Impact of MASLD and MetALD on clinical outcomes: A meta-analysis of preliminary evidence.

A recent Delphi consensus proposed a new definition for metabolic dysfunction associated steatotic liver disease (MASLD) and introduced a disease entity called MetALD, a condition in which steatotic liver disease (SLD), metabolic dysfunction and moderate alcohol intake coexist. Given the limited available data on the prognostic implications of these disease entities, we performed a systematic review and meta-analysis of available cohort studies to evaluate the association of MASLD and MetALD with hard clinical outcomes. We included 5 studies for a total of 9 824 047 participants. Compared with participants without SLD, increased rates of all-cause mortality and incident cardiovascular disease were present for both MASLD and MetALD. Moreover, MetALD was also associated with significantly higher risks of cancer-related mortality (n = 2 studies, random-effects HR 2.10, 95% CI 1.35-3.28) and cardiovascular mortality (n = 3 studies, random-effects HR 1.17, 95% CI 1.12-1.22). Although preliminary, available evidence indicates a more unfavourable prognosis for patients with MetALD compared with those with MASLD.

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.

Long-term benefits of dapagliflozin on renal outcomes of type 2 diabetes under routine care: a comparative effectiveness study on propensity score matched cohorts at low renal risk.

Background: Despite the overall improvement in care, people with type 2 diabetes (T2D) experience an excess risk of end-stage kidney disease. We evaluated the long-term effectiveness of dapagliflozin on kidney function and albuminuria in patients with T2D. Methods: We included patients with T2D who initiated dapagliflozin or comparators from 2015 to 2020. Propensity score matching (PSM) was performed to balance the two groups. The primary endpoint was the change in estimated glomerular filtration rate (eGFR) from baseline to the end of observation. Secondary endpoints included changes in albuminuria and loss of kidney function. Findings: We analysed two matched groups of 6197 patients each. The comparator group included DPP-4 inhibitors (40%), GLP-1RA (22.3%), sulphonylureas (16.1%), pioglitazone (8%), metformin (5.8%), or acarbose (4%). Only 6.4% had baseline eGFR <60 ml/min/1.73 m2 and 15% had UACR >30 mg/g. During a mean follow-up of 2.5 year, eGFR declined significantly less in the dapagliflozin vs comparator group by 1.81 ml/min/1.73 m2 (95% C.I. from 1.13 to 2.48; p < 0.0001). The mean eGFR slope was significantly less negative in the dapagliflozin group by 0.67 ml/min/1.73 m2/year (95% C.I. from 0.47 to 0.88; p < 0.0001). Albuminuria declined significantly in new-users of dapagliflozin within 6 months and remained on average 44.3 mg/g lower (95% C.I. from -66.9 to -21.7; p < 0.0001) than in new-users of comparators. New-users of dapagliflozin had significantly lower rates of new-onset CKD, loss of kidney function, and a composite renal outcome. Results were confirmed for all SGLT2 inhibitors, in patients without baseline CKD, and when GLP-1RA were excluded from comparators. Interpretation: Initiating dapagliflozin improved kidney function outcomes and albuminuria in patients with T2D and a low renal risk. Funding: Funded by the Italian Diabetes Society and partly supported by a grant from AstraZeneca.

Precision prognostics for cardiovascular disease in Type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: Precision medicine has the potential to improve cardiovascular disease (CVD) risk prediction in individuals with Type 2 diabetes (T2D). METHODS: We conducted a systematic review and meta-analysis of longitudinal studies to identify potentially novel prognostic factors that may improve CVD risk prediction in T2D. Out of 9380 studies identified, 416 studies met inclusion criteria. Outcomes were reported for 321 biomarker studies, 48 genetic marker studies, and 47 risk score/model studies. RESULTS: Out of all evaluated biomarkers, only 13 showed improvement in prediction performance. Results of pooled meta-analyses, non-pooled analyses, and assessments of improvement in prediction performance and risk of bias, yielded the highest predictive utility for N-terminal pro b-type natriuretic peptide (NT-proBNP) (high-evidence), troponin-T (TnT) (moderate-evidence), triglyceride-glucose (TyG) index (moderate-evidence), Genetic Risk Score for Coronary Heart Disease (GRS-CHD) (moderate-evidence); moderate predictive utility for coronary computed tomography angiography (low-evidence), single-photon emission computed tomography (low-evidence), pulse wave velocity (moderate-evidence); and low predictive utility for C-reactive protein (moderate-evidence), coronary artery calcium score (low-evidence), galectin-3 (low-evidence), troponin-I (low-evidence), carotid plaque (low-evidence), and growth differentiation factor-15 (low-evidence). Risk scores showed modest discrimination, with lower performance in populations different from the original development cohort. CONCLUSIONS: Despite high interest in this topic, very few studies conducted rigorous analyses to demonstrate incremental predictive utility beyond established CVD risk factors for T2D. The most promising markers identified were NT-proBNP, TnT, TyG and GRS-CHD, with the highest strength of evidence for NT-proBNP. Further research is needed to determine their clinical utility in risk stratification and management of CVD in T2D.

People living with type 2 diabetes (T2D) are more likely to develop problems with their heart or blood circulation, known as cardiovascular disease (CVD), than people who do not have T2D. However, it can be difficult to predict which people with T2D are most likely to develop CVD. This is because current approaches, such as blood tests, do not identify all people with T2D who are at an increased risk of CVD. In this study we reviewed published papers that investigated the differences between people with T2D who experienced CVD compared to those who did not. We found some indicators that could potentially be used to determine which people with T2D are most likely to develop CVD. More studies are needed to determine how useful these are. However, they could potentially be used to enable clinicians to provide targeted advice and treatment to those people with T2D at most risk of developing CVD.

MASLD, hepatic steatosis and fibrosis are associated with the prevalence of chronic kidney disease and retinopathy in adults with type 1 diabetes mellitus.

AIM: We examined whether metabolic dysfunction-associated steatotic liver disease (MASLD) with or without significant fibrosis (assessed by validated non-invasive biomarkers) was associated with an increased risk of prevalent chronic kidney disease (CKD) or diabetic retinopathy in people with type 1 diabetes mellitus (T1DM). METHODS: We performed a retrospective multicenter cross-sectional study involving 1,409 adult outpatients with T1DM, in whom hepatic steatosis index (HSI) and fibrosis (FIB)-4 index were calculated for non-invasively detecting hepatic steatosis (defined by HSI > 36), with or without coexisting significant fibrosis (FIB-4 index ≥ 1.3 or < 1.3). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or urine albumin/creatinine ratio ≥ 3.0 mg/mmol. The presence of diabetic retinopathy was also recorded in all participants. RESULTS: Patients with MASLD and significant fibrosis (n = 93) had a remarkably higher prevalence of CKD and diabetic retinopathy than their counterparts with MASLD without fibrosis (n = 578) and those without steatosis (n = 738). After adjustment for sex, diabetes duration, hemoglobin A1c, hypertension, and use of antihypertensive or lipid-lowering medications, patients with SLD and significant fibrosis had a higher risk of prevalent CKD (adjusted-odds ratio 1.76, 95 % confidence interval 1.05-2.96) than those without steatosis. Patients with MASLD without fibrosis had a higher risk of prevalent retinopathy (adjusted-odds ratio 1.49, 95 % CI 1.13-1.46) than those without steatosis. CONCLUSION: This is the largest cross-sectional study showing that MASLD with and without coexisting significant fibrosis was associated, independently of potential confounders, with an increased risk of prevalent CKD and retinopathy in adults with T1DM.

Deep-learning-based natural-language-processing models to identify cardiovascular disease hospitalisations of patients with diabetes from routine visits' text.

Writing notes is the most widespread method to report clinical events. Therefore, most of the information about the disease history of a patient remains locked behind free-form text. Natural language processing (NLP) provides a solution to automatically transform free-form text into structured data. In the present work, electronic healthcare records data of patients with diabetes were used to develop deep-learning based NLP models to automatically identify, within free-form text describing routine visits, the occurrence of hospitalisations related to cardiovascular disease (CVDs), an outcome of diabetes. Four possible time windows of increasing level of expected difficulty were considered: infinite, 24 months, 12 months, and 6 months. Model performance was evaluated by means of the area under the precision recall curve, as well as precision, recall, and F1-score after thresholding. Results showed that the proposed NLP approach was successful for both the infinite and 24-month windows, while, as expected, performance deteriorated with shorter time windows. Possible clinical applications of tools based on the proposed NLP approach include the retrospective filling of medical records with respect to a patient's CVD history for epidemiological and research purposes as well as for clinical decision making.

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care.

INTRODUCTION: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. METHODS: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. RESULTS: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42% < 5 years), and a minority (15.6%) had a history of cardiovascular events. Importantly, oral semaglutide was started in subjects with various disease durations and background therapies. Notably, its initiation was accompanied by de-prescription of sulfonylureas, pioglitazone, DPP-4 inhibitors, and insulin. Choice of oral semaglutide was influenced by patient profiles and ongoing glucose-lowering regimens. Factors such as younger age, higher HbA1c, and ongoing SGLT-2 inhibitor therapy drove the choice of oral semaglutide with the aim of improving glycemic control. Projected glycemic effectiveness analysis revealed that oral semaglutide could potentially lead HbA1c to target in > 60% of patients, and more often than sitagliptin or empagliflozin. CONCLUSION: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Improved prediction of long-term kidney outcomes in people with type 2 diabetes by levels of circulating haematopoietic stem/progenitor cells.

AIM/HYPOTHESIS: We examined whether prediction of long-term kidney outcomes in individuals with type 2 diabetes can be improved by measuring circulating levels of haematopoietic stem/progenitor cells (HSPCs), which are reduced in diabetes and are associated with cardiovascular risk. METHODS: We included individuals with type 2 diabetes who had a baseline determination of circulating HSPCs in 2004-2019 at the diabetes centre of the University Hospital of Padua and divided them into two groups based on their median value per ml of blood. We collected updated data on eGFR and albuminuria up to December 2022. The primary endpoint was a composite of new-onset macroalbuminuria, sustained ≥40% eGFR decline, end-stage kidney disease or death from any cause. The analyses were adjusted for known predictors of kidney disease in the population with diabetes. RESULTS: We analysed 342 participants (67.8% men) with a mean age of 65.6 years. Those with low HSPC counts (n=171) were significantly older and had a greater prevalence of hypertension, heart failure and nephropathy (45.0% vs 33.9%; p=0.036), as evidenced by lower eGFR and higher albuminuria at baseline. During a median follow-up of 6.7 years, participants with high vs low HSPC counts had lower rates of the composite kidney outcome (adjusted HR 0.69 [95% CI 0.49, 0.97]), slower decline in eGFR and a similar increase in albuminuria. Adding the HSPC information to the risk score of the CKD Prognosis Consortium significantly improved discrimination of individuals with future adverse kidney outcomes. CONCLUSIONS/INTERPRETATION: HSPC levels predict worsening of kidney function and improve the identification of individuals with type 2 diabetes and adverse kidney outcomes over and beyond a clinical risk score.

Association between different modalities of insulin administration and metabolic dysfunction-associated fatty liver disease in adults with type 1 diabetes mellitus.

AIM: We examined whether different insulin administration modalities, i.e., multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII by insulin pumps), are differently associated with the risk of having metabolic dysfunction-associated fatty liver disease (MAFLD), with or without coexisting significant liver fibrosis (assessed by validated non-invasive biomarkers), in adults with type 1 diabetes mellitus (T1DM). METHODS: We conducted a retrospective, multicenter, cross-sectional study involving 1,417 adult individuals with established T1DM treated with MDI or CSII. We calculated hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting MAFLD (defined by HSI >36), with or without coexisting significant fibrosis (defined by FIB-4 index ≥ 1.3 or <1.3, respectively). RESULTS: Compared to the MDI group (n = 1,161), insulin-pump users (n = 256; 18.1%) were more likely to be younger (mean age: 40 vs. 48 years, P < 0.001), had better glycemic control (mean hemoglobin A1c: 7.7%  vs. 7.9%, P = 0.025) and a markedly lower prevalence of MAFLD with coexisting significant fibrosis (2.7%  vs. 8.1%, P = 0.010), but a comparable prevalence of MAFLD without fibrosis. In multinomial logistic regression analysis, CSII therapy was associated with a ∼70%-lower risk of MAFLD with significant fibrosis (unadjusted odds ratio 0.32, 95% confidence interval 0.14-0.70; P = 0.004), but this association was no longer significant after adjustment for age, hemoglobin A1c and other potential confounders. CONCLUSION: The lower prevalence of MAFLD with coexisting significant fibrosis we observed in adults with T1DM using CSII therapy, compared to those using MDI therapy, is primarily mediated by inter-group differences in age.

Hepatic steatosis with significant fibrosis is associated with an increased 10-year estimated risk of cardiovascular disease in adults with type 1 diabetes mellitus.

BACKGROUND: We assessed whether hepatic steatosis with or without significant fibrosis (determined by validated non-invasive biomarkers) is associated with an increased 10-year estimated risk for cardiovascular disease (CVD) in people with type 1 diabetes mellitus (T1DM). METHODS: We conducted a retrospective, multicenter, cross-sectional study involving 1,254 adults with established T1DM without pre-existing CVD. We used the hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting hepatic steatosis (defined as HSI > 36), with or without coexisting significant fibrosis (defined as FIB-4 index ≥ 1.3 or < 1.3). We calculated the Steno type 1 risk engine and the atherosclerotic CVD (ASCVD) risk score to estimate the 10-year risk of developing a first fatal or nonfatal CVD event. RESULTS: Using the Steno type 1 risk engine, a significantly greater proportion of patients with hepatic steatosis and significant fibrosis (n = 91) had a high 10-year estimated CVD risk compared to those with hepatic steatosis alone (n = 509) or without steatosis (n = 654) (75.8% vs. 23.2% vs. 24.9%, p < 0.001). After adjustment for sex, BMI, diabetes duration, hemoglobin A1c, chronic kidney disease, and lipid-lowering medication use, patients with hepatic steatosis and significant fibrosis had an increased 10-year estimated risk of developing a first fatal or nonfatal CVD event (adjusted-odds ratio 11.4, 95% confidence interval 3.54-36.9) than those without steatosis. We observed almost identical results using the ASCVD risk calculator. CONCLUSIONS: The 10-year estimated CVD risk is remarkably greater in T1DM adults with hepatic steatosis and significant fibrosis than in their counterparts with hepatic steatosis alone or without steatosis.

Rapid kidney function decline and increased risk of heart failure in patients with type 2 diabetes: findings from the ACCORD cohort : Rapid kidney function decline and heart failure in T2D.

BACKGROUND: Impaired kidney function and albuminuria are associated with increased risk of heart failure (HF) in patients with type 2 diabetes (T2D). We investigated whether rapid kidney function decline over time is an additional determinant of increased HF risk in patients with T2D, independent of baseline kidney function, albuminuria, and other HF predictors. METHODS: Included in the study were 7,539 participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study with baseline urinary albumin-to-creatinine ratio (UACR) data, who had completed 4 years of follow-up and had ≥ 3 eGFR measurements during that period (median eGFR/year = 1.9, IQR 1.7-3.2). The association between rapid kidney function decline (eGFR loss ≥ 5 ml/min/1.73 m2/year) and odds of HF hospitalization or HF death during the first 4 years of follow-up was estimated by logistic regression. The improvement in risk discrimination provided by adding rapid kidney function decline to other HF risk factors was evaluated as the increment in the area under the Receiving Operating Characteristics curve (ROC AUC) and integrated discrimination improvement (IDI). RESULTS: Over 4 years of follow-up, 1,573 participants (20.9%) experienced rapid kidney function decline and 255 (3.4%) experienced a HF event. Rapid kidney function decline was associated with a ~ 3.2-fold increase in HF odds (3.23, 95% CI, 2.51-4.16, p < 0.0001), independent of baseline CVD history. This estimate was not attenuated by adjustment for potential confounders, including eGFR and UACR at baseline as well as at censoring (3.74; 95% CI 2.63-5.31). Adding rapid kidney function decline during follow-up to other clinical predictors (WATCH-DM score, eGFR, and UACR at study entry and end of follow-up) improved HF risk classification (ROC AUC = + 0.02, p = 0.027; relative IDI = + 38%, p < 0.0001). CONCLUSIONS: In patients with T2D, rapid kidney function decline is associated with a marked increase in HF risk, independent of starting kidney function and/or albuminuria. These findings highlight the importance of serial eGFR measurements over time to improve HF risk estimation in T2D.

Precision Prognostics for Cardiovascular Disease in Type 2 Diabetes: A Systematic Review and Meta-analysis.

Background Precision medicine has the potential to improve cardiovascular disease (CVD) risk prediction in individuals with type 2 diabetes (T2D). Methods We conducted a systematic review and meta-analysis of longitudinal studies to identify potentially novel prognostic factors that may improve CVD risk prediction in T2D. Out of 9380 studies identified, 416 studies met inclusion criteria. Outcomes were reported for 321 biomarker studies, 48 genetic marker studies, and 47 risk score/model studies. Results Out of all evaluated biomarkers, only 13 showed improvement in prediction performance. Results of pooled meta-analyses, non-pooled analyses, and assessments of improvement in prediction performance and risk of bias, yielded the highest predictive utility for N-terminal pro b-type natriuretic peptide (NT-proBNP) (high-evidence), troponin-T (TnT) (moderate-evidence), triglyceride-glucose (TyG) index (moderate-evidence), Genetic Risk Score for Coronary Heart Disease (GRS-CHD) (moderate-evidence); moderate predictive utility for coronary computed tomography angiography (low-evidence), single-photon emission computed tomography (low-evidence), pulse wave velocity (moderate-evidence); and low predictive utility for C-reactive protein (moderate-evidence), coronary artery calcium score (low-evidence), galectin-3 (low-evidence), troponin-I (low-evidence), carotid plaque (low-evidence), and growth differentiation factor-15 (low-evidence). Risk scores showed modest discrimination, with lower performance in populations different from the original development cohort. Conclusions Despite high interest in this topic, very few studies conducted rigorous analyses to demonstrate incremental predictive utility beyond established CVD risk factors for T2D. The most promising markers identified were NT-proBNP, TnT, TyG and GRS-CHD, with the highest strength of evidence for NT-proBNP. Further research is needed to determine their clinical utility in risk stratification and management of CVD in T2D.

Sex Differences in Cardiovascular Disease and Cardiovascular Risk Estimation in Patients With Type 1 Diabetes.

CONTEXT: Patients with type 1 diabetes (T1D) have higher cardiovascular disease (CVD) risk than the general population. OBJECTIVE: This observational study aims to evaluate sex-related differences in CVD prevalence and CVD risk estimates in a large cohort of T1D adults. METHODS: We conducted a multicenter, cross-sectional study involving 2041 patients with T1D (mean age 46 years; 44.9% women). In patients without pre-existing CVD (primary prevention), we used the Steno type 1 risk engine to estimate the 10-year risk of developing CVD events. RESULTS: CVD prevalence (n = 116) was higher in men than in women aged ≥55 years (19.2 vs 12.8%, P = .036), but comparable between the 2 sexes in those aged <55 years (P = .91). In patients without pre-existing CVD (n = 1925), mean 10-year estimated CVD risk was 15.4 ± 0.4% without any significant sex difference. However, stratifying this patient group by age, the 10-year estimated CVD risk was significantly higher in men than in women until age 55 years (P < .001), but this risk equalized after this age. Carotid artery plaque burden was significantly associated with age ≥55 years and with a medium and high 10-year estimated CVD risk, without any significant sex difference. Diabetic retinopathy and sensory-motor neuropathy were also associated with higher 10-year CVD risk and female sex. CONCLUSION: Both men and women with T1D are at high CVD risk. The 10-year estimated CVD risk was higher in men aged <55 years than in women of similar age, but these sex differences disappeared at age ≥55 years, suggesting that female sex was no longer protective.

Management of type 2 diabetes with a treat-to-benefit approach improved long-term cardiovascular outcomes under routine care.

BACKGROUND: Results of cardiovascular outcome trials enabled a shift from "treat-to-target" to "treat-to-benefit" paradigm in the management of type 2 diabetes (T2D). However, studies validating such approach are limited. Here, we examined whether treatment according to international recommendations for the pharmacological management of T2D had an impact on long-term outcomes. METHODS: This was an observational study conducted on outpatient data collected in 2008-2018 (i.e. prior to the "treat-to-benefit" shift). We defined 6 domains of treatment based on the ADA/EASD consensus covering all disease stages: first- and second-line treatment, intensification, use of insulin, cardioprotective, and weight-affecting drugs. At each visit, patients were included in Group 1 if at least one domain deviated from recommendation or in Group 2 if aligned with recommendations. We used Cox proportional hazard models with time-dependent co-variates or Cox marginal structural models (with inverse-probability of treatment weighing evaluated at each visit) to adjust for confounding factors and evaluate three outcomes: major adverse cardiovascular events (MACE), hospitalization for heart failure or cardiovascular mortality (HF-CVM), and all-cause mortality. RESULTS: We included 5419 patients, on average 66-year old, 41% women, with a baseline diabetes duration of 7.6 years. Only 11.7% had pre-existing cardiovascular disease. During a median follow-up of 7.3 years, patients were seen 12 times at the clinic, and we recorded 1325 MACE, 1593 HF-CVM, and 917 deaths. By the end of the study, each patient spent on average 63.6% of time in Group 1. In the fully adjusted model, being always in Group 2 was associated with a 45% lower risk of MACE (HR 0.55; 95% C.I. 0.46-0.66; p < 0.0001) as compared to being in Group 1. The corresponding HF-CVM and mortality risk were similar (HR 0.56; 95%CI 0.47-0.66, p < 0.0001 and HR 0.56; 95% C.I. 0.45-0.70; p < 0.0001. respectively). Sensitivity analyses confirmed these results. No single domain individually explained the better outcome of Group 2, which remained significant in all subgroups. CONCLUSION: Managing patients with T2D according to a "treat-to-benefit" approach based international standards was associated with a lower risk of MACE, heart failure, and mortality. These data provide ex-post validation of the ADA/EASD treatment algorithm.

Glucose-lowering drugs with cardiovascular benefits as modifiers of critical elements of the human life history.

The life history theory assumes that all organisms are under selective pressure to harvest external resources and allocate them to maximise fitness: only organisms making the best use of energy obtain the greatest fitness benefits. The trade-off of energy spans four functions: maintenance, growth, reproduction, and defence against pathogens. The innovative antihyperglycaemic agents glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease bodyweight and have the potential to counter low-grade inflammation. These key activities could rewire two components of the life history theory operative in adulthood-ie, maintenance and defence. In this Personal View, we postulate that the benefits of these medications on the cardiovascular system, beyond their glucose-lowering effects, could be mediated by the reduction of the maintenance cost driven by obesity and efforts spent on blunting low-grade inflammation.

Pharmacogenetics of Cardiovascular Prevention in Diabetes: From Precision Medicine to Identification of Novel Targets.

Pharmacogenetics-a branch of precision medicine-holds the promise of becoming a novel tool to reduce the social and healthcare burdens of cardiovascular disease (CVD) and coronary artery disease (CAD) in diabetes. The improvement in cardiovascular risk stratification resulting from adding genetic characteristics to clinical data has moved from the modest results obtained with genetic risk scores based on few genetic variants, to the progressively better performances of polygenic risk scores based on hundreds to millions of variants (CAD-PGRS). Similarly, over the past few years, the number of studies investigating the use of CAD-PGRS to identify different responses to cardio-preventive treatment has progressively increased, yielding striking results for lipid-lowering drugs such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and statins. The use of CAD-PGRS to stratify patients based on their likely response to diabetes-specific interventions has been less successful, but promising results have been obtained with regard to specific genetic variants modulating the effects of interventions such as intensive glycemic control and fenofibrate. The finding of diabetes-specific CAD-loci, such as GLUL, has also led to the identification of promising new targets that might hopefully result in the development of specific therapies to reduce CVD burden in patients with diabetes. As reported in consensus statements from international diabetes societies, some of these pharmacogenetic approaches are expected to be introduced in clinical practice over the next decade. For this to happen, in addition to continuing to improve and validate these tools, it will be necessary to educate physicians and patients about the opportunities and limits of pharmacogenetics, as summarized in this review.

The Fast-Glycator Phenotype, Skin Advanced Glycation End Products, and Complication Burden Among People With Type 1 Diabetes.

OBJECTIVE: Existence of a fast-glycator phenotype among people with type 1 diabetes (T1D) is debated. Routine use of glucose sensors allows the comparison of long-term average glucose levels with laboratory HbA1c values. We herein evaluated whether participants with T1D and HbA1c values higher than their glucose management indicator (GMI) had greater accumulation of advanced glycation end products (AGEs) and chronic complications. RESEARCH DESIGN AND METHODS: We included participants with T1D using the intermittently scanned continuous glucose monitoring system consecutively for at least 90 days and having a laboratory-determined HbA1c at the end of observation. Skin AGEs were estimated using the skin autofluorescence (SAF) method. The complication burden was assessed by a standardized screening. The fast-glycator phenotype was defined as having a GMI to HbA1c ratio <0.9. RESULTS: We included 135 individuals with T1D (58% men; mean age, 44.4 years) with a mean diabetes duration of 21 years and a mean HbA1c value of 7.7%. Thirty (22.2%) were defined as having the fast-glycator phenotype. As expected, fast glycators had higher HbA1c (8.6% vs. 7.5%; P < 0.001) with similar 90-day mean glucose level (172 vs. 168 mg/dL; P = 0.52). Fast glycators had higher SAF than did other participants (2.5 vs. 2.1 arbitrary units; P = 0.005) and had a significantly higher prevalence of dyslipidemia (73% vs. 44%; P = 0.005), macroangiopathy (38% vs. 9%; P = 0.001), albuminuria (25% vs. 7%; P = 0.038), and retinopathy (61% vs. 38%; P = 0.022). After adjusting for age and dyslipidemia, the fast-glycator phenotype remained significantly associated with macroangiopathy (odds ratio 3.72; 95% CI 1.22-11.4). CONCLUSIONS: In T1D, a fast-glycator phenotype defined by the GMI to HbA1c ratio is characterized by elevated skin AGEs and is associated with the complication burden.