The risk stratification of adverse neonatal outcomes in women with gestational diabetes (STRONG) study

Aims: To assess the risk of adverse neonatal outcomes in women with gestational diabetes (GDM) by identifying subgroups of women at higher risk to recognize the characteristics most associated with an excess of risk. Methods: Observational, retrospective, multicenter study involving consecutive women with GDM. To identify distinct and homogeneous subgroups of women at a higher risk, the RECursive Partitioning and AMalgamation (RECPAM) method was used. Overall, 2736 pregnancies complicated by GDM were analyzed. The main outcome measure was the occurrence of adverse neonatal outcomes in pregnancies complicated by GDM. Results: Among study participants (median age 36.8 years, pre-gestational BMI 24.8 kg/m2), six miscarriages, one neonatal death, but no maternal death was recorded. The occurrence of the cumulative adverse outcome (OR 2.48, 95% CI 1.59–3.87), large for gestational age (OR 3.99, 95% CI 2.40–6.63), fetal malformation (OR 2.66, 95% CI 1.00–7.18), and respiratory distress (OR 4.33, 95% CI 1.33–14.12) was associated with previous macrosomia. Large for gestational age was also associated with obesity (OR 1.46, 95% CI 1.00–2.15). Small for gestational age was associated with first trimester glucose levels (OR 1.96, 95% CI 1.04–3.69). Neonatal hypoglycemia was associated with overweight (OR 1.52, 95% CI 1.02–2.27) and obesity (OR 1.62, 95% CI 1.04–2.51). The RECPAM analysis identified high-risk subgroups mainly characterized by high pre-pregnancy BMI (OR 1.68, 95% CI 1.21–2.33 for obese; OR 1.38 95% CI 1.03–1.87 for overweight). Conclusions: A deep investigation on the factors associated with adverse neonatal outcomes requires a risk stratification. In particular, great attention must be paid to the prevention and treatment of obesity

Effect of sodium intake on blood pressure and albuminuria in Type 2 diabetic patients: the role of insulin resistance

AIMS/HYPOTHESIS: This study was done to measure the effect of Na+ intake on blood pressure and albuminuria, in relation with insulin sensitivity and kidney haemodynamics, in Type 2 diabetic patients with and without microalbuminuria. METHODS: Type 2 diabetic patients, 20 with microalbuminuria, 21 without, spent two consecutive 7-day periods, one on a high (250 mmol), the other on a low-Na+ (20 mmol) diet. Body weight, 24-h blood pressure and albuminuria were measured at the end of each period. At the end of high-Na+ diet insulin sensitivity (euglycaemic insulin clamp; 2 mU.kg(-1).min(-1)) and kidney haemodynamics were measured in nine patients from each group. RESULTS: Switching from low to high-Na+ diet resulted in an increase in blood pressure (7.4+/-4.7 mmHg; p<0.001), body weight (1.9+/-0.4 kg; p<0.05) and albuminuria [from 80 (31-183) microg/min to 101 (27-965) microg/min; p<0.01) in patients with microalbuminuria. No changes occurred in patients without microalbuminuria. Patients with microalbuminuria also had greater intraglomerular pressure (44+/-1 mmHg vs 36+/-1; p<0.001), calculated from glomerular filtration rate, renal plasma flow, plasma protein concentration and the relationship between pressure and natriuresis. In these patients insulin sensitivity was lower (5.16+/-49 vs 7.36+/-0.63 mg.kg(-1).min(-1); p=0.007). Urinary albumin excretion (r=0.40; p=0.009) and insulin sensitivity (r=-0.59; p=0.01) were correlated with intraglomerular pressure. CONCLUSION/INTERPRETATION: High salt intake increases blood pressure and albuminuria in Type 2 diabetic patients with microalbuminuria. These responses are associated with insulin resistance and increased glomerular pressure. Insulin resistance could contribute to greater salt sensitivity, increased glomerular pressure and albuminuria

The remission clinic approach to halt the progression of kidney disease

Randomized multicenter studies in diabetic and nondiabetic patients with chronic proteinuric nephropathies have clearly demonstrated that renin-angiotensin system (RAS) inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) used alone or in combination, effectively retard renal disease progression. Proteinuria reduction, in addition to arterial blood pressure control, largely mediates the nephroprotective effect of RAS inhibitor therapy. Despite RAS inhibition, however, most patients with chronic kidney disease (CKD) progress to end-stage renal disease (ESRD). This highlights the importance of innovative therapies to halt or revert CKD progression in those at risk. Along this line, a multimodal strategy (Remission Clinic) targeting urinary proteins by dual RAS inhibition with ACE inhibitors and ARBs up-titrated to maximum tolerated doses, by intensified blood pressure control, amelioration of dyslipidemia by statins, smoking cessation and healthy lifestyle implementation was safely and effectively applied at our outpatient clinic to normalize urinary proteins and prevent renal function loss in patients otherwise predicted to rapidly progress to ESRD because of nephrotic-range proteinuria refractory to standard antihypertensive dosages of an ACE inhibitor. This approach achieved remission or regression of proteinuria and stabilized kidney function in most cases, and almost fully prevented progression to ESRD. Provided patients are closely monitored and treatment is cautiously up-titrated according to tolerability, this approach might be safely applied in day-by-day hospital practice. Effective prevention of ESRD would reduce costs of renal replacement therapy by dialysis or transplantation and would be life-saving where these are not available for all patients in need

Glomerular hyperfiltration and renal disease progression in type 2 diabetes

OBJECTIVE - To describe the prevalence and determinants of hyperfiltration (glomerular filtration rate [GFR] 65120 mL/min/1.73 m2), GFR decline, and nephropathy onset or progression in type 2 diabetic patients with normo- or microalbuminuria. RESEARCH DESIGN AND METHODS - We longitudinally studied 600 hypertensive type 2 diabetic patients with albuminuria <200 \u3bcg/min and who were retrieved from two randomized trials testing the renal effect of trandolapril and delapril. Target blood pressure (BP) was <120/80 mmHg, and HbA1c was <7%. GFR, albuminuria, and glucose disposal rate (GDR) were centrally measured by iohexol plasma clearance, nephelometry in three consecutive overnight urine collections, and hyperinsulinemic euglycemic clamp, respectively. RESULTS - Over a median (range) follow-up of 4.0 (1.7-8.1) years, GFR declined by 3.37 (5.71-1.31) mL/min/1.73 m2 per year. GFR change was bimodal over time: a larger reduction at 6 months significantly predicted slower subsequent decline (coefficient: -0.0054; SE: 0.0009), particularly among hyperfiltering patients. A total of 90 subjects (15%) were hyperfiltering at inclusion, and 11 of 47 (23.4%) patients with persistent hyperfiltration progressed to micro- or macroalbuminuria versus 53 (10.6%) of the 502 who had their hyperfiltration ameliorated at 6 months or were nonhyperfiltering since inclusion (hazard ratio 2.16 [95% CI 1.13-4.14]). Amelioration of hyperfiltration was independent of baseline characteristics or ACE inhibition. It was significantly associated with improved BP and metabolic control, amelioration of GDR, and slower long-term GFR decline on follow-up. CONCLUSIONS - Despite intensified treatment, patients with type 2 diabetes have a fast GFR decline. Hyperfiltration affects a subgroup of patients and may contribute to renal function loss and nephropathy onset or progression. Whether amelioration of hyperfiltration is renoprotective is worth investigating

Measurable urinary albumin predicts cardiovascular risk among normoalbuminuric patients with type 2 diabetes

Micro- or macroalbuminuria is associated with increased cardiovascular risk factors among patients with type 2 diabetes, but whether albuminuria within the normal range predicts long-term cardiovascular risk is unknown. We evaluated the relationships between albuminuria and cardiovascular events in 1208 hypertensive, normoalbuminuric patients with type 2 diabetes from the BErgamo NEphrologic Diabetes Complication Trial (BENEDICT), all of whom received angiotensin-converting enzyme inhibitor (ACEI) therapy at the end of the trial and were followed for a median of 9.2 years. The main outcome was time to the first of fatal or nonfatal myocardial infarction; stroke; coronary, carotid, or peripheral artery revascularization; or hospitalization for heart failure. Overall, 189 (15.6%) of the patients experienced a main outcome event (2.14 events/100 patient-years); 24 events were fatal. Albuminuria independently predicted events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02-1.08). Second-degree polynomial multivariable analysis showed a continuous nonlinear relationship between albuminuria and events without thresholds. Considering the entire study population, even albuminuria at 1-2 \u3bcg/min was significantly associated with increased risk compared with albuminuria <1 \u3bcg/min (HR, 1.04; 95%CI, 1.02-1.07). This relationship was similar in the subgroup originally randomly assigned to non-ACEI therapy. Among those originally receiving ACEI therapy, however, the event rate was uniformly low and was not significantly associated with albuminuria. Taken together, among normoalbuminuric patients with type 2 diabetes, any degree of measurable albuminuria bears significant cardiovascular risk. The association with risk is continuous but is lost with early ACEI therapy

Sitagliptin treatment at the time of hospitalization was associated with reduced mortality in patients with type 2 diabetes and covid-19: A multicenter case-control retrospective observational study

OBJECTIVE Poor outcomes have been reported in patients with type 2 diabetes and coronavirus disease 2019 (COVID-19); thus, it is mandatory to explore novel therapeutic approaches for this population. RESEARCH DESIGN AND METHODS In a multicenter, case-control, retrospective, observational study, sitagliptin, an oral and highly selective dipeptidyl peptidase 4 inhibitor, was added to standard of care (e.g., insulin administration) at the time of hospitalization in patients with type 2 diabetes who were hospitalized with COVID-19. Every center also recruited at a 1:1 ratio untreated control subjects matched for age and sex. All patients had pneumonia and exhibited oxygen saturation <95% when breathing ambient air or when receiving oxygen support. The primary end points were discharge from the hospital/death and improvement of clinical outcomes, defined as an increase in at least two points on a seven-category modified ordinal scale. Data were collected retrospectively from patients receiving sitagliptin from 1 March through 30 April 2020. RESULTS Of the 338 consecutive patients with type 2 diabetes and COVID-19 admitted in Northern Italy hospitals included in this study, 169 were on sitagliptin, while 169 were on standard of care. Treatment with sitagliptin at the time of hospitalization was associated with reduced mortality (18% vs. 37% of deceased patients; hazard ratio 0.44 [95% CI 0.29–0.66]; P = 0.0001), with an improvement in clinical outcomes (60% vs. 38% of improved patients; P = 0.0001) and with a greater number of hospital discharges (120 vs. 89 of discharged patients; P = 0.0008) compared with patients receiving standard of care, respectively. CONCLUSIONS In this multicenter, case-control, retrospective, observational study of patients with type 2 diabetes admitted to the hospital for COVID-19, sitagliptin treatment at the time of hospitalization was associated with reduced mortality and improved clinical outcomes as compared with standard-of-care treatment. The effects of sitagliptin in patients with type 2 diabetes and COVID-19 should be confirmed in an ongoing randomized, placebo-controlled trial

Effects of manidipine and delapril in hypertensive patients with type 2 diabetes mellitus: The delapril and manidipine for nephroprotection in diabetes (DEMAND) randomized clinical trial

To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria >200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m 2 (IQR: 0.16-0.50 mL/min per 1.73 m 2) on combined therapy, 0.36 mL/min per 1.73 m 2 (IQR: 0.18-0.53 mL/min per 1.73 m 2) on delapril, and 0.30 mL/min per 1.73 m 2 (IQR: 0.12- 0.50 mL/min per 1.73 m 2) on placebo (P=0.87 and P=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04-0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07-0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24-0.87; P=0.017) and 0.52 (0.27-0.99; P=0.048), respectively. Glucose disposal rate decreased from 5.8\ub12.4 to 5.3\ub11.9 mg/kg per min on placebo (P=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity