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

Greater efforts are needed to overcome the worldwide reported low achievement of LDL-c targets. This survey aimed to dissect whether and how the physician-based evaluation of patients with diabetes is associated with the achievement of LDL-c targets

PPARγ Pro12Ala and ACE ID polymorphisms are associated with BMI and fat distribution, but not metabolic syndrome

<p>Abstract</p> <p>Background</p> <p>Metabolic Syndrome (MetS) results from the combined effect of environmental and genetic factors. We investigated the possible association of peroxisome proliferator-activated receptor-γ2 (PPARγ2) Pro12Ala and Angiotensin Converting Enzyme (ACE) I/D polymorphisms with MetS and interaction between these genetic variants.</p> <p>Methods</p> <p>Three hundred sixty four unrelated Caucasian subjects were enrolled. Waist circumference, blood pressure, and body mass index (BMI) were recorded. Body composition was estimated by impedance analysis; MetS was diagnosed by the NCEP-ATPIII criteria. A fasting blood sample was obtained for glucose, insulin, lipid profile determination, and DNA isolation for genotyping.</p> <p>Results</p> <p>The prevalence of MetS did not differ across PPARγ2 or ACE polymorphisms. Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but lower systolic blood pressure compared with Pro/Pro homozygotes. A significant PPARγ2 gene-gender interaction was observed in the modulation of BMI, fat mass, and blood pressure, with significant associations found in women only. A PPARγ2-ACE risk genotype combination for BMI and fat mass was found, with ACE DD/PPARγ2 Ala subjects having a higher BMI (p = 0.002) and Fat Mass (p = 0.002). Pro12Ala was independently associated with waist circumference independent of BMI and gender.</p> <p>Conclusions</p> <p>Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but not a worse metabolic profile, possibly because of a more favorable adipose tissue distribution. A gene interaction exists between Pro12Ala and ACE I/D on BMI and fat mass. Further studies are needed to assess the contribution of Pro12Ala polymorphism in adiposity distribution.</p

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

Genetic Variants in \u3cem\u3eHSD17B3\u3c/em\u3e, \u3cem\u3eSMAD3\u3c/em\u3e, and \u3cem\u3eIPO11\u3c/em\u3e Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin‐treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed‐up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P \u3c 5 × 10‐6). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q \u3c 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q \u3c 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor‐beta (TGF‐β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D

Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 x 10(-6)). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor-beta (TGF-) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D

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%  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

Genotype-stratified treatment for monogenic insulin resistance: a systematic review

This is the final version. Available from Nature Research via the DOI in this record. Data availability: All data used in this review is available from publicly available and herein referenced sources. A list of included studies is provided in Supplementary Data 1. All data generated or analyzed during this study are included in this published article and its supplementary information files. Source data for the figures are available as Supplementary Data 2.BACKGROUND: Monogenic insulin resistance (IR) includes lipodystrophy and disorders of insulin signalling. We sought to assess the effects of interventions in monogenic IR, stratified by genetic aetiology. METHODS: Systematic review using PubMed, MEDLINE and Embase (1 January 1987 to 23 June 2021). Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual data were extracted and duplicates were removed. Outcomes were analysed for each gene and intervention, and in aggregate for partial, generalised and all lipodystrophy. RESULTS: 10 non-randomised experimental studies, 8 case series, and 23 case reports meet inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin use is associated with the lowering of triglycerides and haemoglobin A1c (HbA1c) in all lipodystrophy (n = 111), partial (n = 71) and generalised lipodystrophy (n = 41), and in LMNA, PPARG, AGPAT2 or BSCL2 subgroups (n = 72,13,21 and 21 respectively). Body Mass Index (BMI) is lowered in partial and generalised lipodystrophy, and in LMNA or BSCL2, but not PPARG or AGPAT2 subgroups. Thiazolidinediones are associated with improved HbA1c and triglycerides in all lipodystrophy (n = 13), improved HbA1c in PPARG (n = 5), and improved triglycerides in LMNA (n = 7). In INSR-related IR, rhIGF-1, alone or with IGFBP3, is associated with improved HbA1c (n = 17). The small size or absence of other genotype-treatment combinations preclude firm conclusions. CONCLUSIONS: The evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to improve metabolic markers in lipodystrophy, and rhIGF-1 appears to lower HbA1c in INSR-related IR. For other interventions, there is insufficient evidence to assess efficacy and risks in aggregated lipodystrophy or genetic subgroups.Wellcome TrustWellcome Trus

Farmacogenetica del fenofibrato: verso una medicina di precisione nella prevenzione delle complicanze micro e macro-vascolari del diabete

Diversi studi hanno dimostrato come il fenofibrato possa ridurre le complicanze cardiovascolari e retiniche del diabete di tipo 2. Tuttavia, i benefici cardiovascolari di questo trattamento appaiono limitati ai pazienti con dislipidemia aterogena, mentre per la retinopatia, a coloro che hanno già questa complicanza. Abbiamo pertanto studiato la possibilità che la variabilità genetica nel gene PPARA, che codifica per il target farmacologico dei fibrati (PPAR-alfa), possa essere utilizzata per migliorare la selezione dei pazienti con diabete che potrebbero trarre beneficio dalla terapia con fenofibrato. Tra i 3.065 soggetti bianchi trattati con simvastatina e randomizzati a fenofibrato o placebo nello studio sui Action-to-Control-Cardiovascular-Risk-in-Diabetes (ACCORD- Lipid), abbiamo identificato una variante comune nel locus PPARA (rs6008845, C/T) che mostrava un'influenza significativa sull'effetto del fenofibrato sugli eventi cardiovascolari maggiori (MACE). Gli omozigoti T/T (36% dei partecipanti) mostravano una riduzione dei MACE del 51% in risposta al fenofibrato (HR=0,49; IC 95% 0,34-0,72) mentre non si osservava alcun beneficio per gli altri genotipi (p per interazione=3,7x10-4). L'interazione "rs6008845 x fenofibrato" su MACE è stata replicata nei pazienti afroamericani dell’ACCORD (N=585, p=0,02) e in coorti esterne (ACCORD-BP, ORIGIN e TRIUMPH, totale N=3059, p =0,005). Sorprendentemente, gli omozigoti rs6008845 T/T mostravano un beneficio cardiovascolare del fenofibrato anche in assenza di dislipidemia aterogena, e tale effetto non era spiegato da cambiamenti nel profilo lipidico plasmatico. Un'interazione simile e significativa è stata riscontrata anche sulla progressione della retinopatia diabetica tra i 592 soggetti con anamnesi di retinopatia diabetica (DR) inclusi nel sotto-studio ACCORD-Eye, con gli omozigoti rs6008845 T/T che traevano un beneficio maggiore dal fenofibrato su progressione di DR (OR 0,10, IC 95% 0,02-0,74) rispetto a quella che si osservava nei genotipi T/C e C/C (p per interazione = 0,01). La stessa interazione è stata trovata per la riduzione dell’incidenza di grave riduzione del visus (valutata in 3.650 soggetti dallo studio ACCORD-Lipid, p per interazione = 0,03). Il ruolo regolatorio di rs6008845 è stato suggerito da analisi bioinformatiche e inoltre i dati Genotype-Tissue Expression hanno rivelato un'associazione tra rs6008845 ed espressione di PPARA in molti tessuti, che è stata confermata in un ampio dataset di eQTL retinici (GtExEye) dove l'allele T si associava a una maggiore espressione di PPARA (P 4x10-38). In linea con questo, i soggetti con un punteggio genetico più elevato per l'espressione di PPARA nella retina hanno avuto una migliore risposta al fenofibrato sulla progressione di DR (P = 0,008). Tra gli omozigoti T/T, il fenofibrato si associava ad un marcato aumento dei livelli di FGF21 (+0,87 SD aumento del valore log2 di FGF21; IC 95% 0,67-1,07, P=10x10-13), che a sua volta si associava a una riduzione del 45% rischio di grave riduzione del visus (HR per SD = 0,55; IC 95% 0,34-0,91, p=0,01) e che spiegava in large parte l'effetto del fenofibrato su questo outcome (90%, p=0,03). In conclusione questo studio ha permesso di identificare una variante comune di PPARA in grado di influenzare gli effetti cardiovascolari del fenofibrato e che potrebbe essere utilizzata per identificare i pazienti con T2D che trarrebbero un beneficio clinicamente rilevante anche senza dislipidemia aterogena. La stessa variante ha anche identificato soggetti con una migliore risposta al fenofibrato su DR. Inoltre, se da un lato il meccanismo alla base dell'effetto protettivo cardiovascolare è ancora da chiarire, questo studio mostra come l'efficacia sulla DR del fenofibrato sia mediata da un aumento dei livelli di FGF21, una citochina metabolica e antinfiammatoria che potrebbe rappresentare un nuovo bersaglio terapeutico per il trattamento della retinopatia diabetica.Background and aims: Fenofibrate has been shown to have a beneficial effect on cardiovascular and retinal complications of type 2 diabetes. However, for cardiovascular disease, the benefits of this treatment are limited to patients with atherogenic dyslipidemia, and for retinopathy, to those who already have this complication. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-alpha), could be used to improve the selection, and possibly increase the number of patients with type 2 diabetes who may derive a benefit from fenofibrate treatment. Methods and results: Among 3,065 self-reported White subjects treated with simvastatin and randomized to fenofibrate or placebo in the Action-to-Control-Cardiovascular-Risk-in-Diabetes (ACCORD) Lipid Trial, we identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide-significant influence on the effect of fenofibrate on major cardiovascular events (MACE). T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (HR=0.49; 95%C.I. 0.34-0.72) whereas no benefit was observed for other genotypes (p for interaction=3.7x10-4). The “rs6008845-by-fenofibrate” interaction on MACE was replicated in patients of African-Americans ancestry from ACCORD (N=585, p=0.02) and in external cohorts (ACCORD-Blood-Pressure, ORIGIN, and TRIUMPH, total N=3059, p=0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia and this was not explained by changes in plasma lipid profile. A similar and significant interaction was also found on progression of diabetic retinopathy among the 592 subjects with prior-history of diabetic retinopathy (DR) included in the ACCORD-Eye sub-study, with rs6008845 T/T homozygotes deriving a larger benefit from fenofibrate on DR progression (OR 0.10, 95% C.I. 0.02-0.74) than that observed in T/C and C/C genotypes (OR 0.47, 95% C.I. 0.17-0.29 and 0.54, 95% C.I. 0.21-1.42, respectively; p for interaction = 0.01). The same interaction was found for severe vision loss (evaluated in 3,650 subjects from the ACCORD-Lipid study, p for interaction=0.03). The regulatory role of rs6008845 was suggested by bioinformatic analyses and supported by the Genotype-Tissue Expression (GTEx) dataset revealing an association between rs6008845 and PPARA expression in many tissues, that was confirmed also in a large retina-eQTL dataset (GtExEye) showing that T allele was associated with higher PPARA expression in the retina (P 4x10-38). In line with this, subjects with higher genetic score for PPARA expression in the retina had better response to fenofibrate on DR progression (P=0.008). Among the T/T homozygotes, fenofibrate was associated with markedly increase in FGF21 levels (+0.87 S.D. increase in log2-value of FGF21; 95% C.I. 0.67-1.07, P=10x10-13), that was associated with a 45% lower risk of severe vision loss (per S.D. HR=0.55; 95%C.I. 0.34-0.91, p=0.01), and explained most of the effect of fenofibrate on this outcome (90%, p=0.03). Conclusions: We have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify T2D patients who would derive a clinically relevant benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia. The same variant also identified subjects with better response to fenofibrate on DR. Moreover, while the mechanism underlying the beneficial effect on CVD is still unclear, this study shows that the effectiveness on DR is mediated by an increase in FGF21 levels, a metabolic and anti-inflammatory cytokine that might represents a novel therapeutic target to treat diabetic eye diseases