Prevalence and risk factors of glomerular hyperfiltration in adults with type 2 diabetes: A population-based study.

AIMS: Glomerular hyperfiltration characterises the earliest stage of diabetic nephropathy and predicts adverse kidney and cardiovascular outcomes. We aimed to assess the prevalence and risk factors of glomerular hyperfiltration in a population-based contemporary cohort of individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: The prevalence of unequivocal glomerular hyperfiltration (defined by an estimated glomerular filtration rate >120 mL/min/1.73 m2 ) and its associated risk factors were identified in a cohort of 202,068 adult patients with T2D receiving specialist care in 2021-2022, whose center-aggregated data were automatically extracted from electronic medical records of 75 diabetes clinics in Italy. RESULTS: Glomerular hyperfiltration was identified in 1262 (0.6%) participants. The prevalence of glomerular hyperfiltration varied widely across centers (0%-3.4%) and correlated with mean center age, HbA1c , body mass index (BMI), and low-density lipoprotein cholesterol. Patients in centers with high glomerular hyperfiltration prevalence (>0.8%) were more often men and had lower age and BMI, but more frequent albuminuria and worse glucose, lipid, and blood pressure control, compared with low-normal prevalence centers. CONCLUSIONS: Unequivocal glomerular hyperfiltration can be identified in up to 3.4% of patients receiving up-to-date specialist diabetes care. Glomerular hyperfiltration prevalence varies across centers and substantially increases with suboptimal control of metabolic risk factors, which would require improved management to mitigate the negative health consequences of this pathological condition.

A review of the latest real-world evidence studies in diabetic kidney disease: What have we learned about clinical practice and the clinical effectiveness of interventions?

Diabetic nephropathy, also known as diabetic kidney disease (DKD), remains a challenge in clinical practice as this is the major cause of kidney failure worldwide. Clinical trials do not answer all the questions raised in clinical practice and real-world evidence provides complementary insights from randomized controlled trials. Real-life longitudinal data highlight the need for improved screening and management of diabetic nephropathy in primary care. Adherence to the recommended guidelines for comprehensive care appears to be suboptimal in clinical practice in patients with DKD. Barriers to the initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors for patients with DKD persist in clinical practice, in particular for the elderly. Attainment of blood pressure targets often remains an issue. Initiation of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in routine clinical practice is associated with a reduced risk of albuminuria progression and a possible beneficial effect on kidney function. Real-world evidence confirms a beneficial effect of SGLT2 inhibitors on the decline of glomerular filtration, even in the absence of albuminuria, with a lower risk of acute kidney injury events compared to GLP-1RA use. In addition, SGLT2 inhibitors confer a lower risk of hyperkalaemia after initiation compared with dipeptidyl peptidase-4 inhibitors in patients with DKD. Data from a large population indicate that diuretic treatment increases the risk of a significant decline in glomerular filtration rate in the first few weeks of treatment after SGLT2 inhibitor initiation. The perspective for a global approach targeting multifaceted criteria for diabetic individuals with DKD is emerging based on real-world evidence but there is still a long way to go to achieve this goal.

Treatment intensification following glucagon-like peptide-1 receptor agonists in type 2 diabetes: Comparative effectiveness analyses between different basal insulins. RESTORE-G real-world study.

AIM: To compare the effectiveness of different basal insulins (BI) prescribed as an add-on to or switch from glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy. MATERIALS AND METHODS: Retrospective, real-world data from electronic medical records of 32 Italian diabetes clinics were used, after propensity score adjustment, to compare effectiveness after 6 months of treatment with second- versus first-generation BI (2BI vs. 1BI) or glargine 300 U/ml versus degludec 100 U/ml (Gla-300 vs. Deg-100), when added to (ADD-ON) or in substitution of (SWITCH) GLP-1 RA. Only comparisons, including a minimum of 100 patients per group, were performed to ensure adequate robustness of the analyses. RESULTS: In the ADD-ON cohort (N = 700), greater benefits of 2BI versus 1BI were found in glycated haemoglobin {HbA1c; estimated mean difference: -0.32% [95% confidence interval (CI) -0.62; -0.02]; p = .04} and fasting blood glucose [FBG; -20.73 mg/dl (95% CI -35.62; -5.84); p = .007]. In the SWITCH cohort (N = 2097), greater benefits of 2BI versus 1BI were found in HbA1c [-0.22% (95% CI -0.42; -0.02); p = .03], FBG [-10.15 mg/dl (95% CI -19.04; -1.26); p = .03], and body weight [-0.67 kg (95% CI -1.30; -0.04); p = .04]. In the SWITCH cohort starting 2BI (N = 688), marked differences in favour of Gla-300 versus Deg-100 were documented in HbA1c [-0.89% (95% CI -1.26; -0.52); p < .001] and FBG [-17.89 mg/dl (95% CI -32.45; -3.33); p = .02]. Using propensity score matching as a sensitivity analysis, the benefit on HbA1c was confirmed [-0.55% (95% CI -1.02; -0.08); p = .02]. BI titration was suboptimal in all examined cohorts. CONCLUSIONS: 2BI are a valuable option to intensify GLP-1 RA therapy. Switching to Gla-300 versus Deg-100 was associated with greater HbA1c improvement.

Treatment intensification following glucagon-like peptide-1 receptor agonist in type 2 diabetes: Comparative effectiveness analyses between free vs. fixed combination of GLP-1 RA and basal insulin. RESTORE-G real-world study.

BACKGROUND AND AIMS: Add-on of basal insulin (BI) to intensify the ongoing therapy with glucagon-like peptide 1 receptor agonist (GLP-1 RA) is recommended, but it is unclear if free or fixed combination of BI and GLP-1 RA produce similar outcomes. A retrospective comparative effectiveness analysis of the add-on of glargine 300 U/mL (Gla-300) to ongoing GLP-1 RA vs. switch to fixed ratio combination of degludec and liraglutide (iDegLira) was performed. METHODS AND RESULTS: Real-world data collected in electronic medical records by 32 Italian diabetes clinics. Propensity score (PS) adjustment was applied to assess changes in glycated hemoglobin (HbA1c), fasting blood glucose (FBG), body weight, and BI dose after 6 months from Gla-300 or iDegLira initiation. Compared to iDegLira group (N = 260), Gla-300+GLP-1 RA group (N = 255) had older age and higher levels of HbA1c (9.1 vs. 8.9%). After 6 months, statistically significant greater FBG improvement [estimated mean difference and 95% confidence intervals: -24.05 mg/dl (-37.04; -11.06; p = 0.0003) and BI dose increase [+0.03 U/kg (95%CI 0.00; 0.06); p = 0.009] were found in the free vs. fixed combination group, although low doses of BI (0.2 U/kg) were reached in both groups. Trends of larger HbA1c and body weight reductions with the free combination were also found, without reaching the statistical significance. CONCLUSION: Although inertia in insulin initiation and titration was documented in both groups, higher benefit on FBG control was obtained with free vs. fixed combination, likely due to a better titration of BI and GLP-1 RA.

Effects of glucose-lowering agents on cardiovascular and renal outcomes in subjects with type 2 diabetes: An updated meta-analysis of randomized controlled trials with external adjudication of events.

AIMS: To investigate the effects of glucose-lowering agents on all-cause mortality, and cardiovascular and renal outcomes in adults with type 2 diabetes. METHODS: A MEDLINE and EMBASE search was performed to identify randomized controlled trials, published up to 28 February 2022, with a follow-up ≥52 weeks, in which glucose-lowering drugs were compared with either placebo or active comparators. We included only trials reporting formal external adjudication of events. All-cause mortality, 3-point MACE (major cardiovascular events), and hospitalization for heart failure (HHF) were considered as principal outcomes. Doubling of serum creatinine, worsening albuminuria, and renal death were considered as secondary endpoints. RESULTS: We included randomized controlled trials performed on metformin (n = 17), pioglitazone (n = 20), alpha-glucosidase inhibitors (n = 9), insulin secretagogues (n = 42), dipeptidyl-peptidase-4 inhibitors (n = 67), glucagon-like peptide-1 receptor agonists (n = 45) or sodium-glucose co-transporter-2 inhibitors (SGLT-2i; n = 42) and insulin (n = 18). Glucagon-like peptide-1 receptor agonist and SGLT-2i were associated with a significant reduction in all-cause mortality [Mantel-Haenszel odds ratio (MH-OR), 95% confidence interval: 0.88 (0.83; 0.95) and 0.85 (0.79; 0.91), respectively] and MACE [MH-OR, 95% confidence interval: 0.89 (0.84; 0.94) and 0.90 (0.84; 0.96), respectively]. SGLT-2i was associated with a reduced risk of HHF [MH-OR 0.68 (0.62; 0.75)], worsening albuminuria [MH-OR 0.67 (0.55; 0.80)] and doubling of serum creatinine [MH-OR 0.58 (0.44; 0.79)]. Metformin and pioglitazone were associated with a significantly lower risk of MACE [MH-OR 0.60 (0.47; 0.80) and 0.85 (0.74; 0.97), respectively] and pioglitazone with a higher risk of HHF [MH-OR 1.30 (1.04; 1.62)]. Insulin secretagogues were associated with increased risk of all-cause mortality [MH-OR 1.12 (1.01; 1.24)] and MACE [MH-OR 1.19 (1.02; 1.39)]. CONCLUSIONS: The results of this updated meta-analysis need to be considered in the choice of drug treatment for type 2 diabetes mellitus, which cannot be merely based on the effect of glucose-lowering drugs on long-term glycaemic control.

Treatment intensification following glucagon-like peptide-1 receptor agonist treatment in type 2 diabetes: The RESTORE-G real-world study.

BACKGROUND AND AIMS: To assess intensification approaches with basal insulin (BI) following glucagon-like peptide-1 receptor agonist (GLP-1 RA) treatment in type 2 diabetes (T2D). METHODS AND RESULTS: Real-world data were collected in electronic medical records by 32 Italian diabetes clinics between 2011 and 2021. Primary endpoint was the proportion of insulin-naïve T2D patients treated with GLP-1 RA who initiated (add-on or switch) BI. Secondary endpoints were: treatment approaches, mean time to BI start, effectiveness and safety. Among 7,962 eligible patients, BI was prescribed to 3,164 (39.7%; 95%CI 38.7; 40.8): 67.6% switched to BI (22.1% also starting 1-3 injections of short-acting insulin), 22.7% added BI while maintaining GLP-1 RA, and 9.7% switched to a fixed-ratio combination of GLP-1 RA and BI (FRC). Median time since the first GLP-1 RA to BI/FRC prescription was 27.4 (IQ range 11.8-53.5) months. In this study 60.3% of patients did not start BI/FRC, among whom 15.2% intensified GLP-1 RA therapy with other oral agents. Effectiveness and safety were documented in all intensification approaches with BI/FRC, but HbA1c level at intensification time of ≥9.0% and suboptimal BI titration suggested clinical inertia. Use of second generation BI and add-on to GLP-1 RA schemes increased over time and effectiveness improved. CONCLUSION: Clinical inertia should be overcome using innovative insulin options. Timely combination therapy of BI and GLP-1 RA is a valuable choice.

Preliminary Study on the Effect of a Night Shift on Blood Pressure and Clock Gene Expression.

Night shift work has been found to be associated with a higher risk of cardiovascular and cerebrovascular disease. One of the underlying mechanisms seems to be that shift work promotes hypertension, but results have been variable. This cross-sectional study was carried out in a group of internists with the aim of performing a paired analysis of 24 h blood pressure in the same physicians working a day shift and then a night shift, and a paired analysis of clock gene expression after a night of rest and a night of work. Each participant wore an ambulatory blood pressure monitor (ABPM) twice. The first time was for a 24 h period that included a 12 h day shift (08.00-20.00) and a night of rest. The second time was for a 30 h period that included a day of rest, a night shift (20.00-08.00), and a subsequent period of rest (08.00-14.00). Subjects underwent fasting blood sampling twice: after the night of rest and after the night shift. Night shift work significantly increased night systolic blood pressure (SBP), night diastolic blood pressure (DBP), and heart rate (HR) and decreased their respective nocturnal decline. Clock gene expression increased after the night shift. There was a direct association between night blood pressure and clock gene expression. Night shifts lead to an increase in blood pressure, non-dipping status, and circadian rhythm misalignment. Blood pressure is associated with clock genes and circadian rhythm misalignement.

Type 1 diabetes is associated with significant changes of ACE and ACE2 expression in peripheral blood mononuclear cells.

BACKGROUND AND AIMS: The renin-angiotensin system (RAS), which is a key mediator of cardiovascular homeostasis, has two main axes. The classic one, including angiotensin-converting enzyme (ACE) and Angiotensin (Ang) II, promoting vasoconstriction, and the "alternative" one, including ACE2 and Ang1-7, with opposed actions to AngII. ACE2 has been identified as the main receptor of SARS-CoV2, whereby it enters the cells, leading to the downregulation of surface ACE2 and RAS tissue unbalance. Given that diabetes is associated with an increase in COVID-19 severity and death, we aimed at evaluating RAS expression in patients with type 1 diabetes (T1D). METHODS AND RESULTS: This is a case-control study comparing 39 T1D patients to 33 controls, with a median age of 29 and 32 years, and no comorbidities. ACE and ACE2 gene expression was assessed in peripheral blood mononuclear cells. T1D patients had higher ACE expression and circulating AngII, which were related to glucose levels. T1D patients had lower ACE2 expression. However, ACE2 expression was also related to the sex of participants, being higher in the female group. T1D women did not show the same increase of ACE2 expression that was seen in control women. CONCLUSION: T1D promotes the increase of ACE, AngII, and ACE/ACE2, which might contribute to the higher cardiovascular risk, as well as to severe tissue injury induced by SARS-CoV2 in these patients. The ratio ACE/ACE2 does not differ between men and women with T1D, which might explain why CVD or COVID-19 do not show substantial gender differences in these patients.

Effects of insulin on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials.

AIM: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin with this respect. DATA SYNTHESIS: A MEDLINE database search was performed to identify all RCTs, up to June 1st, 2021, with duration≥52 weeks, in which insulin was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Six RCTs (enrolling 8091 patients and 10,139 in the insulin and control group, respectively) were included in the analysis for MACEs and HF, and 18 in that for all-cause mortality (9760 and 11,694 patients in the insulin and control group, respectively). Treatment with insulin neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 1.09, 95% CI 0.97-1.23; 0.99, 95% CI 0.91, 1.08; and 0.90, 95% CI 0.78, 1.04, respectively). CONCLUSIONS: This meta-analysis showed no significant effects of insulin on incident MACE, all-cause mortality, and HHF.

All-cause mortality and cardiovascular events in patients with type 2 diabetes treated with alpha-glucosidase inhibitors: A meta-analysis of randomized controlled trials.

AIM: Alpha-glucosidase inhibitors are approved drugs for treating type 2 diabetes (T2DM); however, their effects on mortality and cardiovascular safety are unclear. This meta-analysis was aimed at evaluating the effects of alpha-glucosidase inhibitors on all-cause mortality and major cardiovascular events (MACE). DATA SYNTHESIS: A Medline, Embase, Cochrane database searching for alpha-glucosidase inhibitors was performed up to July 1st, 2021. All randomized controlled trials (RCT) with a duration ≥52 weeks and comparing the effects of alpha-glucosidase inhibitors with placebo or active drugs were collected. Further inclusion criteria were: RCT reporting MACE within their primary outcome, or as pre-defined secondary outcome; and RCT enrolling at least 100 patients with T2DM. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence intervals were calculated for the aforementioned outcomes. A total of eight RCTs, enrolling 1124 and 908 patients on alpha-glucosidase inhibitors and comparators, respectively, were identified. No trials reported information on MACE. Treatment with alpha-glucosidase inhibitors was not associated with a significant increase of all-cause mortality compared with other therapies or no therapy/placebo (MH-OR 0.76 [0.28; 2.05]). CONCLUSIONS: The evidence of beneficial or detrimental effects of alpha-glucosidase inhibitors on all-cause mortality and cardiovascular events is not sufficient to draw any conclusions.

Effects of pioglitazone on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials.

AIM: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. After identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, the experts decided to perform a systematic review and meta-analysis on the effect of pioglitazone with this respect. DATA SYNTHESIS: A MEDLINE database search was performed to identify RCTs, up to June 1st, 2021, with duration≥52 weeks, in which pioglitazone was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Eight RCTs were included in the analysis for MACEs and HF (5048 and 5117 patients in the pioglitazone and control group, respectively), and 24 in that for all-cause mortality (10,682 and 9674 patients). Pioglitazone neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 0.90, 95% CI 0.78-1.03, 0.91, 95% CI 0.77, 1.09, and 1.16, 95% CI 0.73, 1.83, respectively). Pioglitazone was associated with a significant reduction of MACE in patients with prior cardiovascular events (MH-OR 0.84, 95% CI 0.72-0.99). CONCLUSIONS: This meta-analysis showed no significant effects of pioglitazone on incident MACE, all-cause mortality, and HHF.

Improvement of glycemic control in type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.

AIM: Different guidelines provide similar, but not identical, therapeutic targets for HbA1c in type 2 diabetes. These targets can also depend from the different pharmacological strategies adopted for intensifying glycemic control. DATA SYNTHESIS: This meta-analysis includes randomized trials adopting any pharmacological regimen for intensifying glycemic control in T2DM (versus standard of care/placebo), with a trial duration ≥2 years and a between-group HbA1c difference≥0.5%. The primary outcome was to assess the effects of the improvement of glycemic control on major cardiovascular events (MACE), ocular and renal complications, and severe hypoglycemia. Mantel-Haenszel odds ratios (MH-OR) with 95% Confidence Intervals were calculated for all the outcomes considered. We included 13 trials fulfilling the inclusion criteria. The improvement of glycemic control was associated with a lower risk of MACE (MH-OR:0.89 [95%CI 0.85-0.94]) and renal adverse events (MH-OR 0.73 [0.65-0.82]), but not all-cause mortality (MH-OR 0.95 [0.88-1.01]) and ocular adverse complications (MH-OR 0.94 [0.72-1.22]). For glucose-lowering drugs inducing hypoglycemia, a protective effect on the risk of microvascular complications, but not of MACE and all-cause mortality, was observed only for HbA1c ≤ 48 mmol/mol, but with higher risk of severe hypoglycaemia (MH-OR 2.72 [1.79-4.13]). Drugs not inducing hypoglycaemia were associated with a reduction of MACE, renal adverse events, and all-cause mortality, for HbA1c< 7% (no data for lower targets). CONCLUSIONS: The present meta-analysis show that the improvement of glycemic control with drugs not inducing hypoglycemia is associated with a reduction in the risk of long-term chronic vascular and renal complications, and all-cause mortality.

Effect of metformin on all-cause mortality and major adverse cardiovascular events: An updated meta-analysis of randomized controlled trials.

AIMS: The Italian Society of Diabetology and the Italian Association of Clinical Diabetologists are developing new guidelines for drug treatment of type 2 diabetes. The effects of anti-hyperglycaemic drugs on all-cause mortality and major adverse cardiovascular events (MACEs) were included among the critical clinical outcomes. We have therefore carried out an updated meta-analysis on the effects of metformin on these outcomes. DATA SYNTHESIS: A MEDLINE and EMBASE search was performed to identify all randomized controlled trials (RCTs) with duration ≥52 weeks (published up to August 2020), in which metformin was compared with either placebo/no therapy or active comparators. MACEs (restricted for RCT reporting MACEs within their study endpoints) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified endpoints) were considered as the primary endpoints. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence interval was calculated for all endpoints considered. Metformin was associated with a nonsignificant reduction of all-cause mortality (n = 13 RCTs; MH-OR 0.80 [95% CI 0.60, 1.07]). However, this association became statistically significant after excluding RCTs comparing metformin with sulfonylureas, SGLT-2 inhibitors or GLP-1 analogues (MH-OR 0.71 [0.51, 0.99]). Metformin was associated with a lower risk of MACEs compared with comparator treatments (n = 2 RCTs; MH-OR 0.52 [0.37, 0.73]), p < 0.001. Similar results were obtained in a post-hoc analysis including all RCTs fulfilling criteria for inclusion in the analysis (MH-OR: 0.57 [0.42, 0.76]). CONCLUSIONS: This updated meta-analysis suggests that metfomin is significantly associated with lower risk of MACEs and tendentially lower all-cause mortality compared to placebo or other anti-hyperglycaemic drugs.

Effect of insulin secretagogues on major cardiovascular events and all-cause mortality: A meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs) and all-cause mortality as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin secretagogues (sulfonylureas and glinides) with this respect. METHODS AND RESULTS: A MEDLINE database search was performed to identify all RCTs, up to January 1st, 2020, with duration≥52 weeks, in which insulin secretagogues (glibenclamide, gliclazide, glimepiride, glipizide, chlorpropamide, repaglinide, nateglinide) were compared with either placebo or active comparators. The principal endpoints were MACE (restricted for RCT reporting MACEs within their outcomes) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Fourteen RCTs were included in the analysis for MACEs (919 in insulin secretagogues and 1,087 in control group). Insulin secretagogues were not significantly associated with an increased risk of MACEs in comparison with controls (MH-OR 1.08 [95% CI 0.96, 1.22], p = 0.20). When considering the 48 RCTs fulfilling criteria for inclusion in the analysis on all-cause mortality, insulin secretagogues were associated with a significantly increased risk of all-cause mortality (MH-OR 1.11 [1.00, 1.23], p = 0.04). CONCLUSIONS: This meta-analysis suggests that insulin secretagogues are associated with an increased risk of all-cause mortality when compared with placebo or other anti-hyperglycaemic drugs.

Circulating osteoprotegerin is associated with chronic kidney disease in hypertensive patients.

BACKGROUND: Osteoprotegerin (OPG) is a glycoprotein that plays an important regulatory role in the skeletal, vascular, and immune system. It has been shown that OPG predicts chronic kidney disease (CKD) in diabetic patients. We hypothesized that OPG could be a risk marker of CKD development also in non-diabetic hypertensive patients. METHODS: A case-control study was carried out to measure circulating OPG levels in 42 hypertensive patients with CKD and in 141 hypertensive patients without CKD. A potential relationship between OPG and the presence of CKD was investigated and a receiver-operating characteristic (ROC) curve was designed thereafter to identify a cut-off value of OPG that best explained the presence of CKD. Secondly, to evaluate whether OPG increase could affect the kidney, 18 C57BL/6J mice were randomized to be treated with saline or recombinant OPG every 3 weeks for 12 weeks. RESULTS: Circulating OPG levels were significantly higher in hypertensive patients with CKD, and there was a significant inverse association between OPG and renal function, that was independent from other variables. ROC analysis showed that OPG levels had a high statistically predictive value on CKD in hypertensive patients, which was greater than that of hypertension. The OPG best cut-off value associated with CKD was 1109.19 ng/L. In the experimental study, OPG delivery significantly increased the gene expression of pro-inflammatory and pro-fibrotic mediators, as well as the glomerular nitrosylation of proteins. CONCLUSIONS: This study shows that OPG is associated with CKD in hypertensive patients, where it might have a higher predictive value than that of hypertension for CKD development. Secondly, we found that OPG delivery significantly increased the expression of molecular pathways involved in kidney damage. Further longitudinal studies are needed not only to evaluate whether OPG predicts CKD development but also to clarify whether OPG should be considered a risk factor for CKD.

Analysis of left atrial performance in patients with type 2 diabetes mellitus without overt cardiac disease and inducible ischemia: high prevalence of increased systolic force related to enhanced left ventricular systolic longitudinal function.

OBJECTIVES: In patients with chronic pressure overload, higher left atrial systolic force (LASF) is associated with high-risk cardiovascular (CV) phenotype, with increased left ventricular (LV) mass, concentric hypertrophy, and diastolic dysfunction. In hypertension and aortic stenosis, LASF predicts increased rate of CV events independent of traditional risk factors. Moreover, LASF is an independent predictor of heart failure in diabetic and nondiabetic patients. Limited data are available about LASF and its relationship with LV systolic function in type 2 diabetes mellitus (T2DM). METHODS: We used baseline clinic and echocardiographic data from 333 patients recruited in the SHORTWAVE study evaluating LV and left atrial performance in T2DM patients without cardiac disease. LASF was calculated by Manning's method and defined high when exceeded 16 Kdynes (90th percentile of LASF found in 120 healthy subjects used as controls). RESULTS: Mean LASF was 15.8 Â ± 9.4 Kdynes/cm(2) and showed a close positive correlation with peak mitral annular systolic velocity (function of LV longitudinal fibers), independent of E/E', age, systolic blood pressure, heart rate, and concentric geometry (multiple R = 0.57, P < 0.0001). Such independent correlation (tested in patients with and without concomitant hypertension) was confirmed at multiple logistic regression analysis where patients were dichotomized for having high (119 = 36%) or normal LASF. CONCLUSIONS: High LASF is present in one third of T2DM patients without overt cardiac disease and is positively and independently related to an increased LV longitudinal shortening function, suggesting a close interaction between LV systolic and diastolic function.

The osteoprotegerin/tumor necrosis factor related apoptosis-inducing ligand axis in the kidney.

PURPOSE OF REVIEW: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytokine belonging to the TNF superfamily. TRAIL may modulate cell survival and proliferation through interaction with two different receptors, TRAIL-R1 and TRAIL-R2. The actions of TRAIL are regulated by three decoy receptors, TRAIL-R3, TRAIL-R4 and osteoprotegerin (OPG). There is evidence that both TRAIL and OPG are expressed by renal cells. The OPG/TRAIL axis has been recently linked to the pathogenesis of renal damage and, in particular, diabetic nephropathy. RECENT FINDINGS: In patients with kidney diseases, serum TRAIL and OPG levels are increased in parallel and are significantly associated with each other. In diabetic nephropathy, the renal expression of TRAIL and OPG is elevated, and in tubular cells proinflammatory cytokines enhance TRAIL expression. Additionally, a high-glucose microenvironment sensitizes tubular cells to apoptosis induced by TRAIL, whereas OPG counteracts the actions of TRAIL in cultured cells. SUMMARY: It seems that the expression and levels of TRAIL and OPG at serum and kidney levels are crucial for the pathogenesis of kidney diseases, and in particular diabetic nephropathy. Although further studies are necessary to clarify the exact role of the OPG/TRAIL axis in the kidney, this system seems to hold promise to provide therapeutic approaches for the management of renal damage. VIDEO ABSTRACT AVAILABLE: See the Video Supplementary Digital Content 1 (http://links.lww.com/CONH/A5).

Open questions on basal insulin therapy in T2D: a Delphi consensus.

AIMS: The revolution in the therapeutic approach to type 2 diabetes (T2D) requires a rethinking of the positioning of basal insulin (BI) therapy. Given the considerable number of open questions, a group of experts was convened with the aim of providing, through a Delphi consensus method, practical guidance for doctors. METHODS: A group of 6 experts developed a series of 29 statements on: the role of metabolic control in light of the most recent guidelines; BI intensification strategies: (1) add-on versus switch; (2) inertia in starting and titrating; (3) free versus fixed ratio combination; basal-bolus intensification and de-intensification strategies; second generation analogues of BI (2BI). A panel of 31 diabetologists, by accessing a dedicated website, assigned each statement a relevance score on a 9-point scale. The RAND/UCLA Appropriateness Method was adopted to assess the existence of disagreement among participants. RESULTS: Panelists showed agreement for all 29 statements, of which 26 were considered relevant, one was considered not relevant and two were of uncertain relevance. Panelists agreed that the availability of new classes of drugs often allows the postponement of BI and the simplification of therapy. It remains essential to promptly initiate and titrate BI when required. BI should always, unless contraindicated, be started in addition to, and not as a replacement, for ongoing treatments with cardiorenal benefits. 2BIs should be preferred for their pharmacological profile, greater ease of self-titration and flexibility of administration. CONCLUSION: In a continuously evolving scenario, BI therapy still represents an important option in the management of T2D patients.

Comparing the effectiveness and cost-effectiveness of sulfonylureas and newer diabetes drugs as second-line therapy for patients with type 2 diabetes.

INTRODUCTION: We aimed to compare the effectiveness and cost-effectiveness profiles of glucagon-like peptide-1 receptor agonist (GLP-1-RA), sodium-glucose cotransporter 2 inhibitor (SGLT2i), and dipeptidyl peptidase-4 inhibitor (DPP-4i) compared with sulfonylureas and glinides (SU). RESEARCH DESIGN AND METHODS: Population-based retrospective cohort study based on linked regional healthcare utilization databases. The cohort included all residents in Lombardy aged ≥40 years, treated with metformin in 2014, who started a second-line treatment between 2015 and 2018 with SU, GLP-1-RA, SGLT2i, or DPP-4i. For each cohort member who started SU, one patient who began other second-line treatments was randomly selected and matched for sex, age, Multisource Comorbidity Score, and previous duration of metformin treatment. Cohort members were followed up until December 31, 2022. The association between second-line treatment and clinical outcomes was assessed using Cox proportional hazards models. The incremental cost-effectiveness ratios (ICERs) were calculated and compared between newer diabetes drugs and SU. RESULTS: Overall, 22 867 patients with diabetes were included in the cohort, among which 10 577, 8125, 2893 and 1272 started a second-line treatment with SU, DPP-4i, SGLT2i and GLP-1-RA, respectively. Among these, 1208 patients for each group were included in the matched cohort. As compared with SU, those treated with DPP-4i, SGLT2i and GLP-1-RA were associated to a risk reduction for hospitalization for major adverse cardiovascular events (MACE) of 22% (95% CI 3% to 37%), 29% (95% CI 12% to 44%) and 41% (95% CI 26% to 53%), respectively. The ICER values indicated an average gain of €96.2 and €75.7 each month free from MACE for patients on DPP-4i and SGLT2i, respectively. CONCLUSIONS: Newer diabetes drugs are more effective and cost-effective second-line options for the treatment of type 2 diabetes than SUs.