Urine tricarboxylic acid cycle metabolites and risk of end stage kidney disease in patients with type 2 diabetes.

CONTEXT: Metabolites in tricarboxylic acid (TCA) pathway have pleiotropic functions. OBJECTIVE: To study the association between urine TCA cycle metabolites and the risk for chronic kidney disease (CKD) progression in individuals with type 2 diabetes. DESIGN, SETTING AND PARTICIPANTS: A prospective study in a discovery (n = 1826) and a validation (n = 1235) cohort of type 2 diabetes in a regional hospital and a primary care facility. EXPOSURE AND OUTCOME: Urine lactate, pyruvate, citrate, alpha-ketoglutarate, succinate, fumarate and malate were measured by mass spectrometry. CKD progression was defined as a composite of sustained eGFR below 15 ml/min/1.73 m2 , dialysis, renal death or doubling of serum creatinine. RESULTS: During a median of 9.2 (IQR 8.1-9.7) and 4.0 (3.2-5.1) years of follow-up, 213 and 107 renal events were identified. Cox regression suggested that urine lactate, fumarate and malate were associated with an increased risk (adjusted hazard ratio, aHR [95% CI] 1.63 [1.16-2.28], 1.82 [1.17-2.82] and 1.49 [1.05-2.11], per SD), while citrate was associated with a low risk (aHR 0.83 [0.72-0.96] per SD) for the renal outcome after adjustment for cardio-renal risk factors. These findings were reproducible in the validation cohort. Noteworthy, fumarate and citrate were independently associated with the renal outcome after additional adjustment for other metabolites. CONCLUSION: Urine fumarate and citrate predict the risk for progression to ESKD independent of clinical risk factors and other urine metabolites. These two metabolites in TCA cycle pathway may play important roles in the pathophysiological network underpinning progressive loss of kidney function in patients with type 2 diabetes.

Elevated remnant cholesterol and non-HDL cholesterol concentrations from real-world laboratory results: a cross-sectional study in Southeast Asians.

Introduction: Triglyceride-rich remnant lipoproteins (TRLs) are considered atherogenic due to the presence of remnant cholesterol, which is transported by apolipoprotein B. In clinical practice, the concentration of TRLs can be estimated by calculating remnant cholesterol or non-HDL cholesterol levels. Aim: This study aims to investigate the proportion of patients who have low LDL cholesterol (LDL-C) concentration but elevated remnant cholesterol concentration, stratified by the presence of hypertriglyceridaemia and ethnicity, using real-world hospital data. Our secondary aim is to investigate the proportion of patients with elevated non-HDL cholesterol levels using guideline-recommended goals. Methods: A 2-year retrospective study was conducted at a single centre, analyzing lipid blood tests of all patients, including directly measured LDL-C. Fasting for blood tests was not mandatory. Results: The study included a total of 21,605 consecutive patients with plasma lipid profiles analyzed in our hospital laboratory. The median age was 61 years. In patients with ASCVD (n = 14,704), 23.7% had an LDL-C level of <1.8 mmol/L, 11.3% had elevated remnant cholesterol concentrations at ≥0.65 mmol/L, and 48.8% were at the non-high-density lipoprotein cholesterol (non-HDL-C) goal (<2.6 mmol/L). Among patients diagnosed with atherosclerotic cardiovascular disease (ASCVD) with LDL-C levels of <1.8 mmol/L (n = 3,484), only 11.9% had high levels of remnant cholesterol, but 96% of the ASCVD patients also achieved the recommended non-HDL-C target of <2.6 mmol/L. When the LDL-C level was <1.8 mmol/L, the mean concentration of remnant cholesterol was 0.214 mmol/L when the triglyceride level was <1.7 mmol/L (n = 3,380), vs. 0.70 mmol/L when the triglyceride level was elevated (n = 724), p < 0.001. Among patients with a triglyceride level of ≥1.7 mmol/L and an LDL-C level of <.8 mmol/L, there were 254 patients with elevated remnant cholesterol concentration and 71 patients with suboptimal non-HDL levels. Malays had a higher mean remnant cholesterol concentration compared with both Chinese and Indians across all LDL-C levels, particularly in the presence of hypertriglyceridaemia. Conclusions: An elevated remnant cholesterol concentration of >0.65 mmol/L was present in 11% of all patients. The current guideline-recommended non-HDL-C goal, which uses a 0.8 mmol/L estimate of remnant cholesterol concentration, was achieved in >92% of patients, suggesting that it is unlikely to be clinically useful for the majority of our patient population except where there is concomitant hypertriglyceridaemia. Further studies are needed to establish the appropriate non-HDL-C goal or calculated remnant cholesterol concentration, paired with the LDL-C goal or otherwise, in a Southeast Asian population.

Association of Triglyceride Glucose Index with Prevalence and Incidence of Diabetic Retinopathy in a Singaporean Population.

Objective: To examine the association of triglyceride glucose (TyG) index (product of fasting triglyceride and glucose) with prevalence and incidence of diabetic retinopathy (DR) in type 2 diabetes. Methods: 1339 patients from an ongoing Singapore Study of Macro-angiopathy and Micro-Vascular Reactivity in Type 2 Diabetes (SMART2D) were included in this study. Fasting triglyceride and glucose levels were quantified and color fundus photographs were assessed for DR presence and severity. Logistic regression models were used to evaluate associations of TyG index with DR prevalence and incidence (median follow-up period = 3.2 years). Results: Mean TyG index was higher in patients with DR than no DR (9.24±0.7 versus 9.04± 0.6, p<0.001). TyG index was significantly associated with DR prevalence (OR=1.4, CI 1.1-1.7, p=0.002) and incidence (OR=1.8, CI 1.04-2.9, p=0.03), after adjusting for confounders. In a stratified analysis, the association between TyG index and DR prevalence reached significance only in the subgroup with HbA1c levels < 7.0% (OR=2, CI 1.1-3.8, p=0.03). TyG index significantly predicted DR prevalence and incidence with area under receiver operating curve as 0.77 (CI 0.74-0.80, p <0.001) and 0.66 (CI 0.57-0.76, p value <0.01), respectively. Conclusion: TyG index is a good predictor for DR prevalence and incidence. It can also be a secondary treatment target for patients with optimally controlled levels of HbA1c.

Diabetic foot in primary and tertiary (DEFINITE) Care: A health services innovation in coordination of diabetic foot ulcer (DFU) Care within a healthcare cluster - 18-month results from an observational population health cohort study.

Diabetic Foot in Primary and Tertiary (DEFINITE) Care is an inter-institutional and multi-disciplinary team (MDT) health systems innovation programme at a healthcare cluster in Singapore. We aim to achieve coordinated MDT care across primary and tertiary care for patients with diabetic foot ulcers (DFU), within our public healthcare cluster - an integrated network of seven primary care polyclinics and two acute care tertiary hospitals (1700-bed and 800-bed) with a total catchment population of 2.2 million residents. Results from prospective DEFINITE Care is referenced against a retrospective 2013-2017 cohort, which was previously published. Cardiovascular profile of the study population is compared against the same population's profile in the preceding 12 months. Between June 2020 and December 2021, there were 3475 unique patients with DFU with mean age at 65.9 years, 61.2% male, mean baseline HbA1c at 8.3% with mean diabetes duration at 13.3 years, mean diabetes complication severity index (DCSI) at 5.6 and mean Charlson Comorbidity Index (CCI) at 6.8. In the 12-months preceding enrolment to DEFINITE Care, 35.5% had surgical foot debridement, 21.2% had minor lower extremity amputation (LEA), 7.5% had major LEA whilst 16.8% had revascularisation procedures. At 18-months after the implementation of DEFINITE Care programme, the absolute minor and major amputation rates were 8.7% (n = 302) and 5.1% (n = 176), respectively, equating to a minor and major LEA per 100000 population at 13.7 and 8.0, respectively. This represents an 80% reduction in minor amputation rates (P < .001) and a 35% reduction in major amputation rates (P = .005) when referenced against a retrospective 2013-2017 cohort, which had minor and major LEA per 100000 population at 68.9 and 12.4, respectively. As compared to the preceding 12 months, there was also a significant improvement in cardiovascular profile (glycemic and lipid control) within the DEFINITE population, with improved mean HbAc1 (7.9% from 8.4%, P < .001), low-density lipoprotein (LDL) levels (2.1 mmol/L from 2.2, P < .001), total cholesterol (3.9 mmol/L from 4.1, P < .001) and triglycerides levels (1.6 mmol/L from 1.8, P = .002). Multivariate analysis revealed a history of minor amputation in the preceding 12 months to be an independent predictor for major and minor amputation within the study period of 18 months (Hazard Ratio 3.4 and 1.8, respectively, P < .001). In conclusion, within DEFINITE care, 18-month data showed a significant reduction of minor and major LEA rates, with improved medical optimisation and cardiovascular profile within the study population.

Urine Leucine-Rich α-2 Glycoprotein 1 (LRG1) Predicts the Risk of Progression to End-Stage Kidney Disease in Patients With Type 2 Diabetes.

OBJECTIVE: Leucine-rich α-2 glycoprotein 1 (LRG1) was recently identified as an amplifier of transforming growth factor-ß (TGF-ß)-induced kidney fibrosis in animal models. We aimed to study whether urine LRG1 is associated with risk of progression to end-stage kidney disease (ESKD) in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 1,837 participants with type 2 diabetes and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 were recruited from a regional hospital and a primary care facility. Association of urine LRG1 with risk of ESKD (progression to sustained eGFR <15 mL/min/1.73 m2, dialysis, or death resulting from renal causes) was assessed by survival analyses. RESULTS: During a median follow-up of 8.6 (interquartile range 5.8-9.6) years, 134 incident ESKD events were identified. Compared with those in the lowest tertile, participants with baseline urine LRG1 in the highest tertile had a 1.91-fold (95% CI 1.04-3.50) increased risk of progression to ESKD, after adjustment for cardiorenal risk factors, including eGFR and albuminuria. As a continuous variable, 1 SD increment in urine LRG1 was associated with a 1.53-fold (95% CI 1.19-1.98) adjusted risk of ESKD. Of note, the association of urine LRG1 with ESKD was independent of plasma LRG1. Moreover, urine LRG1 was associated with rapid kidney function decline and progression to macroalbuminuria, two common pathways leading to ESKD. CONCLUSIONS: Urine LRG1, a TGF-ß signaling modulator, predicts risk of progression to ESKD independently of clinical risk factors in patients with type 2 diabetes, suggesting that it may be a novel factor involved in the pathophysiological pathway leading to kidney disease progression.

Clinical variable-based cluster analysis identifies novel subgroups with a distinct genetic signature, lipidomic pattern and cardio-renal risks in Asian patients with recent-onset type 2 diabetes.

AIMS/HYPOTHESIS: We sought to subtype South East Asian patients with type 2 diabetes by de novo cluster analysis on clinical variables, and to determine whether the novel subgroups carry distinct genetic and lipidomic features as well as differential cardio-renal risks. METHODS: Analysis by k-means algorithm was performed in 687 participants with recent-onset diabetes in Singapore. Genetic risk for beta cell dysfunction was assessed by polygenic risk score. We used a discovery-validation approach for the lipidomics study. Risks for cardio-renal complications were studied by survival analysis. RESULTS: Cluster analysis identified three novel diabetic subgroups, i.e. mild obesity-related diabetes (MOD, 45%), mild age-related diabetes with insulin insufficiency (MARD-II, 36%) and severe insulin-resistant diabetes with relative insulin insufficiency (SIRD-RII, 19%). Compared with the MOD subgroup, MARD-II had a higher polygenic risk score for beta cell dysfunction. The SIRD-RII subgroup had higher levels of sphingolipids (ceramides and sphingomyelins) and glycerophospholipids (phosphatidylethanolamine and phosphatidylcholine), whereas the MARD-II subgroup had lower levels of sphingolipids and glycerophospholipids but higher levels of lysophosphatidylcholines. Over a median of 7.3 years follow-up, the SIRD-RII subgroup had the highest risks for incident heart failure and progressive kidney disease, while the MARD-II subgroup had moderately elevated risk for kidney disease progression. CONCLUSIONS/INTERPRETATION: Cluster analysis on clinical variables identified novel subgroups with distinct genetic, lipidomic signatures and varying cardio-renal risks in South East Asian participants with type 2 diabetes. Our study suggests that this easily actionable approach may be adapted in other ethnic populations to stratify the heterogeneous type 2 diabetes population for precision medicine.

Risk of Incident Heart Failure in Individuals With Early-Onset Type 2 Diabetes.

CONTEXT: Early-onset diabetes has been associated with unfavorable cardiovascular risk but data on heart failure (HF) in this subpopulation are scarce. OBJECTIVE: We aimed to study the risk of, and risk factors for, incident HF in individuals with early-onset type 2 diabetes. METHODS: We studied 606 individuals with type 2 diabetes diagnosed before 40 years of age (early-onset) and 1258 counterparts with diabetes diagnosed from 41 to 65 years of age (usual-onset) with no HF history, at a regional hospital, over a median follow-up period of 7.1 years. Incident HF by European Cardiology Society criteria was determined. RESULTS: A total of 62 and 108 HF events were identified in the early- and usual-onset groups (1.55 and 1.29 per 100 patient-years), respectively. Compared with usual-onset counterparts, individuals with early-onset diabetes had a 1.20-fold unadjusted (95% CI, 0.88-1.63; P = 0.26) and 1.91-fold age-adjusted (95% CI, 1.37-2.66; P < 0.001) hazard ratio (HR) for incident HF. Adjustment for traditional cardiometabolic risk factors only moderately mitigated the hazards (adjusted HR 1.69; 95% CI, 1.19-2.40; P = 0.003). However, additional adjustment for estimated glomerular filtration rate and albuminuria markedly attenuated the association of early-onset age with incident HF (adjusted HR 1.24; 95% CI, 0.87-1.77; P = 0.24). Notably, a long diabetes duration was not significantly associated with HF risk after accounting for kidney measures. CONCLUSION: Individuals with early-onset diabetes have at least the same absolute risk and a 2-fold age-adjusted relative risk for incident HF. Excess cardiorenal risk factors but not a long diabetes duration are main drivers for HF development in this diabetic population.

Association of Plasma Leucine-Rich Alpha-2 Glycoprotein 1 (LRG1) with All-Cause and Cause-Specific Mortality in Individuals with Type 2 Diabetes.

BACKGROUND: Leucine-rich alpha-2 glycoprotein 1 (LRG1) is a circulating protein in the transforming growth factor-beta superfamily. We sought to study whether LRG1 might predict risk for all-cause and cause-specific mortality in individuals with type 2 diabetes. METHODS: 2012 outpatients with type 2 diabetes were followed for a median of 7.2 years and 188 death events were identified. Association of LRG1 with risk for mortality was assessed by multivariable Cox regression models. RESULTS: Participants with a higher concentration of LRG1 had an increased risk for all-cause mortality [HR (95% CI), 1.76 (1.03-3.01), 1.75 (1.03-2.98), and 4.37 (2.72-7.02) for quartiles 2, 3, and 4, respectively, compared to quartile 1]. The association remained significant after adjustment for known cardio-renal risk factors including estimated glomerular filtration rate and albuminuria [adjusted HR 2.76 (1.66-4.59), quartile 4 versus 1]. As a continuous variable, a 1-SD increment in LRG1 was associated with 1.34 (1.14-1.57)-fold adjusted risk for all-cause mortality. High plasma LRG1 was independently associated with mortality attributable to cardiovascular disease, infection, and renal diseases. Adding LRG1 into a clinical variable-based model improved discrimination (c statistics from 0.828 to 0.842, P = 0.006) and reclassification (net reclassification improvement 0.47, 95% CI 0.28-0.67) for prediction of 5-year all-cause mortality. CONCLUSION: Plasma LRG1 predicts risk for all-cause mortality and mortality attributable to cardiovascular disease, infection, and renal disease independent of known cardio-renal risk factors. It may be a potential novel biomarker to improve risk stratification in individuals with type 2 diabetes.

Impact of COVID-19 and partial lockdown on access to care, self-management and psychological well-being among people with diabetes: A cross-sectional study.

BACKGROUND: The impact of lockdown measures can be widespread, affecting both clinical and psychosocial aspects of health. This study aims to assess changes in health services access, self-care, behavioural, and psychological impact of COVID-19 and partial lockdown amongst diabetes patients in Singapore. METHODS: We conducted a cross-sectional online survey amongst people with diabetes with the Diabetes Health Profile-18 (DHP-18). Hierarchical regression analyses were performed for each DHP-18 subscale (Psychological Distress, Disinhibited Eating and Barriers to Activity) as dependent variables in separate models. RESULTS: Among 301 respondents, 45.2% were women, 67.1% of Chinese ethnicity, 24.2% were aged 40 to 49 years, 68.4% have Type 2 diabetes and 42.2% on oral medications alone. During the pandemic and the lockdown, nearly all respondents were able to receive care safely from the clinics they attend (94%) and obtain their medications and diabetes equipment and supplies (97%) when needed. Respondents reported less frequent engagement in physical activity (38%), checking of blood pressure (29%) and blood glucose (22%). Previous diagnosis of mental health conditions (ß = 9.33, P = .043), Type 1 diabetes (ß = 12.92, P = .023), number of diabetes-related comorbidities (ß = 3.16, P = .007) and Indian ethnicity (ß = 6.65, P = .034) were associated with higher psychological distress. Comorbidities were associated with higher disinhibited eating (ß = 2.49, P = .014) while ability to reach their doctor despite not going to the clinic is negatively associated with psychological distress (ß = -9.50 P = .002) and barriers to activity (ß = -7.53, P = .007). CONCLUSION: Health services access were minimally affected, but COVID-19 and lockdown had mixed impacts on self-care and management behaviours. Greater clinical care and attention should be provided to people with diabetes with multiple comorbidities and previous mental health disorders during the pandemic and lockdown.

Association of Plasma Leucine-Rich α-2 Glycoprotein 1, a Modulator of Transforming Growth Factor-ß Signaling Pathway, With Incident Heart Failure in Individuals With Type 2 Diabetes.

OBJECTIVE: Leucine-rich α-2 glycoprotein 1 (LRG1) is a circulating protein potentially involved in several pathways related to pathogenesis of heart failure (HF). We aimed to study whether plasma LRG1 is associated with risks of incident HF and hospitalization attributable to HF (HHF) in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 1,978 individuals with type 2 diabetes were followed for a median of 7.1 years (interquartile range 6.1-7.6). Association of LRG1 with HF was studied using cause-specific Cox regression models. RESULTS: In follow-up, 191 incident HF and 119 HHF events were identified. As compared with quartile 1, participants with LRG1 in quartiles 3 and 4 had 3.60-fold (95% CI 1.63-7.99) and 5.99-fold (95% CI 2.21-16.20) increased risk of incident HF and 5.88-fold (95% CI 1.83-18.85) and 10.44-fold (95% CI 2.37-45.98) increased risk of HHF, respectively, after adjustment for multiple known cardiorenal risk factors. As a continuous variable, 1 SD increment in natural log-transformed LRG1 was associated with 1.78-fold (95% CI 1.33-2.38) adjusted risk of incident HF and 1.92-fold (95% CI 1.27-2.92) adjusted risk of HHF. Adding LRG1 to the clinical variable-based model improved risk discrimination for incident HF (area under the curve [AUC] 0.79-0.81; P = 0.02) and HHF (AUC 0.81-0.84; P = 0.02). CONCLUSIONS: Plasma LRG1 is associated with risks of incident HF and HHF, suggesting that it may potentially be involved in pathogenesis of HF in individuals with type 2 diabetes. Additional studies are warranted to determine whether LRG1 is a novel biomarker for HF risk stratification.

Medical Costs Associated with Severity of Chronic Kidney Disease in Type 2 Diabetes Mellitus in Singapore.

INTRODUCTION: This was a retrospective cross-sectional study to assess the impact of chronic kidney disease (CKD) and its severity in Type 2 diabetes mellitus (T2DM) on direct medical costs, and the effects of economic burden on CKD related complications in T2DM in Singapore. METHODS: A total of 1,275 T2DM patients were recruited by the diabetes centre at Khoo Teck Puat Hospital from 2011-2014. CKD stages were classified based on improving global outcome (KDIGO) categories, namely the estimated glomerular filtration rate (eGFR) and albuminuria kidney disease. Medical costs were extracted from the hospital administrative database. RESULTS: CKD occurred in 57.3% of patients. The total mean cost ratio for CKD relative to non-CKD was 2.2 (P<0.001). Mean (median) baseline annual unadjusted costs were significantly higher with increasing CKD severity-S$1,523 (S$949), S$2,065 (S$1,198), S$3,502 (S$1,613), and S$5,328 (S$2,556) for low, moderate, high, and very high risk respectively (P<0.001). CKD (P<0.001), age at study entry (P=0.001), Malay ethnicity (P=0.035), duration of diabetes mellitus (DM; P<0.001), use of statins/fibrates (P=0.021), and modified Diabetes Complications Severity Index (DCSI) (P<0.001) were positively associated with mean annual direct medical costs in the univariate analysis. In the fully adjusted model, association with mean annual total costs persisted for CKD, CKD severity and modified DCSI. CONCLUSION: The presence and increased severity of CKD is significantly associated with higher direct medical costs in T2DM patients. Actively preventing the occurrence and progression in DM-induced CKD may significantly reduce healthcare resource consumption and healthcare costs.

Fall Risk and Balance Confidence in Patients With Diabetic Peripheral Neuropathy: An Observational Study.

Objective: Individuals with diabetic peripheral neuropathy (DPN) have functional deficits that increase their risk of falling. However, psychological aspects such as loss of confidence in undertaking activities could also contribute to this risk. We examined correlations between balance confidence and fall risk among individuals with DPN. Methods: This was a cross-sectional study of 146 individuals with DPN. Elevated fall risk was determined by timed up-and-go test with standard cut-off time of 13.5 seconds, and balance confidence was measured by 16-item Activities Specific Balance Confidence scale. Functional parameters assessed included functional reach, body sway velocity during quiet standing and muscle strength at ankle and toe. Results: Twenty percent of the DPN patients were at increased risk of falls. Every unit increase in balance confidence was associated with 9% (95% confidence interval: 0.88, 0.95; p<0.001) reduced odds of falling, after adjusting for socio-demographic, health and functional characteristics. No other functional parameters had significant associations with fall risk in adjusted analyses. Conclusions: Psychological factors like balance confidence appear to be more important for fall risk among DPN patients, compared to objective functional performance. Interventions targeting balance confidence may be beneficial in reducing the risk of falls in this population.

A Multifunctional Role of Leucine-Rich α-2-Glycoprotein 1 in Cutaneous Wound Healing Under Normal and Diabetic Conditions.

Delayed wound healing is commonly associated with diabetes. It may lead to amputation and death if not treated in a timely fashion. Limited treatments are available partially due to the poor understanding of the complex disease pathophysiology. Here, we investigated the role of leucine-rich α-2-glycoprotein 1 (LRG1) in normal and diabetic wound healing. First, our data showed that LRG1 was significantly increased at the inflammation stage of murine wound healing, and bone marrow-derived cells served as a major source of LRG1. LRG1 deletion causes impaired immune cell infiltration, reepithelialization, and angiogenesis. As a consequence, there is a significant delay in wound closure. On the other hand, LRG1 was markedly induced in diabetic wounds in both humans and mice. LRG1-deficient mice were resistant to diabetes-induced delay in wound repair. We further demonstrated that this could be explained by the mitigation of increased neutrophil extracellular traps (NETs) in diabetic wounds. Mechanistically, LRG1 mediates NETosis in an Akt-dependent manner through TGFß type I receptor kinase ALK5. Taken together, our studies demonstrated that LRG1 derived from bone marrow cells is required for normal wound healing, revealing a physiological role for this glycoprotein, but that excess LRG1 expression in diabetes is pathogenic and contributes to chronic wound formation.

Successful pharmacological management of a child with compound heterozygous familial hypercholesterolemia and review of the recent literature.

Severe familial hypercholesterolemia (SFH) is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) and severe early-onset cardiovascular disease if left untreated. We report on the decade-long therapeutic journey of a 15-year-old boy with SFH due to a severe compound heterozygous genotype. He presented at the age of 5 years with widespread xanthomas and LDL-C of 17.4 mmol/L. He was diagnosed with SFH, initially treated with colestyramine that was subsequently combined with simvastatin. At the age of 12 years, he was diagnosed to have supravalvular aortic stenosis and ezetimibe/atorvastatin was introduced in place of colestyramine/simvastatin. At the age of 14 years, he received triple therapy with evolocumab, initially at the recommended dose of 420 mg monthly and then reduced to 140 mg biweekly. Currently at the age of 15 years, he is on atorvastatin 40 mg ON, ezetimibe 10 mg OM, and evolocumab 140 mg biweekly, achieving LDL-C levels of 2.4 mmol/L. Genetic testing identified compound heterozygous mutations in the LDL receptor genes [c.(940 + 1_941-1) (1845 + 1_1846-1)dup] and exon 12, nucleotide c.1747 C > T, amino acid p.(His583Tyr). Medical management without lipoprotein apheresis can achieve target LDL-C in children with SFH. Our patient, who developed supravalvular aortic stenosis at the age of 12 years, needed early aggressive treatment when SFH guidelines and newer drugs for young children were unavailable. Our patient demonstrated that 140 mg biweekly of evolocumab has the same cholesterol-lowering effect as the recommended 420 mg monthly dose.

Aortic pulse wave velocity, central pulse pressure, augmentation index and chronic kidney disease progression in individuals with type 2 diabetes: a 3- year prospective study.

BACKGROUND: Pulse wave velocity (PWV), central pulse pressure and augmentation index are arterial stiffness- related hemodynamic parameters but their associations with renal outcome are still controversial. We hereby aim to study, 1) which hemodynamic parameter is independently associated with progressive chronic kidney disease (CKD), 2) the association of 3-year change in PWV with CKD progression and, 3) the additive predictive value of PWV for progressive CKD. METHODS: Carotid- femoral PWV, central pulse pressure and augmentation index were measured in 1444 participants with type 2 diabetes at baseline and 3 years apart. Progressive CKD was defined as confirmed eGFR decline 40% or greater. RESULTS: In the follow-up, 102 participants experienced progressive CKD. All 3 hemodynamic parameters were significantly associated with progressive CKD In univariable analysis. However, only PWV remained statistically significant after adjustment for known clinical risk factors and the other 2 hemodynamic parameters (OR 1.14 [95% CI 1.01-1.29] per m/s increment). One m/s regression (decrement) in PWV in the 3-year follow-up was associated with 26% lower adjusted- risk of progressive CKD (OR 0.74, 95% CI 0.56-0.97). Adding PWV onto traditional risk factor- based model significantly improved classification (net reclassification improvement 0.25, 95% CI 0.05-0.45, P = 0.01) and positive prediction rate (24.5 to 32.3%). CONCLUSIONS: Of 3 arterial stiffness- related hemodynamic parameters, only PWV is independently associated with progressive CKD. PWV may be a potential intervention target to mitigate risk of CKD progression and also a biomarker to improve risk-stratification of adverse renal outcome in individuals with type 2 diabetes.

Endothelin-1 predicts incident diabetic peripheral neuropathy in Type 2 Diabetes: a cohort study.

INTRODUCTION: Diabetic peripheral neuropathy (DPN) is a common microvascular complication in patients with type 2 diabetes (T2D). Apart from hyperglycemia, few modifiable risk factors have been identified. Endothelin-1 is a potent vasoconstrictor peptide, implicated in the causal pathway of microangiopathy. We investigated whether baseline plasma endothelin-1 and other metabolic and vascular risk factors predicted the incidence of DPN. DESIGN: This is a 3-year observational, cohort study. METHODS: In patients with T2D (n = 2057), anthropometric data, fasting blood, and urine were collected for biochemistry and urine albumin/creatinine measurements. Forearm cutaneous endothelial reactivity was assessed by iontophoresis and laser Doppler flowmetry/imaging. Measurements were repeated on follow-up. Incident DPN was considered present if an abnormal finding in monofilament (<8 of 10 points) or neurothesiometer testing was ≥25 volts on either foot at 3-year follow-up, but normal at baseline. Plasma endothelin-1 was assessed by ELISA. RESULTS: At baseline, mean age of patients was 57.4 ± 10.8 years old and prevalence of DPN was 10.8%. Of the 1767 patients without DPN, 1250 patients returned for follow-up assessment ((2.9 ± 0.7) years), with a 10.7% incidence of DPN. Patients with incident DPN had significantly higher baseline endothelin-1 (1.43 (1.19-1.73) vs 1.30 (1.06-1.63)) pg/mL, P < 0.0001. Multivariable Cox proportional hazards ratio showed a 1-s.d. increase in log endothelin-1 (adjusted HR: 4.345 (1.451-13.009), P = 0.009), systolic blood pressure (per 10-unit) (adjusted HR: 1.107 (1.001-1.223), P = 0.047) and diabetes duration (adjusted HR: 1.025 (1.004-1.047), P = 0.017) predicted incident DPN, after adjustment for glycemic control, eGFR, albuminuria, peripheral arterial disease and retinopathy status. CONCLUSION: Higher baseline endothelin-1, blood pressure and diabetes duration were significant and independent predictors for incident DPN. Validation of our findings in independent cohorts and molecular mechanistic studies will help better our understanding on the role of endothelin-1 in DPN.

Association of traditional and novel measures of central obesity with cognitive performance in older multi-ethnic Asians with type 2 diabetes.

Literature evaluating the relationship between central obesity and cognitive deficits in type 2 diabetes (T2DM) remains scarce. This cross-sectional analysis explored the association of novel and traditional central obesity measures with cognitive performance in older (aged ≥60 years) non-demented multi-ethnic Asians with T2DM, including a stratified analysis by body mass index (BMI). Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status. Central obesity measures including visceral fat area (VFA), waist circumference, waist:hip ratio, waist:height ratio, abdominal volume index, body roundness index and conicity index were measured and/or computed. In our cohort (N = 677; mean age = 67 ± 5 years, 51.7% men), VFA emerged as an associate of overall cognitive performance after covariate adjustment and Bonferroni correction (ß = -.10, 95% CI = -0.18, -0.03), outperforming the other adiposity indices. Specifically, VFA was inversely associated with delayed memory and language scores. Additionally, compared with normal-weight individuals, excess visceral obesity (VFA ≥100 cm2 ) was independently associated with lower cognitive scores to a greater extent in normal BMI (<23 kg/m2 ) adults than in those with high BMI (≥23 kg/m2 ). Assessment and management of visceral adiposity may help to prevent cognitive decline in older people with T2DM, and reduce the global burden of dementia in ageing populations.

Risk of progressive chronic kidney disease in individuals with early-onset type 2 diabetes: a prospective cohort study.

BACKGROUND: The progression trajectory of renal filtration function has not been well characterized in patients with early-onset type 2 diabetes mellitus (T2DM) although albuminuria is often reported in this population. We aim to study the risk of progressive chronic kidney disease (CKD) in individuals with early-onset T2DM. METHODS: In total, 1189 T2DM participants were followed for 3.9 (interquartile range 3.2-4.7) years. Progressive CKD was defined as estimated glomerular filtration rate (eGFR) decline of ≥5 mL/min/1.73 m2 per year. Early-onset T2DM was defined as age at T2DM diagnosis between 18 and 30 years. RESULTS: Compared with later-onset counterparts (N = 1032), participants with early-onset T2DM (N = 157) were more obese and had poorer glycaemic control at baseline. In the follow-up, 24.2% and 15.6% experienced progressive CKD in early-onset and later-onset participants, respectively (P = 0.007). Logistic regression suggested that participants with early-onset T2DM had 2.63-fold [95% confidence interval (CI) 1.46-4.75] higher risk of progressive CKD after accounting for multiple traditional risk factors. Furthermore, the excess risk of progressive CKD associated with early-onset T2DM mainly occurred in participants with preserved renal function [eGFR ≥60 mL/min/1.73 m2, odds ratio (OR) 2.85, 95% CI 1.50-5.42] and was more pronounced in those with diabetes duration <10 years (OR 3.67, 95% CI 1.51-8.90). CONCLUSIONS: Individuals with early-onset T2DM have a higher risk of progressive CKD. The excess risk mainly exhibits in early stage of CKD and cannot be solely attributed to traditional risk factors and a longer diabetes duration.

Arterial Stiffness Modulates the Association of Resting Heart Rate With Rapid Renal Function Decline in Individuals With Type 2 Diabetes Mellitus.

OBJECTIVE: Resting heart rate (RHR) has been associated with cardiovascular risk, but data on renal outcomes are still scarce. We aimed to study the association of RHR with rapid renal function decline (RRFD) and to explore whether the association of RHR with RRFD is modulated by arterial stiffness in individuals with type 2 diabetes mellitus. Approach and Results: One thousand one hundred forty-two Asian people with type 2 diabetes mellitus were followed for 3.9±0.9 years in a regional hospital and a primary care facility. RRFD was defined as eGFR decline of 5 mL/min per 1.73 m2 or greater per year. Arterial stiffness was assessed by carotid-femoral pulse wave velocity. One hundred sixty-eight participants (15%) were classified as having RRFD. Participants with elevated RHR were younger, had higher levels of HbA1c, albuminuria, C-reactive protein, and pulse wave velocity. Compared with the lowest quartile, participants in quartile 4 had a higher risk for RRFD after adjustment for known risk factors (adjusted odds ratio 1.91 [1.11-3.28]). RHR improved discrimination and net reclassification for prediction of RRFD above traditional risk factors. Remarkably, arterial stiffness modulated the association of RHR with RRFD (P for interaction =0.03). RHR was significantly associated with risk of RRFD only in those with increased arterial stiffness (pulse wave velocity above age-reference value 7.7 m/s). CONCLUSIONS: RHR independently predicts RRFD, and the association is modulated by arterial stiffness. An elevated heart rate may be one factor in the spectrum of cardiovascular risk factors associated with renal functional impairment, especially in those with type 2 diabetes mellitus and an increased arterial stiffness.