IDegLira for the real-world treatment of type 2 diabetes in Italy. Final results from the REX observational study.

AIM: The study was designed to generate real-world evidence on IDegLira in the Italian clinical practice in two groups of patients with type 2 diabetes (T2D), switching to IDegLira either from a basal only (basal group) or basal-bolus insulin regimen (BB group). MATERIALS AND METHODS: This was a non-interventional, multicentre, single-cohort, prospective study assessing the long-term glycaemic control in patients with T2D, who switched to IDegLira from a basal insulin ± glucose-lowering medication regimen with or without a bolus insulin component for approximately 18 months, conducted in 28 Italian diabetes centres. The primary endpoint was the change in glycated haemoglobin (HbA1c) levels from baseline to 6 months after IDegLira initiation. RESULTS: The study included 358 patients with a mean age 67.2 years and diabetes duration of 15.7 years. HbA1c significantly decreased from IDegLira start to all study time points in the overall population (basal group -1.19%; BB group -0.60% at the end of observation). Patients achieving HbA1c <7% levels increased from 12.9% (n = 43) to 40.3% (n = 110) at 18 months. Fasting blood glucose and body weight also significantly decreased in both groups, although more in the BB group. Overall, 14.3% of completed patients had an intensification of treatment (mainly in the basal group) and 48.6% had a simplification of treatment (mainly in the BB group). CONCLUSIONS: Switching to IDegLira in a real-world clinical setting is a valid therapeutic option for patients with T2D with inadequate glycaemic control on basal or BB insulin regimen and/or need to simplify their insulin therapy, with specific reasons and therapeutic goals according to different T2D management trajectories.

Vascular and metabolic effects of SGLT2i and GLP-1 in heart failure patients.

Alterations of endothelial function, inflammatory activation, and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway are involved in the pathophysiology of heart failure. Metabolic alterations have been studied in the myocardium of heart failure (HF) patients; alterations in ketone body and amino acid/protein metabolism have been described in patients affected by HF, as well as mitochondrial dysfunction and other modified metabolic signaling. However, their possible contributions toward cardiac function impairment in HF patients are not completely known. Recently, sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have emerged as a new class of drugs designed to treat patients with type 2 diabetes (T2D), but have also been shown to be protective against HF-related events and CV mortality. To date, the protective cardiovascular effects of these drugs in patients with and without T2D are not completely understood and several mechanisms have been proposed. In this review, we discuss on vascular and metabolic effects of SGLT2i and GLP-1 in HF patients.

Albuminuria improves R2CHA2DS2-VASc score in predicting mortality in high cardiovascular risk population.

BACKGROUND AND AIMS: The CHA2DS2-VASc score estimates the risk of cardioembolism in patients with atrial fibrillation (AF). It also predicts vascular events and death in different clinical settings, even in the absence of AF. The R2CHA2DS2-VASc score, obtained by adding the glomerular filtration rate to CHA2DS2-VASc, shows a higher prediction ability for new events and all-cause mortality. The present study aims to assess whether the addition of albuminuria to R2CHA2DS2-VASc score further improves its discrimination ability in predicting all-cause mortality in a sample of high cardiovascular risk population. METHODS AND RESULTS: Prospective, monocentric, observational study, evaluating a subset of 737 subjects consecutively undergoing to coronary angiography at Coronary Unit of Scientific Institute "Casa Sollievo della Sofferenza" from June 2016 to December 2018. The presence of albuminuria was significantly associated with all-cause mortality (p < 0.0001). Any one-point increase of Alb-R2CHA2DS2-VASc score increased mortality of about 1.5-fold (adjusted HR 1.49; 95%CI: 1.37-1.63; p < 0.0001). Considering tertiles of Alb-R2CHA2DS2-VASc, the third tertile showed a 9.5-fold increased risk of mortality (HR 9.52; 95% CI: 5.15-17.60, p < 0.001). Comparing the two scores, the Alb-R2CHA2DS2-VASc score (C-statistic = 0.751; 95%CI: 0.69-0.81) outperformed the R2-CHA2DS2-VASc score (C-statistic = 0.736; 95%CI: 0.68-0.961) in predicting mortality (delta C-statistic = 0.015; 95%CI: 0.001-0.029). The better prediction ability of the Alb-R2CHA2DS2-VASc score was also proven by an IDI of 0.024 (p < 0.0001) and a relative IDI of 24.11% (p < 0.0001), with an NRI = 0.608 (p < 0.00001). CONCLUSIONS: The addition of albuminuria to R2CHA2DS2-VASc significantly and independently predicts the risk of all-cause mortality in a sample of high CV risk patients. Moreover, Alb-R2CHA2DS2-VASc outperforms R2CHA2DS2-VASc.

Physicians' misperceived cardiovascular risk and therapeutic inertia as determinants of low LDL-cholesterol targets achievement in diabetes.

BACKGROUND: Greater efforts are needed to overcome the worldwide reported low achievement of LDL-c targets. This survey aimed to dissect whether and how the physician-based evaluation of patients with diabetes is associated with the achievement of LDL-c targets. METHODS: This cross-sectional self-reported survey interviewed physicians working in 67 outpatient services in Italy, collecting records on 2844 patients with diabetes. Each physician reported a median of 47 records (IQR 42-49) and, for each of them, the physician specified its perceived cardiovascular risk, LDL-c targets, and the suggested refinement in lipid-lowering-treatment (LLT). These physician-based evaluations were then compared to recommendations from EAS/EASD guidelines. RESULTS: Collected records were mostly from patients with type 2 diabetes (94%), at very-high (72%) or high-cardiovascular risk (27%). Physician-based assessments of cardiovascular risk and of LDL-c targets, as compared to guidelines recommendation, were misclassified in 34.7% of the records. The misperceived assessment was significantly higher among females and those on primary prevention and was associated with 67% lower odds of achieving guidelines-recommended LDL-c targets (OR 0.33, p < 0.0001). Peripheral artery disease, target organ damage and LLT-initiated by primary-care-physicians were all factors associated with therapeutic-inertia (i.e., lower than expected probability of receiving high-intensity LLT). Physician-suggested LLT refinement was inadequate in 24% of overall records and increased to 38% among subjects on primary prevention and with misclassified cardiovascular risk. CONCLUSIONS: This survey highlights the need to improve the physicians' misperceived cardiovascular risk and therapeutic inertia in patients with diabetes to successfully implement guidelines recommendations into everyday clinical practice.

Body mass index versus surrogate measures of central adiposity as independent predictors of mortality in type 2 diabetes.

BACKGROUND: An "obesity paradox" for mortality has been shown in chronic disorders such as diabetes, and attributed to methodological bias, including the use of body mass index (BMI) for obesity definition. This analysis investigated the independent association of BMI versus surrogate measures of central adiposity with all-cause mortality in individuals with type 2 diabetes. METHODS: The Renal Insufficiency And Cardiovascular Events Italian Multicentre Study is a prospective cohort study that enrolled 15,773 patients in 19 Italian centres in 2006-2008. Exposures were BMI and the surrogate measures of central adiposity waist circumference (WC), waist-to-height ratio (WHtR), and A Body Shape Index (ABSI). Vital status was retrieved on 31 October 2015 for 15,656 patients (99.3%), RESULTS: Age- and sex-adjusted hazard ratios and 95% confidence intervals were significantly higher in BMI-based underweight (1.729 [1.193-2.505), P = 0.004), moderately obese (1.214 [1.058-1.392), P = 0.006) and severely obese (1.703 [1.402-2.068), P < 0.0001), lower in overweight (0.842 [0.775-0.915), P < 0.0001) and similar in mildly obese (0.950 [0.864-1.045), P = 0.292), compared to normal-weight individuals. When further adjusting for smoking, physical activity (PA), and comorbidities, risk was lower also in mildly obese versus normal-weight patients. The BMI-mortality relationship did not change after sequentially excluding ever smokers, individuals with comorbidities, and those died within two years from enrollment and when analyzing separately participants below and above the median age. Conversely, a paradox relationship was observed among inactive/moderately inactive, but not moderately/highly active patients. Mortality risk adjusted for age, gender, smoking, PA and comorbidities was significantly higher in the highest tertile of WC (1.279 [1.089-1.501], P = 0.003), WHtR (1.372 [1.165-1.615], P < 0.0001), and ABSI (1.263 [1.067-1.495], P = 0.007) versus the lowest tertile. However, risk was lower in the intermediate versus lowest tertile for WC (0.823 [0.693-0.979], P = 0.028), similar for WHtR, and higher, though not significantly, for ABSI. CONCLUSIONS: An "overweight paradox" remained after controlling for age, smoking, and comorbidities, arguing against a collider bias or reverse causation. However, it could be partly explained by confounding from PA level, possibly through its impact on lean mass and cardiorespiratory fitness. No obesity paradox was observed with WHtR and especially ABSI, which predicted mortality risk associated with central adiposity better than WC. Trial registration ClinicalTrials.gov, NCT00715481, 15 July, 2008.

CHA2DS2-VASc and R2CHA2DS2-VASc scores predict mortality in high cardiovascular risk population.

BACKGROUND: The CHA2 DS2 -VASc score, widely used to estimate cardioembolic risk in patients with atrial fibrillation (AF), appears to be useful also in predicting vascular adverse events and death in different sets of patients without AF. The R2 CHA2 DS2 -VASc score, which includes renal impairment, allows a better prediction of death and thromboembolism in patients without AF. The aims of our study were to assess, in a large sample of patients at high cardiovascular (CV) risk, (i) the correlation between CHA2 DS2 -VASc and R2 CHA2 DS2 -VASc with all-cause mortality, and (ii) to compare the performances of CHA2 DS2 -VASc and R2 CHA2 DS2 -VASc in predicting all-cause mortality. METHODS: In this single-centre prospective observational study, conducted at the Research Hospital 'Casa Sollievo della Sofferenza' between June 2016 and December 2018, 1017 CV patients at high risk of undergoing coronary angiography were enrolled. RESULTS: CHA2DS2-VASc and R2 CHA2 DS2 -VASc scores significantly associated with all-cause mortality. For each one-point increase in CHA2 DS2 -VASc or R2 CHA2 DS2 -VASc scores, mortality increased by almost 1.5-fold. The R2 CHA2 DS2 -VASc score (C-statistic = 0.71; 95% CI = 0.65-76) outperformed the CHA2 DS2 -VASc score (C-statistic = 0.66; 95% CI = 0.61-0.71) in predicting 4-year mortality (delta C-statistic = 0.05; 95% CI = 0.02-0.07). The better predictive ability of the R-CHA2 DS2 -VASc score was also demonstrated by an IDI = 0.027 (95% CI = 0.021-0.034, p < .00001) and a relative IDI = 62.8% (95% CI = 47.9%-81.3%, p < .00001). The R2 CHA2 DS2 -VASc score correctly reclassified the patients with a NRI = 0.715 (95% = 0.544-0.940, p < .00001). CONCLUSIONS: The CHA2DS2-VASc and R2 CHA2 DS2 -VASc scores are useful predictors of all-cause mortality in subjects at high CV risk, with the R2 CHA2 DS2 -VASc score being the best performer.

Switch to SGLT2 Inhibitors and Improved Endothelial Function in Diabetic Patients with Chronic Heart Failure.

PURPOSE: The use of sodium-glucose-cotransporter-type-2 inhibitors (SGLT2i) was associated in previous studies with an improved vascular function in non-human experimental models. We therefore sought to evaluate possible changes in endothelial function assessed by flow-mediated dilation (FMD) in patients with chronic heart failure (CHF) and type-2 diabetes mellitus (T2DM), switching from other oral hypoglycemic agents to SGLT2i in an observational study. METHODS: Twenty-two consecutive outpatients with CHF and T2DM were enrolled after switching to SGLT2i therapy, and compared with 23 consecutive controls from the same registry comparable for principal clinical characteristics. In all patients, endothelial function was assessed by FMD at baseline and after 3 months of follow-up. RESULTS: Three months of therapy with SGLT2i were associated with a statistically significant improvement in endothelial function (19.0 ± 5.7% vs 8.5 ± 4.1%, p < 0.0001); baseline levels of FMD were comparable between groups (p n.s.). Therapy with SGLT2i was significantly associated to improved FMD levels even at multivariable stepwise regression analysis (p < 0.001). CONCLUSIONS: Switch to SGLT2i in patients with CHF and T2DM was associated in an observational non-randomized study with an improved endothelial function.

Insulin resistance, diabetic kidney disease, and all-cause mortality in individuals with type 2 diabetes: a prospective cohort study.

BACKGROUND: It is unclear whether insulin resistance (IR) contributes to excess mortality in patients with type 2 diabetes independent of diabetic kidney disease (DKD), which is strongly associated with IR and is a major risk factor for cardiovascular disease (CVD), the main cause of death in these individuals. We tested this hypothesis in patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events Italian Multicentre Study. METHODS: This observational, prospective, cohort study enrolled 15,773 patients with type 2 diabetes attending 19 Italian Diabetes Clinics in 2006-2008. Insulin sensitivity was assessed as estimated glucose disposal rate (eGDR), which was validated against the euglycaemic-hyperinsulinemic clamp technique. Vital status on October 31, 2015, was retrieved for 15,656 patients (99.3%). Participants were stratified by eGDR tertiles from T1 (≥ 5.35 mg/kg/min) to T3 (≤ 4.14 mg/kg/min, highest IR). RESULTS: CVD risk profile was worse in T2 and T3 vs T1. eGDR tertiles were independently associated with micro- and macroalbuminuria and the albuminuric DKD phenotypes (albuminuria with preserved or reduced estimated glomerular filtration rate [eGFR]) as well as with eGFR categories or the nonalbuminuric DKD phenotype. Over a 7.4-year follow-up, unadjusted death rates and mortality risks increased progressively across eGDR tertiles, but remained significantly elevated after adjustment only in T3 vs T1 (age- and gender- adjusted death rate, 22.35 vs 16.74 per 1000 person-years, p < 0.0001, and hazard ratio [HR] adjusted for multiple confounders including DKD, 1.140 [95% confidence interval [CI], 1.049-1.238], p = 0.002). However, eGDR was independently associated with mortality in participants with no DKD (adjusted HR, 1.214 [95% CI, 1.072-1.375], p = 0.002) and in those with nonalbuminuric DKD (1.276 [1.034-1.575], p = 0.023), but not in those with the albuminuric DKD phenotypes. Moreover, the association was stronger in males and in younger individuals and was observed in those without but not with prior CVD, though interaction was significant only for age. CONCLUSIONS: The proxy of insulin sensitivity eGDR predicts all-cause mortality in type 2 diabetes, independent of confounders including DKD. However, the impact of IR in individuals with albuminuric DKD may be mediated by its relationship with albuminuria. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00715481, retrospectively registered 15 July 2008.

Enrolment criteria for diabetes cardiovascular outcome trials do not inform on generalizability to clinical practice: The case of glucagon-like peptide-1 receptor agonists.

AIM: To evaluate the generalizability of cardiovascular outcome trials (CVOTs) on glucagon-like peptide-1 receptor agonists (GLP-1RAs), we assessed what proportion of real-world patients with type 2 diabetes (T2D) constitute true CVOT-like populations. MATERIALS AND METHODS: We applied inclusion/exclusion (I/E) criteria of each GLP-1RA CVOT to a cross-sectional database of 281 380 T2D patients from Italian diabetes outpatient clinics. We calculated the proportion of patients eligible for each CVOT and compared their clinical characteristics with those of trial patients. In addition, we used a Bayesian network-based method to sample the greatest subsets of real-world patients yielding true CVOT-like populations. RESULTS: Between 98 725 and 124 164 T2D patients could be evaluated for CVOT eligibility. After excluding patients who were already on GLP-1RAs and applying I/E criteria, 35.8% of patients would be eligible for REWIND, 34.1% for PIONEER-6, 13.4% for EXSCEL, 10.1% for SUSTAIN-6, 9.5% for HARMONY and 9.4% for LEADER. Overall, 45.4% of patients could be eligible for at least one of the CVOTs. These patients, however, were extremely different to trial patients in most of the clinical characteristics, including demographics, concomitant medications and complications. The greatest CVOT-like subsets of real-world patients were 0.5% for SUSTAIN-6, 1.0% for EXSCEL, 1.2% for LEADER, 1.8% for PIONEER-6 and 7.9% for REWIND. CONCLUSIONS: A very small proportion of real-world patients constitute true CVOT-like populations. These findings question whether any meaningful information can be drawn from applying trial enrolment criteria to real-world T2D patients.

Is resistant hypertension an independent predictor of all-cause mortality in individuals with type 2 diabetes? A prospective cohort study.

BACKGROUND: Resistant hypertension is independently associated with an increased risk of death in the general hypertensive population. We assessed whether resistant hypertension is an independent predictor of all-cause mortality in individuals with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study. METHODS: On 31 October 2015, vital status information was retrieved for 15,656 of the 15,773 participants enrolled in 2006-2008. Based on baseline blood pressure (BP) values and treatment, participants were categorized as normotensive, untreated hypertensive, controlled hypertensive (i.e., on-target with < 3 drugs), uncontrolled hypertensive (i.e., not on-target with 1-2 drugs), or resistant hypertensive (i.e., uncontrolled with > 3 drugs or controlled with > 4 drugs). Kaplan-Meier and Cox proportional hazards regression analyses were used to assess the association with all-cause mortality. RESULTS: Using the 130/80 mmHg targets for categorization, crude mortality rates and Kaplan-Meier estimates were highest among resistant hypertension participants, especially those with controlled resistant hypertension. As compared with resistant hypertension, risk for all-cause mortality was significantly lower for all the other groups, including individuals with controlled hypertension (hazard ratio 0.81 [95% confidence interval 0.74-0.89], P < 0.0001), but became progressively similar between resistant and controlled hypertension after adjustment for cardiovascular risk factors and complications/comorbidities. Also when compared with controlled resistant hypertension, mortality risk was significantly lower for all the other groups, including controlled hypertension, even after adjusting for cardiovascular risk factors (0.77 [0.63-0.95], P = 0.012), but not for complications/comorbidities (0.88 [0.72-1.08], P = 0.216). BP was well below target in the controlled hypertensive groups (resistant and non-resistant) and values < 120/70 mmHg were associated with an increased mortality risk. Results changed only partly when using the 140/90 mmHg targets for categorization. CONCLUSIONS: In the RIACE cohort, at variance with the general hypertensive population, resistant hypertension did not predict death beyond target organ damage. Our findings may be explained by the high mortality risk conferred by type 2 diabetes and the low BP values observed in controlled hypertensive patients, which may mask risk associated with resistant hypertension. Less stringent BP goals may be preferable in high-risk patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00715481 , retrospectively registered 15 July, 2008.

The Long-Term Impact of Renin-Angiotensin System (RAS) Inhibition on Cardiorenal Outcomes (LIRICO): A Randomized, Controlled Trial.

BACKGROUND: The comparative effectiveness of treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear. METHODS: In a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP<130/80 in patients with moderate or severe albuminuria and diabetes or other cardiovascular risk factors. End points included a primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes and a revised end point of all-cause mortality. Additional end points included ESRD, doubling of serum creatinine, albuminuria, eGFR, BP, and adverse events. RESULTS: Because of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%). CONCLUSIONS: Patients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors.

Non-albuminuric renal impairment is a strong predictor of mortality in individuals with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study.

AIMS/HYPOTHESIS: Non-albuminuric renal impairment has become the prevailing diabetic kidney disease (DKD) phenotype in individuals with type 2 diabetes and an estimated GFR (eGFR) <60 ml min-1 1.73 m-2. In the present study, we compared the rate and determinants of all-cause death in individuals with this phenotype with those in individuals with albuminuric phenotypes. METHODS: This observational prospective cohort study enrolled 15,773 individuals with type 2 diabetes in 2006-2008. Based on baseline albuminuria and eGFR, individuals were classified as having: no DKD (Alb-/eGFR-), albuminuria alone (Alb+/eGFR-), reduced eGFR alone (Alb-/eGFR+), or both albuminuria and reduced eGFR (Alb+/eGFR+). Vital status on 31 October 2015 was retrieved for 15,656 individuals (99.26%). RESULTS: Mortality risk adjusted for confounders was lowest for Alb-/eGFR- (reference category) and highest for Alb+/eGFR+ (HR 2.08 [95% CI 1.88, 2.30]), with similar values for Alb+/eGFR- (1.45 [1.33, 1.58]) and Alb-/eGFR+ (1.58 [1.43, 1.75]). Similar results were obtained when individuals were stratified by sex, age (except in the lowest age category) and prior cardiovascular disease. In normoalbuminuric individuals with eGFR <45 ml min-1 1.73 m-2, especially with low albuminuria (10-29 mg/day), risk was higher than in microalbuminuric and similar to macroalbuminuric individuals with preserved eGFR. Using recursive partitioning and amalgamation analysis, prevalent cardiovascular disease and lower HDL-cholesterol were the most relevant correlates of mortality in all phenotypes. Higher albuminuria within the normoalbuminuric range was associated with death in non-albuminuric DKD, whereas the classic 'microvascular signatures', such as glycaemic exposure and retinopathy, were correlates of mortality only in individuals with albuminuric phenotypes. CONCLUSIONS/INTERPRETATION: Non-albuminuric renal impairment is a strong predictor of mortality, thus supporting a major prognostic impact of renal dysfunction irrespective of albuminuria. Correlates of death partly differ from the albuminuric forms, indicating that non-albuminuric DKD is a distinct phenotype. TRIAL REGISTRATION: ClinicalTrials.gov NCT00715481.

HypoparaNet: A Database of Chronic Hypoparathyroidism Based on Expert Medical-Surgical Centers in Italy.

Hypoparathyroidism is a rare disease characterized by low serum calcium levels and absent or deficient parathyroid hormone level. Regarding the epidemiology of chronic hypoparathyroidism, there are limited data in Italy and worldwide. Therefore, the purpose of this study was to build a unique database of patients with chronic hypoparathyroidism, derived from the databases of 16 referral centers for endocrinological diseases, affiliated with the Italian Society of Endocrinology, and four centers for endocrine surgery with expertise in hypoparathyroidism, to conduct an epidemiological analysis of chronic hypoparathyroidism in Italy. The study was approved by the Institutional Review Board. A total of 537 patients with chronic hypoparathyroidism were identified. The leading etiology was represented by postsurgical hypoparathyroidism (67.6%), followed by idiopathic hypoparathyroidism (14.6%), syndromic forms of genetic hypoparathyroidism (11%), forms of defective PTH action (5.2%), non-syndromic forms of genetic hypoparathyroidism (0.9%), and, finally, other forms of acquired hypoparathyroidism, due to infiltrative diseases, copper or iron overload, or ionizing radiation exposure (0.7%). This study represents one of the first large-scale epidemiological assessments of chronic hypoparathyroidism based on data collected at medical and/or surgical centers with expertise in hypoparathyroidism in Italy. Although the study presents some limitations, it introduces the possibility of a large-scale national survey, with the final aim of defining not only the prevalence of chronic hypoparathyroidism in Italy, but also standards for clinical and therapeutic approaches.

The rs12917707 polymorphism at the UMOD locus and glomerular filtration rate in individuals with type 2 diabetes: evidence of heterogeneity across two different European populations.

BACKGROUND: UMOD variability has been associated at a genome-wide level of statistical significance with glomerular filtration rate (GFR) in Swedish individuals with type 2 diabetes (T2D; n = 4888). Whether this finding is extensible also to diabetic patients from other populations deserves further study. Our aim was to investigate the relationship between UMOD variability and GFR in patients with T2D from Italy. METHODS: Genotyping of the single nucleotide polymorphism (SNP) rs12917707 at the UMOD locus has been carried out in 3087 individuals from four independent Italian cohorts of patients with T2D by TaqMan allele discrimination. RESULTS: In none of the four study cohorts was rs12917707 significantly associated with GFR (P > 0.05 for all). Similar results were obtained when the four samples were pooled and analyzed together (ß = 0.83, P = 0.19). Such effect was strikingly smaller than that previously reported in Swedish patients (P for heterogeneity = 1.21 × 10-7). CONCLUSIONS: The previously reported strong association between rs12917707 and GFR in diabetic patients from Sweden is not observed in Italian diabetic patients, thus clearly pointing to a heterogeneous effect across the two different samples. This suggests that UMOD is a strong genetic determinant of kidney function in patients with T2D in some, but not all, populations.

Glucose targets for preventing diabetic kidney disease and its progression.

BACKGROUND: Diabetes is the leading cause of end-stage kidney disease (ESKD) around the world. Blood pressure lowering and glucose control are used to reduce diabetes-associated disability including kidney failure. However there is a lack of an overall evidence summary of the optimal target range for blood glucose control to prevent kidney failure. OBJECTIVES: To evaluate the benefits and harms of intensive (HbA1c < 7% or fasting glucose levels < 120 mg/dL versus standard glycaemic control (HbA1c ≥ 7% or fasting glucose levels ≥ 120 mg/dL for preventing the onset and progression of kidney disease among adults with diabetes. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 31 March 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials evaluating glucose-lowering interventions in which people (aged 14 year or older) with type 1 or 2 diabetes with and without kidney disease were randomly allocated to tight glucose control or less stringent blood glucose targets. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for eligibility and risks of bias, extracted data and checked the processes for accuracy. Outcomes were mortality, cardiovascular complications, doubling of serum creatinine (SCr), ESKD and proteinuria. Confidence in the evidence was assessing using GRADE. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS: Fourteen studies involving 29,319 people with diabetes were included and 11 studies involving 29,141 people were included in our meta-analyses. Treatment duration was 56.7 months on average (range 6 months to 10 years). Studies included people with a range of kidney function. Incomplete reporting of key methodological details resulted in uncertain risks of bias in many studies. Using GRADE assessment, we had moderate confidence in the effects of glucose lowering strategies on ESKD, all-cause mortality, myocardial infarction, and progressive protein leakage by kidney disease and low or very low confidence in effects of treatment on death related to cardiovascular complications and doubling of serum creatinine (SCr).For the primary outcomes, tight glycaemic control may make little or no difference to doubling of SCr compared with standard control (4 studies, 26,874 participants: RR 0.84, 95% CI 0.64 to 1.11; I2= 73%, low certainty evidence), development of ESKD (4 studies, 23,332 participants: RR 0.62, 95% CI 0.34 to 1.12; I2= 52%; low certainty evidence), all-cause mortality (9 studies, 29,094 participants: RR 0.99, 95% CI 0.86 to 1.13; I2= 50%; moderate certainty evidence), cardiovascular mortality (6 studies, 23,673 participants: RR 1.19, 95% CI 0.73 to 1.92; I2= 85%; low certainty evidence), or sudden death (4 studies, 5913 participants: RR 0.82, 95% CI 0.26 to 2.57; I2= 85%; very low certainty evidence). People who received treatment to achieve tighter glycaemic control probably experienced lower risks of non-fatal myocardial infarction (5 studies, 25,596 participants: RR 0.82, 95% CI 0.67 to 0.99; I2= 46%, moderate certainty evidence), onset of microalbuminuria (4 studies, 19,846 participants: RR 0.82, 95% CI 0.71 to 0.93; I2= 61%, moderate certainty evidence), and progression of microalbuminuria (5 studies, 13,266 participants: RR 0.59, 95% CI 0.38 to 0.93; I2= 75%, moderate certainty evidence). In absolute terms, tight versus standard glucose control treatment in 1,000 adults would lead to between zero and two people avoiding non-fatal myocardial infarction, while seven adults would avoid experiencing new-onset albuminuria and two would avoid worsening albuminuria. AUTHORS' CONCLUSIONS: This review suggests that people who receive intensive glycaemic control for treatment of diabetes had comparable risks of kidney failure, death and major cardiovascular events as people who received less stringent blood glucose control, while experiencing small clinical benefits on the onset and progression of microalbuminuria and myocardial infarction. The adverse effects of glycaemic management are uncertain. Based on absolute treatment effects, the clinical impact of targeting an HbA1c < 7% or blood glucose < 6.6 mmol/L is unclear and the potential harms of this treatment approach are largely unmeasured.

Distribution of cardiovascular disease and retinopathy in patients with type 2 diabetes according to different classification systems for chronic kidney disease: a cross-sectional analysis of the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study.

BACKGROUND: The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF's KDOQI) staging system for chronic kidney disease (CKD) is based primarily on estimated GFR (eGFR). This study aimed at assessing whether reclassification of subjects with type 2 diabetes using two recent classifications based on both eGFR and albuminuria, the Alberta Kidney Disease Network (AKDN) and the Kidney Disease: Improving Global Outcomes (KDIGO), provides a better definition of burden from cardiovascular disease (CVD) and diabetic retinopathy (DR) than the NKF's KDOQI classification. METHODS: This is a cross-sectional analysis of patients with type 2 diabetes (n = 15,773) from the Renal Insufficiency And Cardiovascular Events Italian Multicenter Study, consecutively visiting 19 Diabetes Clinics throughout Italy in years 2007-2008. Exclusion criteria were dialysis or renal transplantation. CKD was defined based on eGFR, as calculated from serum creatinine by the simplified Modification of Diet in Renal Disease Study equation, and albuminuria, as measured by immunonephelometry or immunoturbidimetry. DR was assessed by dilated fundoscopy. Prevalent CVD, total and by vascular bed, was assessed from medical history by recording previous documented major acute events. RESULTS: Though prevalence of complications increased with increasing CKD severity with all three classifications, it differed significantly between NKF's KDOQI stages and AKDN or KDIGO risk categories. The AKDN and KDIGO systems resulted in appropriate reclassification of uncomplicated patients in the lowest risk categories and a more graded independent association with CVD and DR than the NKF's KDOQI classification. However, CVD, but not DR prevalence was higher in the lowest risk categories of the new classifications than in the lowest stages of the NKF's KDOQI, due to the inclusion of subjects with reduced eGFR without albuminuria. CVD prevalence differed also among eGFR and albuminuria categories grouped into AKDN and KDIGO risk category 1 and moderate, respectively, and to a lesser extent into higher risk categories. CONCLUSIONS: Though the new systems perform better than the NKF's KDOQI in grading complications and identifying diabetic subjects without complications, they might underestimate CVD burden in patients assigned to lower risk categories and should be tested in large prospective studies. TRIAL REGISTRATION: ClinicalTrials.gov; NCT00715481.

A novel mutation in calcium-sensing receptor gene associated to hypercalcemia and hypercalciuria.

BACKGROUND: Familial Hyperparathyroidism (HPT) and Familial benign Hypocalciuric Hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. FHH has been demonstrated to be caused by inactivating mutations of calcium-sensing receptor (CaSR) gene, involved in PTH regulation as well as in renal calcium excretion. CASE PRESENTATION: In two individuals, father and son, we found a novel heterozygous mutation in CaSR gene. The hypercalcemia was present only in father, which, by contrast to the classic form of FHH showed hypercalciuria (from 300 to 600 mg/24 h in different evaluations) and a Calcium/Creatinine ratio of 0.031, instead of low or normal calciuria (<0.01 typical finding in FHH). His son showed the same mutation in CaSR gene, but no clinical signs or hypercalcemia although serum ionized calcium levels were close to the upper limit of normal values (1.30 mmol/L: normal range: 1.12-1.31 mmol/L). Sequence analysis revealed a point mutation at codon 972 of CaSR gene (chromosome 3q), located within cytoplasmic domain of the CaSR, that changes Threonine with Methionine. The father was treated with Cinacalcet 90 mg/day, with a decrease of total serum calcemia from an average value of 12.2 mg/dl to 10.9 mg/dl. CONCLUSION: This is a case of a novel inactivating point mutation of CaSR gene that determines an atypical clinical presentation of FHH, characterized by hypercalcemia, hypercalciuria and inadequate normal PTH levels. Functional assay demonstrated that the 972 M variant influenced the maturation of the protein, in terms of the post-translational glycosylation. The impairment of the receptor activity is in keeping with the specific localization of the 972 residue in the C-terminal tail, assigned to the intracellular signalling, that on the basis of the our findings appears to be differently modulated in parathyroid gland and in kidney.

GFR decline predicts total mortality and mediates the effect of tryptophan metabolism on death risk in type 2 diabetes.

CONTEXT: The independent role of glomerular filtration rate (GFR) decline in shaping the risk of mortality in people with type 2 diabetes has only been partially addressed. OBJECTIVE: The objective of the study was twofold: i) to investigate the association between all-cause mortality and eGFR changes over time; ii) to understand whether renal dysfunction mediates the effect of tryptophan metabolism on death risk. DESIGN: Prospective study with an average follow-up of 14.8 years. SETTING: Research Hospital. PATIENTS: The aggregate Gargano Mortality Study included 962 patients with type 2 diabetes who had at least three eGFR recordings and at least 1.5 years of follow-up. INTERVENTIONS: This was an observational study, with no intervention. MAIN OUTCOME MEASURES: Rate of all-cause mortality. RESULTS: Age and sex adjusted annual incident rate of mortality was 2.75 events per 100 person-years. The median annual rate of decline of eGFR was 1.3 ml/min per 1.73 m2 per year (range -3.7; 7.8). The decline of kidney function was strongly and independently associated with the risk of death. Serum kynurenine-to-tryptophan ratio (KTR) was associated with both eGFR decline and all-cause mortality. Causal mediation analysis showed that 24.3% of the association between KTR and mortality was mediated by eGFR decline. CONCLUSIONS: In patients with type 2 diabetes, eGFR decline is independently associated with the risk of all-cause mortality and mediates a significant proportion of the association between tryptophan metabolism and death.

Inflammation and prediction of death in type 2 diabetes. Evidence of an intertwined link with tryptophan metabolism.

OBJECTIVE: To study whether inflammation is associated with and helps predict mortality risk in patients with type 2 diabetes. To explore the intertwined link between inflammation and tryptophan metabolism on death risk. DESIGN: Two prospective cohorts: the aggregate Gargano Mortality Study (1,731 individuals; 872 all-cause deaths) as discovery sample, the Foggia Mortality Study (490 individuals; 256 deaths) as validation sample. Twenty-seven inflammatory markers were measured. Causal mediation analysis and in vitro studies were carried out to explore the link between inflammatory markers and the kynurenine-to-tryptophan ratio (KTR) in shaping mortality risk. RESULTS: Using multivariable stepwise Cox regression analysis, IL-4, IL-6, IL-8, IL-13, RANTES and IP-10, were independently associated with death. An inflammation score (I-score) comprising these six molecules is strongly associated with death in both the discovery and the validation cohorts HR (95%CI) = 2.13 (1.91-2.37) and 2.20 (1.79-2.72), respectively. The I-score improved discrimination and reclassification measures (all P<0.01) of two mortality prediction models based on clinical variables. The causal mediation analysis showed that 28% of the KTR effect on mortality was mediated by IP-10. Studies in cultured endothelial cells showed that 5-Methoxy-tryptophan, an anti-inflammatory metabolite derived from tryptophan, reduces the expression of IP-10, thus providing a functional basis for the observed causal mediation. CONCLUSIONS: Adding the I-score to clinical prediction models may help identify individuals who are at greater risk of death. Deeply addressing the intertwined relationship between low-grade inflammation and imbalanced tryptophan metabolism in shaping mortality risk may help discover new therapies targeting patients characterized by these abnormalities.