Independent association of history of diabetic foot with all-cause mortality in patients with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study.

BACKGROUND: Foot ulcers and/or infections are common long-term complications of diabetes and are associated with increased mortality, especially from cardiovascular disease, though only a few studies have investigated the independent contribution of these events to risk of death. This study aimed at assessing the association of history of diabetic foot with all-cause mortality in individuals with type 2 diabetes, independent of cardiovascular risk factors, other complications, and comorbidities. METHODS: This prospective cohort study enrolled 15,773 Caucasian patients in 19 Italian centers in the years 2006-2008. Prior lower extremity, coronary, and cerebrovascular events and major comorbidities were ascertained by medical records, diabetic retinopathy by fundoscopy, diabetic kidney disease by albuminuria and estimated glomerular filtration rate, cardiovascular risk factors by standard methods. All-cause mortality was retrieved for 15,656 patients on 31 October 2015. RESULTS: At baseline, 892 patients (5.7%) had a history of diabetic foot, including ulcer/gangrene and/or amputation (n = 565; 3.58%), with (n = 126; 0.80%) or without (n = 439; 2.78%) lower limb revascularization, and revascularization alone (n = 330; 2.09%). History of diabetic foot was associated with all-cause death over a 7.42-year follow-up (adjusted hazard ratio, 1.502 [95% confidence interval, 1.346-1.676], p < 0.0001), independent of confounders, among which age, male sex, smoking, hemoglobin A1c, current treatments, other complications, comorbidities and, inversely, physical activity level and total and HDL cholesterol were correlated independently with mortality. Both ulcer/gangrene and amputation alone were independently associated with death, with a higher strength of association for amputation than for ulcer/gangrene (1.874 [1.144-3.070], p = 0.013 vs. 1.567 [1.353-1.814], p < 0.0001). Both ulcer/gangrene/amputation and lower limb revascularization alone were independently associated with death; mortality risk was much higher for ulcer/gangrene/amputation than for revascularization (1.641 [1.420-1.895], p < 0.0001 vs. 1.229 [1.024-1.475], p = 0.018) and further increased only slightly for combined ulcer/gangrene/amputation and revascularization (1.733 [1.368-2.196], p < 0.0001). CONCLUSIONS: In patients with type 2 diabetes, an history of diabetic foot event, including ulcer/gangrene, amputation, and lower limb revascularization, was associated with a ~ 50% increased risk of subsequent death, independent of cardiovascular risk factors, other complications and severe comorbidities, which were also significantly associated with mortality. The association with mortality was greatest for amputation, whereas that for revascularization alone was relatively modest. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008.

Fatty liver index is an independent risk factor for all-cause mortality and major cardiovascular events in type 1 diabetes: an 11-year observational study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), identified by the Fatty Liver Index (FLI), is associated with increased mortality and cardiovascular (CV) outcomes. Whether this also applies to type 1 diabetes (T1D) has not been yet reported. METHODS: We prospectively observed 774 subjects with type 1 diabetes (males 52%, 30.3 ± 11.1 years old, diabetes duration (DD) 18.5 ± 11.6 years, HbA1c 7.8 ± 1.2%) to assess the associations between FLI (based on BMI, waist circumference, gamma-glutamyl transferase and triglycerides) and all-cause death and first CV events. RESULTS: Over a median 11-year follow-up, 57 subjects died (7.4%) and 49 CV events (6.7%) occurred among 736 individuals with retrievable incidence data. At baseline, FLI was < 30 in 515 subjects (66.5%), 30-59 in 169 (21.8%), and ≥ 60 in 90 (11.6%). Mortality increased steeply with FLI: 3.9, 10.1, 22.2% (p < 0.0001). In unadjusted Cox analysis, compared to FLI < 30, risk of death increased in FLI 30-59 (HR 2.85, 95% CI 1.49-5.45, p = 0.002) and FLI ≥ 60 (6.07, 3.27-11.29, p < 0.0001). Adjusting for Steno Type 1 Risk Engine (ST1-RE; based on age, sex, DD, systolic BP, LDL cholesterol, HbA1c, albuminuria, eGFR, smoking and exercise), HR was 1.52 (0.78-2.97) for FLI 30-59 and 3.04 (1.59-5.82, p = 0.001) for FLI ≥ 60. Inclusion of prior CV events slightly modified HRs. FLI impact was confirmed upon adjustment for EURODIAB Risk Engine (EURO-RE; based on age, HbA1c, waist-to-hip ratio, albuminuria and HDL cholesterol): FLI 30-59: HR 1.24, 0.62-2.48; FLI ≥ 60: 2.54, 1.30-4.95, p = 0.007), even after inclusion of prior CVD. CV events incidence increased with FLI: 3.5, 10.5, 17.2% (p < 0.0001). In unadjusted Cox, HR was 3.24 (1.65-6.34, p = 0.001) for FLI 30-59 and 5.41 (2.70-10.83, p < 0.0001) for FLI ≥ 60. After adjustment for ST1-RE or EURO-RE, FLI ≥ 60 remained statistically associated with risk of incident CV events, with trivial modification with prior CVD inclusion. CONCLUSIONS: This observational prospective study shows that FLI is associated with higher all-cause mortality and increased risk of incident CV events in type 1 diabetes.

Prognostic impact of switching to the 2021 chronic kidney disease epidemiology collaboration creatinine-based equation in Caucasian patients with type 2 diabetes: the Renal Insufficiency and Cardiovascular events (RIACE) Italian Multicenter Study.

BACKGROUND: A Chronic Kidney Disease (CKD) Epidemiology Collaboration (EPI) formula not including a Black race coefficient has been recently developed and is now recommended in the US. The new (2021) equation was shown to yield higher estimated glomerular filtration rate (eGFR) values than the old (2009) one in a non-Black general population sample, thus reclassifying a significant number of individuals to a better eGFR category. However, reclassified individuals were previously shown to have a lower risk of progression to end-stage kidney disease, but higher adjusted risks for all-cause death and morbidity and mortality from cardiovascular disease than those not reclassified. This study evaluated the prognostic impact of switching from the 2009 to the 2021 CKD-EPI equation in non-Black individuals with type 2 diabetes. METHODS: The Renal Insufficiency And Cardiovascular Events (RIACE) was a prospective cohort study enrolling 15,773 Caucasian patients in 19 Italian centers in 2006-2008. Cardiometabolic risk profile, treatments, complications, and comorbidities were assessed at baseline and eGFR was calculated with the two equations. Vital status was retrieved on 31 October 2015 for 15,656 participants (99.3%). RESULTS: With the 2021 equation, the eGFR value increased in all patients, except for 293 individuals with a 2009 eGFR ≥ 105 ml·min- 1·1.73 m- 2. The median difference was 4.10 ml·min- 1·1.73 m- 2 and was higher in males, older individuals and those in the G2 category. Reclassification decreased the percentage of patients with reduced eGFR from 17.28 to 13.96% and with any CKD from 36.23 to 34.03%. Reclassified individuals had better cardiometabolic risk profile and lower prevalence of complications and use of medications than non-reclassified individuals. Risk of death versus the 2009 G1 category was lower for reclassified than non-reclassified participants in all eGFR categories and, particularly, in each 2009 eGFR category, though difference was significant only in the G4-G5 category. The Receiver Operator Characteristic curves were statistically, but not clinically different with the two equations. CONCLUSION: Changing from the 2009 to the 2021 CKD-EPI equation results in higher eGFR and lower CKD prevalence, with a lower risk of death in reclassified patients with an eGFR < 30 ml·min- 1·1.73 m- 2, but virtually no impact on mortality prediction. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008.

Type 2 diabetes albuminuric and non-albuminuric phenotypes have different morphological and functional ultrasound features of diabetic kidney disease.

AIMS: Whether different diabetic kidney disease (DKD) phenotypes recognise differences in morphological and vascular properties of the kidney is still unexplored. We evaluated the potential role of kidney ultrasonography in differentiating DKD phenotypes in subjects with type 2 diabetes. MATERIALS AND METHODS: This is a cross-sectional, single-centre study. Total (TRV) and parenchymal renal volumes (PRV) were calculated by applying the ellipsoid formula for conventional (2D) ultrasonography and with manual segmentation for 3D ultrasonography, and then adjusted for body surface area (aTRV, aPRV). Renal resistive index (RI) was contextually determined. DKD phenotypes have been defined based on increased urinary albumin-to-creatinine ratio (ACR >30 mg/g) and/or reduced eGFR (<60 ml/min/1.73 m2 ). Recruitment was planned to have groups of the same size. RESULTS: Among 256 subjects, 26.2% had No-DKD, 24.6% increased albuminuria only (Alb+ ), 24.2% non-albuminuric DKD (Alb- DKD), and 25.0% albuminuric DKD (Alb+ DKD). Compared to No-DKD, RI was significantly higher in all DKD phenotypes, being the highest in Alb+ DKD, and with a significant trend of RI > 0.70 to increase across phenotypes. In comparison with No-DKD, both 2D and 3D volumes were increased in Alb+ and significantly reduced in Alb- DKD as well as in Alb+ DKD, with significantly lower volumes in Alb- DKD as compared to Alb+ DKD at the same reduced levels of eGFR. In adjusted regressions, compared to No-DKD, RI was associated with Alb+ ; both RI and aPRV3D were associated with Alb+ DKD; only aPRV3D with Alb- DKD. Compared to No-DKD, Receiver Operating Characteristic curve analyses, designed taking into account conventional risk factors, showed that US parameters did not ameliorate the characterisation of Alb+ and Alb+ DKD, while aPRV3D significantly improved the phenotyping of Alb- DKD. CONCLUSIONS: As a novel information, we reported that, in type 2 diabetes, the emerging normoalbuminuric DKD phenotype showed reduced TRVs and PRVs even when compared, at similarly reduced eGFR levels, with Alb+ DKD opening. In perspective, these findings suggest a possible role of imaging for better discrimination of DKD phenotypes in clinical practice.

SIRT1 rs7896005 polymorphism affects major vascular outcomes, not all-cause mortality, in Caucasians with type 2 diabetes: A 13-year observational study.

AIMS: SIRT1 exerts effects on ageing and lifespan, as well cardiovascular (CV) disease risk. SIRT1 gene is very polymorph with a few tagging single nucleotide polymorphisms (SNPs) so far identified. Some SNPs, including rs7896005, were associated with type 2 diabetes (T2DM). We aimed to ascertain whether this SNP may be associated with CV disease at baseline as well with these same outcomes and all-cause mortality over a 13-year follow-up. MATERIALS AND METHODS: Genotypes of SIRT1 gene were determined using TaqMan SNP assay. RESULTS: Out of 905 T2DM, 9.1% had the AA genotype, 43.2% the AG, and 47.7% the GG. Hardy-Weinberg Equilibrium was met (minor allele frequency 0.306; p = 0.8899). At baseline, there was no difference across genotypes for sex, age, diabetes duration, CV risk factors, treatments, and microangiopathy. Major CV outcomes, myocardial infarction (MI), any coronary heart disease (CHD), and peripheral artery disease (PAD) were more frequent in GG than in AA/AG (p from 0.013 to 0.027), with no association with cerebrovascular events. By fully adjusted regression, GG remained independently related to major CV outcomes, MI, CHD, and PAD. Over follow-up, we recorded 258 major CV events (28.5%; AA/AG 25.2%, GG 32.2%; p = 0.014) with an adjusted hazard ratio (HR) of GG versus AA/AG of 1.296 (95% CI 1.007-1.668, p = 0.044); 169 coronary events (18.7%; AA/AG 15.4%, GG 22.2%; p = 0.006) with HR 1.522 (1.113-2.080, p = 0.008); 79 (8.7%) hospitalisation for heart failure (AA/AG 7.0%, GG 10.6%; p = 0.045) and HR 1.457 (0.919-2.309, p = 0.109); 36 PAD (4.0%; AA/AG 2.3%, GG 5.8%; p = 0.007) with HR 2.225 (1.057-4.684, p = 0.035). No association was found with cerebrovascular events, end stage renal disease, and all-cause mortality. CONCLUSIONS: The rs7896005 SNP of SIRT1 might play a role in cardiovascular disease, mainly CHD risk in T2DM. Results call for larger association studies as well as studies to ascertain mechanisms by which this variant confers increased risk.

Microvascular complications burden (nephropathy, retinopathy and peripheral polyneuropathy) affects risk of major vascular events and all-cause mortality in type 1 diabetes: a 10-year follow-up study.

BACKGROUND: Microvascular complications (MC) have been claimed to increase the risk for cardiovascular disease in diabetic subjects. However, the effect of MC burden on the risk of major vascular outcomes and all-cause mortality in type 1 diabetes is still poorly explored. We evaluated the relationship between microvascular complications burden and incidence of major cardiovascular events and all-cause mortality in subjects with type 1 diabetes. METHODS: We recruited 774 participants with type 1 diabetes in a single-center observational study over a follow-up of 10.8 ± 2.5 years. Hazard ratios (HR) for cardiovascular outcomes and all-cause death associated with microvascular complications were determined by unadjusted and adjusted Cox regression analysis. RESULTS: Out of 774 individuals, 54.9% had no-MC, 32.3% 1 MC, 9.7% 2 MC and 3.1% 3 MC. A total of 54 deaths (7.0%) occurred. Death rate increased from no-MC 2.1% (Ref) to 1 MC 7.2% (HR 3.54 [95% CI 1.59-7.87]), 2 MC 14.7% (HR 6.41 [95% CI 2.65-15.49]) and 3 MC 66.7% (HR 41.73 [95% CI 18.42-94.57], p < 0.0001). After adjustments, HRs were: 1 MC 2.05 (95% CI 0.88-4.76), 2 MC 1.98 (95% CI 0.75-5.21), 3 MC 7.02 (95% CI 2.44-20.20, p = 0.002). Forty-nine subjects (6.7%) had at least one cardiovascular event, and cumulative incidence went from no-MC 2.2% (Ref) to 1 MC 5.0%; (HR 2.27 [95% CI 0.96-5.38]), 2 MC 26.8% (HR 12.88 [95% CI 5.82-28.50]) and 3 MC 40.9% (HR 29.34 [95% CI 11.59-74.25], p < 0.0001). Upon adjustments, HRs were: 1 MC 1.59 (95% CI 0.65-3.88), 2 MC 4.33 (95% CI 1.75-10.74), 3 MC 9.31 (95% CI 3.18-27.25, p < 0.0001). Thirty-five individuals (4.8%) had at least one coronary event, which cumulative incidence increased with MC burden (p < 0.0001). CONCLUSIONS: In type 1 diabetes, microvascular complications burden increases in an independent dose-dependent manner the risk of major cardiovascular outcomes and all-cause mortality. The presence and number of microvascular complications should be considered in stratifying overall cardiovascular risk in type 1 diabetes.

Influence of high density lipoprotein cholesterol levels on circulating monocytic angiogenic cells functions in individuals with type 2 diabetes mellitus.

BACKGROUND: High-density lipoproteins (HDLs) can exert anti-atherogenic effects. On top of removing excess cholesterol through reverse cholesterol transport, HDLs play beneficial actions on endothelial function and integrity. In particular, HDLs are strong determinant of endothelial progenitor cells (EPCs) number and function. To gain further insights into such an effect we characterized in vitro functionality of circulating "early" EPCs obtained from 60 type 2 diabetes individuals with low HDL-cholesterol (HDL-C) and 59 with high HDL-C levels. METHODS: After an overnight fast, venous blood was drawn in EDTA tubes and processed within 2-h from sampling. Peripheral blood mononuclear cells were isolated and plated on fibronectin coated culture dishes; after 3 days culture, adherent cells positive for Dil-ac-LDL/Lectin dual fluorescent staining were identified as monocytic angiogenic cells (MACs). After 5-7 days culture in EBM-2 medium, adherent cells were evaluated for viability/proliferation (MTT assay), senescence (beta-galactosidase activity detection), migration (modified Boyden chamber using VEGF as chemoattractant), adhesion capacity (on fibronectin-coated culture dishes) and ROS production (ROS-sensitive fluorescent probe CM-H2DCFDA). RESULTS: MACs obtained from diabetic individuals with high HDL-C had 23% higher viability compared to low HDL-C (111.6 ± 32.7% vs. 90.5 ± 28.6% optical density; p = 0.002). H2O2 exposure impaired MACs viability to a similar extent in both groups (109.2 ± 31.7% vs. 74.5 ± 40.8% in high HDL-C, p < 0.0001; 88.3 ± 25.5% vs. 72.3 ± 22.5% in low-HDL, p = 0.004). MACs senescence was comparable in the two groups (102.7 ± 29.8% vs. 99.2 ± 27.8%; p = 0.703) and was only slightly modified by exposure to H2O2. There was no difference in the MACs migration capacity between the two groups (91.3 ± 34.2% vs. 108.7 ± 39.5%; p = 0.111), as well as in MACs adhesion capacity (105.2 ± 32.7% vs. 94.1 ± 26.1%; p = 0.223). Finally, ROS production was slightly thought not significantly higher in MACs from type 2 diabetes individuals with low- than high-HDL. After stratification of HDL-C levels into quartiles, viability (p < 0.0001) and adhesion (p = 0.044) were higher in Q4 than in Q1-Q3. In logistic regression analysis, HDL-C was correlated to MACs viability and adhesion independently of HbA1c or BMI, respectively. CONCLUSIONS: Our data suggest that in type 2 diabetes subjects, HDL-cholesterol is an independent determinant of circulating MACs functional capacities-mainly viability, to a lesser extent adhesion-likely contributing also through this mechanism to cardiovascular protection even in type 2 diabetes.

Evidence for two distinct phenotypes of chronic kidney disease in individuals with type 1 diabetes mellitus.

AIMS/HYPOTHESIS: In a retrospective, observational, cross-sectional, single-centre study, we assessed the prevalence and correlates of different CKD phenotypes (with and without albuminuria) in a large cohort of patients of white ethnicity with type 1 diabetes. METHODS: From 2001 to 2009, 408 men and 369 women with type 1 diabetes (age 40.2 ± 11.7 years, diabetes duration 19.4 ± 12.2 years, HbA1c 7.83 ± 1.17% [62.0 ± 12.9 mmol/mol]) were recruited consecutively. Albumin-to-creatinine ratio (ACR) and eGFR (Modification of Diet in Renal Disease) were obtained for all individuals, together with CKD stage. Diabetic retinopathy and peripheral polyneuropathy were detected in 41.5% and 8.1%, respectively, and cardiovascular disease (CVD) occurred in 8.5%. Adjudications of CKD phenotype were made by blinded investigators. RESULTS: Normo- (ACR <3.4), micro- (ACR 3.4-34) or macroalbuminuria (ACR ≥34 mg/mmol) were present in 91.6%, 6.4% and 1.9% of individuals, respectively. eGFR categories 1 (≥90 ml min-1 [1.73 m]-2), 2 (60-89 ml min-1 [1.73 m]-2) and 3 (<60 ml min-1 [1.73 m]-2) were present in 57.3%, 39.0% and 3.7%, respectively. The majority of participants had no CKD (89.4%), while stages 1-2 and ≥3 CKD were detected in 6.8% and 3.7%, respectively. The albuminuric (Alb+) and non-albuminuric (Alb-) phenotypes were present in 12 (41.4%) and 17 (58.6%) individuals with stage ≥3 CKD, respectively. Individuals with an ACR <3.4 mg/mmol were subdivided into those with normal albuminuria (<1.1 mg/mmol; 77.2%) and mildly increased albuminuria (1.1-3.4 mg/mmol; 14.4%), and individuals with stage 2 CKD were subdivided into those with eGFR 75-89 ml min-1 [1.73 m]-2 and 60-74 ml min-1 [1.73 m]-2. ACR <3.4 mg/mmol (88.7%) and even <1.1 mg/mmol (70.4%) were common in individuals with eGFR 60-74 ml min-1 [1.73 m]-2. The prevalence of ACR <1.1 mg/mmol was lower but still significant (34.5%) in those with stage ≥3 CKD. In logistic regression analysis, stages 1-2 and ≥3 CKD were independently associated with age, HbA1c, γ-glutamyltransferase, fibrinogen, hypertension, but not with sex, BMI, smoking, HDL-cholesterol or triacylglycerol. Inclusion of advanced retinopathy removed HbA1c from the model. The CKD Alb+ phenotype correlated with diabetes duration, HbA1c, HDL-cholesterol, fibrinogen and hypertension, while the CKD Alb- phenotype was associated with age and hypertension, but not with diabetes duration, HbA1c and fibrinogen. CONCLUSIONS/INTERPRETATION: The Alb- CKD phenotype is present in a significant proportion of individuals with type 1 diabetes supporting the hypothesis of two distinct pathways (Alb+ and Alb-) of progression towards advanced kidney disease in type 1 diabetes. These are probably distinct pathways as suggested by different sets of covariates associated with the two CKD phenotypes.

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.

The current landscape for diabetes treatment: Preventing diabetes-associated CV risk.

Despite the risk of atherosclerosis has progressively declined over the past few decades, subjects with type 2 diabetes mellitus (T2DM) continue to experience substantial excess of atherosclerotic cardiovascular disease (ASCVD)-related events. Therefore, there is urgent need to treat ASCVD disease in T2DM earlier, more intensively, and with greater precision. Many factors concur to increase the risk of atherosclerosis, and multifactorial intervention remains the basis for effective prevention or reduction of atherosclerotic events. The role of anti-hyperglycemic medications in reducing the risk of ASCVD in subjects with T2DM has evolved over the past few years. Multiple cardiovascular outcome trials (CVOTs) with new and emerging glucose-lowering agents, namely SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1-RA), have demonstrated significant reductions of major cardiovascular events and additional benefits. This robust evidence has changed the landscape for managing people with T2DM. In addition to glycemic and ancillary extra-glycemic properties, SGLT2i and GLP1-RA might exert favorable effects on subclinical and clinical atherosclerosis. Therefore, the objective of this review is to discuss the available evidence supporting anti-atherosclerotic properties of SGLT2i and GLP1-RA, with a quick nod to sotagliflozin and tirzepatide.

Association between age at diagnosis and all-cause mortality in type 2 diabetes: the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study.

AIMS: It is unclear whether type 2 diabetes diagnosed in young adulthood is associated with increased severity than that occurring later in life beyond longer lifetime exposure to hyperglycemia. This study aimed at assessing the independent association of age at type 2 diabetes diagnosis with all-cause mortality. METHODS: This prospective cohort study enrolled 15,773 Caucasian patients with type 2 diabetes in 19 Italian centers in 2006-2008. Cardiometabolic risk profile and presence of complications and comorbidities were assessed at baseline and participants were stratified by quartiles of age at diabetes diagnosis. All-cause mortality was verified on 31 October 2015. RESULTS: Valid information on vital status was retrieved for 15,656 participants (99.3%). Patients in the lowest quartile had the longest diabetes duration, the worst glycemic control and the highest prevalence of insulin treatment, obesity, atherogenic dyslipidemia, and smoking habits. All complications were inversely associated with age at diabetes diagnosis after adjustment for age and sex, but not after further adjustment for diabetes duration. Percentages of death, Kaplan-Meier estimates, and unadjusted hazard ratios and mortality rates increased from the lowest to the highest quartile. In contrast, when adjusting for age and sex, participants falling in the lowest quartile, showed the highest mortality risk [hazard ratio 1.321 (95% confidence interval 1.196-1.460), P < 0.0001]. However, differences among quartiles disappeared after adjustment for diabetes duration, complications/comorbidities, or other cardiovascular risk factors. CONCLUSIONS: Type 2 diabetes onset in young adulthood is associated with increased mortality that is mainly driven by longer diabetes duration favoring the development of complications. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008.

Relationship between degree of risk factor control and all-cause mortality in individuals with type 2 diabetes: A prospective cohort study.

AIMS: To assess whether and to what extent excess risk of all-cause death is reduced in individuals with type 2 diabetes by achieving optimal control of traditional cardiovascular risk factors. METHODS: This observational, prospective, cohort study enrolled 15,773 Caucasian patients in 19 Italian centres in 2006-2008. Participants were stratified according to the number of the following risk factors outside target: haemoglobin A1c, blood pressure, micro/macroalbuminuria, current smoking, LDL cholesterol, and triglycerides. All-cause mortality was retrieved for 15,656 patients (99.3 %) on 31 October 2015. RESULTS: Age-adjusted mortality rates and hazard ratios were significantly higher in the whole RIACE cohort (by ∼20 %) and in patients with (by ∼100 %) but not in those without prior cardiovascular disease (CVD), as compared with the coeval Italian general population. In all patients and in those without prior CVD, the relationship with mortality according to the number of risk factors outside target was J-shaped, an effect that was attenuated after either excluding "overtreated " patients, i.e., those with haemoglobin A1c ≤6.0 % on anti-hyperglycaemic agents causing hypoglycaemia and/or systolic blood pressure ≤120 mmHg on anti-hypertensive agents, or adjusting for "overtreatment". Conversely, in patients with prior CVD, mortality remained higher than in the general population in all categories and increased progressively from +70 % to +314 %, without J-effect. CONCLUSIONS: In patients with type 2 diabetes, optimal treatment of traditional cardiovascular risk factors completely eliminated the excess mortality risk versus the general population, provided that they were not "overtreated". However, this effect was observed only in participants without history of CVD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July 2008.

De-intensification of basal-bolus insulin regimen after initiation of a GLP-1 RA improves glycaemic control and promotes weight loss in subjects with type 2 diabetes.

AIMS: To evaluate the impact of adding a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in people with type 2 diabetes (T2D) in basal-bolus (BB) insulin regimen, on insulin requirement, HbA1c, weight loss up to 24 months. METHODS: Data on subjects with T2D on BB who initiated a GLP-1 RA have been retrospectively collected. HbA1c, body weight, and insulin dose were recorded at baseline, 6, 12, and 24 months after initiation of GLP-1 RA therapy. A linear mixed model for repeated measures was used to evaluate the changes in HbA1c, body weight, and insulin requirement over time. RESULTS: We included 156 subjects (63.5% males; age 62 ± 11 years, HbA1c 70 ± 22.0 mmol/mol; 8.6 ± 4.2%). Compared to baseline, HbA1c and body weight were significantly lower at 6 months after introducing a GLP-1RA and remained stable up to 24 months (all p < 0.0001 vs. baseline). At 24 months, 81% of subjects discontinued prandial insulin, while 38.6% discontinued basal insulin as well. Insulin requirement at baseline (aOR 0.144; 95% CI, 0.046-0.456; P = 0.001) was the only significant predictor of prandial insulin discontinuation. CONCLUSIONS: Replacing prandial insulin with GLP-1 RA is a valuable strategy to simplify the BB insulin regimen while improving glycaemic control and promoting weight loss in subjects with T2D.

Retinopathy as an independent predictor of all-cause mortality in individuals with type 2 diabetes.

AIMS: To assess whether the presence and grade of diabetic retinopathy (DR) predict all-cause mortality, independent of risk factors for cardiovascular disease (CVD) and other complications, including diabetes-related kidney disease (DKD) and CVD, in individuals with type 2 diabetes mellitus. METHODS: Prospective cohort study that enroled 15,773 patients in 19 Italian centers in 2006-2008. DR ascertained by fundoscopy, DKD by albuminuria and estimated glomerular filtration rate, and prior CVD by hospital discharge records. All-cause mortality retrieved for 15,656 patients on 31 October 2015. RESULTS: The adjusted risk of death was increased in patients with any DR (hazard ratio, 1.136 [95% confidence interval, 1.054;1.224] P < 0.0001), advanced DR, including severe non-proliferative and proliferative DR and diabetic macula edema (1.213 [1.097;1.340] P < 0.0001), and especially proliferative DR alone (1.381 [1.207;1.580] P < 0.0001), compared with those without DR. The impact of DR was more evident in patients without than in those with DKD or CVD. Mortality risk was increased in participants with DR alone, though much less than in those with DKD or CVD alone and particularly in those with both DR and DKD or CVD. DR grade was related to mortality in individuals without DKD or CVD, whereas it conferred no additional risk to those with albuminuric or nonalbuminuric DKD or established CVD. CONCLUSIONS: In patients with type 2 diabetes mellitus, the excess mortality risk conferred by DR is relatively small and higher in those without DKD and CVD, suggesting that it may be mediated by the concurrent presence of these complications, even at a subclinical level.

Insulin discovery: A pivotal point in medical history.

The discovery of insulin in 1921 - due to the efforts of the Canadian research team based in Toronto - has been a landmark achievement in the history of medicine. Lives of people with diabetes were changed forever, considering that in the pre-insulin era this was a deadly condition. Insulin, right after its discovery, became the first hormone to be purified for human use, the first to be unraveled in its amino acid sequence and to be synthetized by DNA-recombinant technique, the first to be modified in its amino acid sequence to modify its duration of action. As such the discovery of insulin represents a pivotal point in medical history. Since the early days of its production, insulin has been improved in its pharmacokinetic and pharmacodynamic properties in the attempt to faithfully reproduce diurnal physiologic plasma insulin fluctuations. The evolution of insulin molecule has been paralleled by evolution in the way the hormone is administered. Once-weekly insulins will be available soon, and glucose-responsive "smart" insulins start showing their potential in early clinical studies. The first century of insulin as therapy was marked by relentless search for better formulations, a search that has not stopped yet. New technologies may have, indeed, the potential to provide further improvement of safety and efficacy of insulin therapy and, therefore, contribute to improvement of the quality of life of people with diabetes.

Risk of all-cause mortality according to the European Society of Cardiology risk categories in individuals with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study.

AIMS: The 2019 and 2021 European Society of Cardiology (ESC) classifications stratified patients with type 2 diabetes into three categories according to the 10-year risk of death from atherosclerotic cardiovascular disease (ASCVD). The very high-risk category included individuals with established ASCVD, target organ damage (TOD), and/or, in the 2019 classification only, ≥ 3 additional ASCVD risk factors. We assessed risk of all-cause mortality according to the two ESC classifications in the Renal Insufficiency And Cardiovascular Events cohort. METHODS: Participants (n = 15,773) were stratified based on the presence of ASCVD, TOD, and ASCVD risk factors at baseline (2006-2008). Vital status was retrieved in 2015. RESULTS: Less than 1% of participants fell in the moderate-risk category. According to the 2019 classification, ~ 1/3 fell in the high-risk and ~ 2/3 in the very high-risk category, whereas the opposite occurred with the 2021 classification. Mortality risk increased across categories according to both classifications. Among very high-risk patients, mortality was much lower in those with ≥ 3 additional ASCVD risk factors and almost equal in those with TOD and ASCVD ± TOD, using the 2019 classification, whereas it was much higher in those with ASCVD + TOD and, to a lesser extent, TOD only than in those with ASCVD only, using the 2021 classification. CONCLUSIONS: The negligible number of moderate-risk patients suggests that these classifications might overestimate risk of ASCVD death. Downgrading patients with ≥ 3 additional ASCVD risk factors to the high-risk category is consistent with mortality data. Risk of death is very high in the presence of TOD irrespective of established ASCVD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00715481.

Contribution of rare variants in monogenic diabetes-genes to early-onset type 2 diabetes.

AIM: This study investigated whether rare, deleterious variants in monogenic diabetes-genes are associated with early-onset type 2 diabetes (T2D). METHODS: A nested case-control study was designed from 9712 Italian patients with T2D. Individuals with age at diabetes onset ≤35 yrs (n = 300; cases) or ≥65 yrs (n = 300; controls) were selected and screened for variants in 27 monogenic diabetes-genes by targeted resequencing. Rare (minor allele frequency-MAF <1%) and possibly deleterious variants were collectively tested for association with early-onset T2D. The association of a genetic risk score (GRS) based on 17 GWAS-SNPs for T2D was also tested. RESULTS: When all rare variants were considered together, each increased the risk of early-onset T2D by 65% (allelic OR =1.64, 95% CI: 1.08-2.48, p = 0.02). Effects were similar when the 600 study participants were stratified according to their place of recruitment (Central-Southern Italy, 182 cases vs. 142 controls, or Rome urban area, 118 vs. 158, p for heterogeneity=0.53). Progressively less frequent variants showed increasingly stronger effects in the risk of early-onset T2D for those with MAF <0.001% (OR=6.34, 95% CI: 1.87-22.43, p = 0.003). One unit of T2D-GRS significantly increased the risk of early-onset T2D (OR 1.09, 95% CI: 1.01-1.18; p = 0.02). This association was stronger among rare variants carriers as compared to non-carriers (p = 0.02). CONCLUSION: Rare variants in monogenic-diabetes genes are associated with an increased risk of early-onset T2D, and interact with common T2D susceptibility variants in shaping it. These findings might help develop prediction tools to identify individuals at high risk of developing T2D in early adulthood.

All-cause mortality prediction models in type 2 diabetes: applicability in the early stage of disease.

AIMS: The rate of all-cause mortality is twofold higher in type 2 diabetes than in the general population. Being able to identify patients with the highest risk from the very beginning of the disease would help tackle this burden. METHODS: We tested whether ENFORCE, an established prediction model of all-cause mortality in type 2 diabetes, performs well also in two independent samples of patients with early-stage disease prospectively followed up. RESULTS: ENFORCE's survival C-statistic was 0.81 (95%CI: 0.72-0.89) and 0.78 (95%CI: 0.68-0.87) in both samples. Calibration was also good. Very similar results were obtained with RECODe, an alternative prediction model of all-cause mortality in type 2 diabetes. CONCLUSIONS: In conclusion, our data show that two well-established prediction models of all-cause mortality in type 2 diabetes can also be successfully applied in the early stage of the disease, thus becoming powerful tools for educated and timely prevention strategies for high-risk patients.

Glycaemic control during the lockdown for COVID-19 in adults with type 1 diabetes: A meta-analysis of observational studies.

AIMS: To assess the effects of lockdown due to COVID-19 pandemic on glucose metrics, measured by glucose monitoring systems, in adult individuals with type 1 diabetes. METHODS: We conducted a systematic literature search for English language articles from MEDLINE, Scopus and Web of Science up to February 28, 2021, using "diabetes", "lockdown", and "glucose" as key search terms. Time in range (TIR) was the main outcome; other metrics were time above range (TAR), time below range (TBR), mean blood glucose (MBG) and its variability (%CV), estimated HbA1c (eA1c) or glucose management indicator (GMI). RESULTS: Seventeen studies for a total of 3,441 individuals with type 1 diabetes were included in the analysis. In the lockdown period, TIR 70-180 mg/dl increased by 3.05% (95% CI 1.67-4.43%; p < 0.0001) while TAR (>180 mg/dL and > 250 mg/dL) declined by 3.39% (-5.14 to -1.63%) and 1.96% (-2.51 to -1.42%), respectively (p < 0.0001 for both). Both TBR < 70 and <54 mg/dL remained unchanged. MBG slightly decreased by 5.40 mg/dL (-7.29 to -3.51 mg/dL; p < 0.0001) along with a reduction in %CV. Pooled eA1c and GMI decreased by 0.18% (-0.24 to -0.11%; p < 0.0001) and a similar reduction was observed when GMI alone was considered (0.15%, -0.23 to -0.07%; p < 0.0001). Sensor use was only slightly but not significantly reduced during lockdown. CONCLUSIONS: This meta-analysis shows that well-controlled people with type 1 diabetes on both MDI and CSII with continuous or flash glucose monitoring did not experience a deterioration in glucose control throughout the COVID-19 lockdown, showing a modest, though statistically significant improvement in many glucose control parameters.