this prospective study, fifty adult inpatients who were taking prednisolone ≥20 mg/day and experienced hyperglycaemia were prescribed a 24-h intravenous insulin infusion. The daily insulin dose required to attain a mean glucose of 8 mmol/L was calculated. The associations between daily insulin dose and clinical variables were assessed. RESULTS: The participants age was 69 ± 10 years, daily prednisolone dose was 34 ± 10 mg, HbA1c was 7.7 ± 2.0 % (61 ± 10 mmol/mol), 77 % had known type 2 diabetes and 30 % were female. In univariate analysis, weight was associated with daily insulin dose (r2 = 0.11, p = 0.024). A multivariate model comprising sex, HbA1c, a prior diagnosis of diabetes, diabetes treatment and weight explained nearly-two thirds of the variability in daily insulin dose (r2 = 0.65, p < 0.001). CONCLUSIONS: In patients with prednisolone-associated hyperglycaemia, calculating insulin doses based on sex, HbA1c, diabetes status and regular diabetes treatment and weight may improve glycaemic control compared to weight-based dosing.

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.

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.