Lessons from PROMINENT and prospects for pemafibrate.

The neutral result of the PROMINENT trial has led to questions about the future for pemafibrate. This commentary discusses possible reasons for the lack of benefit observed in the trial. There were, however, indicators suggesting therapeutic potential in microvascular ischaemic complications associated with peripheral artery disease, with subsequent analysis showing reduction in the incidence of lower extremity ischaemic ulceration or gangrene. Reassurance about the safety of pemafibrate, together with emerging data from PROMINENT and experimental studies, also suggest benefit with pemafibrate in non-alcoholic fatty liver disease (alternatively referred to as metabolic dysfunction-associated steatotic liver disease) and microangiopathy associated with diabetes, which merit further study.

Maternal mortality in Eastern Democratic Republic of Congo: a 10-year multi-zonal institutional death review.

BACKGROUND: Maternal mortality (MM) remains a real scourge that hits hardest in the poorest regions of the world, particularly those affected by conflict. However, despite this worrying reality, few studies have been conducted about MM ratio in the Democratic Republic of Congo (DRC). The study aimed to describe the trends as well as the epidemiological profile and causes of reported institutional maternal deaths between 2013 and 2022 in Eastern DRC. METHODS: A retrospective descriptive study was conducted between March 2023 and August 2023 in eight Health Zones (HZ), five in South Kivu Province (Mwana, Minova, Miti-Murhesa, Kamituga and Idjwi) and three in North Kivu Province (Kirotshe, Karisimbi and Kayna) in the eastern region of the DRC. Our study covers 242 health facilities: 168 health centers (HC), 16 referral health centers (RHCs),50 referral hospitals (RH) and 8 general referral hospitals (GRHs). Data from registers and medical records of maternal deaths recorded in these zones from 2013-2022 were extracted along with information on the number of deliveries and live births. Sociodemographic, clinical parameters, blood and ultrasound tests and suspected causes of death between provinces were assessed. RESULTS: In total, we obtained 177 files on deceased women. Of these, 143 (80.8%) were retained for the present study, including 75 in the 3 HZs of North Kivu and 68 in the 5 HZs of South Kivu. From 2013 to 2022, study sites experienced two significant drops in maternal mortality ratio (MMR) (in 2015 and 2018), and a spike in 2016-2017. Nonetheless, the combined MMR (across study sites) started and ended the 10-year study period at approximately the same level (53 and 57 deaths per 100,000 live births in 2013 and 2022 respectively). Overall, 62,6% of the deaths were reported from secondary hospital. Most deaths were of married women in their thirties (93.5%). Almost half (47.8%) had not completed four antenatal consultations. The main direct causes of death were, in decreasing order of frequency: post-partum haemorrhage (55.2%), uterine rupture (14.0), hypertensive disorders (8.4%), abortion (7.7%) puerperal infections (2.8%) and placental abruption (0.7%). When comparing among provinces, reported abortion-related maternal mortality (14.1% vs 0%) was more frequent in North Kivu than in South Kivu. CONCLUSION: This study imperatively highlights the need for targeted interventions to reduce maternal mortality. By emphasizing the crucial importance of antenatal consultations, intrapartum/immediate post-partum care and quality of care, significant progress can be made in guaranteeing maternal health and reducing many avoidable deaths.

Population health management in Belgium: a call-to-action and case study.

BACKGROUND: Although there are already success stories, population health management in Belgium is still in its infancy. A health system transformation approach such as population health management may be suited to address the public health issue of atherosclerotic cardiovascular disease, as this is one of the main causes of mortality in Belgium. This article aims to raise awareness about population health management in Belgium by: (a) eliciting barriers and recommendations for its implementation as perceived by local stakeholders; (b) developing a population health management approach to secondary prevention of atherosclerotic cardiovascular disease; and (c) providing a roadmap to introduce population health management in Belgium. METHODS: Two virtual focus group discussions were organized with 11 high-level decision makers in medicine, policy and science between October and December 2021. A semi-structured guide based on a literature review was used to anchor discussions. These qualitative data were studied by means of an inductive thematic analysis. RESULTS: Seven inter-related barriers and recommendations towards the development of population health management in Belgium were identified. These related to responsibilities of different layers of government, shared responsibility for the health of the population, a learning health system, payment models, data and knowledge infrastructure, collaborative relationships and community involvement. The introduction of a population health management approach to secondary prevention of atherosclerotic cardiovascular disease may act as a proof-of-concept with a view to roll out population health management in Belgium. CONCLUSIONS: There is a need to instill a sense of urgency among all stakeholders to develop a joint population-oriented vision in Belgium. This call-to-action requires the support and active involvement of all Belgian stakeholders, both at the national and regional level.

Dysosmobacter welbionis is a newly isolated human commensal bacterium preventing diet-induced obesity and metabolic disorders in mice.

OBJECTIVE: To investigate the abundance and the prevalence of Dysosmobacter welbionis J115T, a novel butyrate-producing bacterium isolated from the human gut both in the general population and in subjects with metabolic syndrome. To study the impact of this bacterium on host metabolism using diet-induced obese and diabetic mice. DESIGN: We analysed the presence and abundance of the bacterium in 11 984 subjects using four human cohorts (ie, Human Microbiome Project, American Gut Project, Flemish Gut Flora Project and Microbes4U). Then, we tested the effects of daily oral gavages with live D. welbionis J115T on metabolism and several hallmarks of obesity, diabetes, inflammation and lipid metabolism in obese/diabetic mice. RESULTS: This newly identified bacterium was detected in 62.7%-69.8% of the healthy population. Strikingly, in obese humans with a metabolic syndrome, the abundance of Dysosmobacter genus correlates negatively with body mass index, fasting glucose and glycated haemoglobin. In mice, supplementation with live D. welbionis J115T, but not with the pasteurised bacteria, partially counteracted diet-induced obesity development, fat mass gain, insulin resistance and white adipose tissue hypertrophy and inflammation. In addition, live D. welbionis J115T administration protected the mice from brown adipose tissue inflammation in association with increased mitochondria number and non-shivering thermogenesis. These effects occurred with minor impact on the mouse intestinal microbiota composition. CONCLUSIONS: These results suggest that D. welbionis J115T directly and beneficially influences host metabolism and is a strong candidate for the development of next-generation beneficial bacteria targeting obesity and associated metabolic diseases.

Prioritizing Pregnant Women for Coronavirus Disease 2019 Vaccination in African Countries.

Coronavirus disease 2019 (COVID-19) in pregnancy is associated with excess maternal and infant morbidity and mortality in both African and higher-resource settings. Furthermore, mounting evidence demonstrates the safety and efficacy of COVID-19 vaccination for pregnant women and infants. However, national guidelines in many African countries are equivocal or lack recommendations on COVID-19 vaccine in pregnancy. We summarize key data on COVID-19 epidemiology and vaccination among pregnant African women to highlight major barriers to vaccination and recommend 4 interventions. First, policymakers should prioritize pregnant women for COVID-19 vaccination, with a target of 100% coverage. Second, empirically supported public health campaigns should be sustainably implemented to inform and support pregnant women and their healthcare providers in overcoming vaccine hesitancy. Third, COVID-19 vaccination for pregnant women should be expanded to include antenatal care, obstetrics/gynecology, and targeted mass vaccination campaigns. Fourth, national monitoring and evaluation of COVID-19 vaccine uptake, safety, surveillance, and prospective outcomes assessment should be conducted.

Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Pregnancy in Sub-Saharan Africa: A 6-Country Retrospective Cohort Analysis.

BACKGROUND: Few data are available on COVID-19 outcomes among pregnant women in sub-Saharan Africa (SSA), where high-risk comorbidities are prevalent. We investigated the impact of pregnancy on SARS-CoV-2 infection and of SARS-CoV-2 infection on pregnancy to generate evidence for health policy and clinical practice. METHODS: We conducted a 6-country retrospective cohort study among hospitalized women of childbearing age between 1 March 2020 and 31 March 2021. Exposures were (1) pregnancy and (2) a positive SARS-CoV-2 RT-PCR test. The primary outcome for both analyses was intensive care unit (ICU) admission. Secondary outcomes included supplemental oxygen requirement, mechanical ventilation, adverse birth outcomes, and in-hospital mortality. We used log-binomial regression to estimate the effect between pregnancy and SARS-CoV-2 infection. Factors associated with mortality were evaluated using competing-risk proportional subdistribution hazards models. RESULTS: Our analyses included 1315 hospitalized women: 510 pregnant women with SARS-CoV-2, 403 nonpregnant women with SARS-CoV-2, and 402 pregnant women without SARS-CoV-2 infection. Among women with SARS-CoV-2 infection, pregnancy was associated with increased risk for ICU admission (adjusted risk ratio [aRR]: 2.38; 95% CI: 1.42-4.01), oxygen supplementation (aRR: 1.86; 95% CI: 1.44-2.42), and hazard of in-hospital death (adjusted sub-hazard ratio [aSHR]: 2.00; 95% CI: 1.08-3.70). Among pregnant women, SARS-CoV-2 infection increased the risk of ICU admission (aRR: 2.0; 95% CI: 1.20-3.35), oxygen supplementation (aRR: 1.57; 95% CI: 1.17-2.11), and hazard of in-hospital death (aSHR: 5.03; 95% CI: 1.79-14.13). CONCLUSIONS: Among hospitalized women in SSA, both SARS-CoV-2 infection and pregnancy independently increased risks of ICU admission, oxygen supplementation, and death. These data support international recommendations to prioritize COVID-19 vaccination among pregnant women.

Evaluation of continuous glucose monitoring-derived person-specific HbA1c in the presence and absence of complications in type 1 diabetes.

AIM: To evaluate the accuracy of a novel kinetic model at predicting HbA1c in a real-world setting and to understand and explore the role of diabetes complications in altering the glucose-HbA1c relationship and the mechanisms involved. MATERIALS AND METHODS: Deidentified HbA1c and continuous glucose monitoring values were collected from 93 individuals with type 1 diabetes. Person-specific kinetic variables were used, including red blood cell (RBC) glucose uptake and lifespan, to characterize the relationship between glucose levels and HbA1c. The resulting calculated HbA1c (cHbA1c) was compared with glucose management indicator (GMI) for prospective agreement with laboratory HbA1c. RESULTS: The cohort (42 men and 51 women) had a median age (IQR) of 61 (43, 72) years and a diabetes duration of 21 (10, 33) years. A total of 24 459 days of continuous glucose monitoring (CGM) data were available and 357 laboratory HbA1c were used to assess the average glucose-HbA1c relationship. cHbA1c had a superior correlation with laboratory HbA1c compared with GMI with a mean absolute deviation of 1.7 and 6.7 mmol/mol, r2  = 0.85 and 0.44, respectively. The fraction within 10% of absolute relative deviation from laboratory HbA1c was 93% for cHbA1c and 63% for GMI. Macrovascular disease had no effect on the model's accuracy, whereas microvascular complications resulted in a trend towards higher HbA1c, secondary to increased RBC glucose uptake. CONCLUSIONS: cHbA1c, which takes into account RBC glucose uptake and lifespan, accurately reflects laboratory HbA1c in a real-world setting and can aid in the management of individuals with diabetes.

The Critical Need for Pooled Data on Coronavirus Disease 2019 in African Children: An AFREhealth Call for Action Through Multicountry Research Collaboration.

Globally, there are prevailing knowledge gaps in the epidemiology, clinical manifestations, and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among children and adolescents; and these gaps are especially wide in African countries. The availability of robust age-disaggregated data is a critical first step in improving knowledge on disease burden and manifestations of coronavirus disease 2019 (COVID-19) among children. Furthermore, it is essential to improve understanding of SARS-CoV-2 interactions with comorbidities and coinfections such as human immunodeficiency virus (HIV), tuberculosis, malaria, sickle cell disease, and malnutrition, which are highly prevalent among children in sub-Saharan Africa. The African Forum for Research and Education in Health (AFREhealth) COVID-19 Research Collaboration on Children and Adolescents is conducting studies across Western, Central, Eastern, and Southern Africa to address existing knowledge gaps. This consortium is expected to generate key evidence to inform clinical practice and public health policy-making for COVID-19 while concurrently addressing other major diseases affecting children in African countries.

Selective Peroxisome Proliferator-Activated Receptor Alpha Modulators (SPPARMα) in the Metabolic Syndrome: Is Pemafibrate Light at the End of the Tunnel?

PURPOSE OF REVIEW: Adoption of poor lifestyles (inactivity and energy-dense diets) has driven the worldwide increase in the metabolic syndrome, type 2 diabetes mellitus and non-alcoholic steatohepatitis (NASH). Of the defining features of the metabolic syndrome, an atherogenic dyslipidaemia characterised by elevated triglycerides (TG) and low plasma concentration of high-density lipoprotein cholesterol is a major driver of risk for atherosclerotic cardiovascular disease. Beyond lifestyle intervention and statins, targeting the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) is a therapeutic option. However, current PPARα agonists (fibrates) have limitations, including safety issues and the lack of definitive evidence for cardiovascular benefit. Modulating the ligand structure to enhance binding at the PPARα receptor, with the aim of maximising beneficial effects and minimising adverse effects, underlies the SPPARMα concept. RECENT FINDINGS: This review discusses the history of SPPARM development, latterly focusing on evidence for the first licensed SPPARMα, pemafibrate. Evidence from animal models of hypertriglyceridaemia or NASH, as well as clinical trials in patients with atherogenic dyslipidaemia, are overviewed. The available data set the scene for therapeutic application of SPPARMα in the metabolic syndrome, and possibly, NASH. The outstanding question, which has so far eluded fibrates in the setting of current evidence-based therapy including statins, is whether treatment with pemafibrate significantly reduces cardiovascular events in patients with atherogenic dyslipidaemia. The PROMINENT study in patients with type 2 diabetes mellitus and this dyslipidaemia is critical to evaluating this.

Impact of rural versus urban setting on kidney markers: a cross-sectional study in South-Kivu, DRCongo.

BACKGROUND: Most studies of chronic kidney disease (CKD) in Sub-Saharan Africa (SSA) have been conducted in urban settings. They relied on GFR estimated from serum creatinine alone and on the inexpensive, convenient urinary dipstick to assess proteinuria. The dipstick for proteinuria has not been directly compared with the gold standard albumin-to-creatinine ratio (ACR) in a large-sized study in SSA. We hereby assessed the influence of rural versus urban location on the level, interpretation, and diagnostic performance of proteinuria dipstick versus ACR. METHODS: In a cross-sectional population-based study of CKD in both urban (n = 587) and rural (n = 730) settings in South-Kivu, Democratic Republic of Congo (DRC), we assessed the prevalence, performance (sensitivity, specificity, positive predictive value and negative predictive value) and determinants of a positive dipstick proteinuria as compared with albuminuria (ACR). Albuminuria was subdivided into: A1 (< 30 mg/g creatinine), A2 (30 to 299 mg/g creatinine) and A3 (≥ 300 mg/g creatinine). RESULTS: The overall prevalence of positive dipstick proteinuria (≥ 1+) was 9.6 % (95 % CI, 7.9-11.3) and was higher in rural than in urban residents (13.1 % vs. 4.8 %, p < 0.001), whereas the prevalence of albuminuria (A2 or A3) was similar in both sites (6 % rural vs. 7.6 % urban, p = 0.31). In both sites, dipstick proteinuria ≥ 1 + had a poor sensitivity (< 50 %) and positive predictive value (< 11 %) for the detection of A2 or A3. The negative predictive value was 95 %. Diabetes [aOR 6.12 (1.52-24.53)] was a significant predictor of A3 whereas alkaline [aOR 7.45 (3.28-16.93)] and diluted urine [aOR 2.19 (1.35-3.57)] were the main predictors of positive dipstick proteinuria. CONCLUSIONS: ACR and dipstick proteinuria have similar positivity rates in the urban site whereas, in the rural site, dipstick was 2-fold more often positive than ACR. The poor sensitivity and positive predictive value of the dipstick as compared with ACR makes it unattractive as a screening tool in community studies of CKD in SSA.

Association between severe acute malnutrition during childhood and blood pressure during adulthood in the eastern Democratic Republic of the Congo: the Lwiro cohort study.

INTRODUCTION: Little is known about the long-term outcomes of Severe Acute Malnutrition (SAM) during childhood. As such, this study aims to explore the association between childhood SAM and blood pressure (BP) in adulthood in a context without nutrition transition. METHODOLOGY: We identified 524 adults (Median age: 22 years) who were treated for SAM during childhood in Eastern DRC between 1988 and 2007. They were compared with 407 age-and-sex matched subjects with no history of SAM in the community. The variables examined for this study were the systolic (SBP), diastolic (DBP), mean (MBP) blood pressure (BP) and pulse pressure (PP), as well as high blood pressure (HBP) defined as BP ≥ 140/90 mmHg and/or use of BP-lowering drug(s) in adulthood. For comparison, linear and logistic regression models were used for analysing continuous and dichotomous variables, respectively. RESULTS: Of the 524 exposed located, 145 were selected according to age. A total of 97 unexposed were recruited. Compared to unexposed, exposed had slightly higher SBP and PP after adjusting for occupation, body mass index (BMI) and food consumption [SBP = 1.4 mmHg (- 2.2, 4.8) and PP = 2.6 mmHg (- 0.3, 6.0)]. However, their DBP was lower than that of the unexposed [- 1.6 mmHg (- 4.6, 1.5)]. MBP and creatinine levels were similar between the two groups. The prevalence of HBP adjusted for age was higher among exposed than unexposed (9.7% vs 5.3%). In addition, the odds of having HBP was higher among exposed than unexposed, however the observed difference was not statistically significant [Odds Ratio (OR) 1.9 (0.7, 5.6)]. Finally, using multiple regression analysis, although the effect was not significant, SAM was a major contributor to HBP [adjusted OR 3.1 (0.9,10.9), p = 0.064], while only male gender and higher BMI (overweight/obesity) emerged as independent predictors of HBP among this young study population. CONCLUSIONS: This study suggests that an episode of SAM in childhood has a weak impact on BP variability in young Congolese adults (from DRC) living in an environment without nutrition transition. However, people who experienced a period of SAM tended to have a higher prevalence of HBP and a much higher risk of developing HBP than unexposed. Additional multicentre studies involving a larger cohort would provide greater understanding of the impact of SAM on the overall risk of BP disorders during adulthood.

Selective Peroxisome Proliferator-Activated Receptor Alpha Modulators (SPPARMα): New Opportunities to Reduce Residual Cardiovascular Risk in Chronic Kidney Disease?

PURPOSE OF REVIEW: Chronic kidney disease (CKD) poses a major global challenge, which is exacerbated by aging populations and the pandemic of type 2 diabetes mellitus. Much of the escalating burden of CKD is due to cardiovascular complications. Current treatment guidelines for dyslipidemia in CKD prioritize low-density lipoprotein cholesterol management, but still leave a high residual cardiovascular risk. Targeting elevated triglycerides and low plasma high-density lipoprotein cholesterol, a common feature of CKD, could offer additional benefit. There are, however, safety issues with current fibrates (peroxisome proliferator-activated receptor alpha [PPARα] agonists), notably the propensity for elevation in serum creatinine, indicating the need for new approaches. RECENT FINDINGS: Interactions between the ligand and PPARα receptor influence the specificity and potency of receptor binding, and downstream gene and physiological effects. The peroxisome proliferator-activated receptor alpha modulator (SPPARMα) concept aims to modulate the ligand structure so as to enhance binding at the PPARα receptor, thereby improving the ligand's selectivity, potency, and safety profile. This concept has led to the development of pemafibrate, a novel SPPARMα agent. This review discusses evidence that differentiates pemafibrate from current fibrates, especially the lack of evidence for elevation in serum creatinine or worsening of renal function in high-risk patients, including those with CKD. Differentiation of pemafibrate from current fibrates aims to address unmet clinical needs in CKD. The ongoing PROMINENT study will provide critical information regarding the long-term efficacy and safety of pemafibrate in patients with type 2 diabetes mellitus, including those with CKD, and whether the favorable lipid-modifying profile translates to reduction in residual cardiovascular risk.

The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation.

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.

Distinction of cardiometabolic profiles among people ≥75 years with type 2 diabetes: a latent profile analysis.

BACKGROUND: Older patients with type 2 diabetes mellitus represent a heterogeneous group in terms of metabolic profile. It makes glucose-lowering-therapy (GLT) complex to manage, as it needs to be individualised according to the patient profile. This study aimed to identify and characterize subgroups existing among older patients with diabetes. METHODS: Retrospective observational cohort study of outpatients followed in a Belgian diabetes clinic. Included participants were all aged ≥75 years, diagnosed with type 2 diabetes, Caucasian, and had a Homeostasis Model Assessment (HOMA2). A latent profile analysis was conducted to classify patients using the age at diabetes diagnosis and HOMA2 variables, i.e. insulin sensitivity (HOMA2%-S), beta-cell-function (HOMA2%-ß), and the product between both (HOMA2%-ßxS; as a measure of residual beta-cell function). GLT was expressed in defined daily dose (DDD). RESULTS: In total, 147 patients were included (median age: 80 years; 37.4% women; median age at diabetes diagnostic: 62 years). The resulting model classified patients into 6 distinct cardiometabolic profiles. Patients in profiles 1 and 2 had an older age at diabetes diagnosis (median: 68 years) and a lesser decrease in HOMA2%-S, as compared to other profiles. They also presented with the highest HOMA2%-ßxS values. Patients in profiles 3, 4 and 5 had a moderate decrease in HOMA2%-ßxS. Patients in profile 6 had the largest decrease in HOMA2%-ß and HOMA2%-ßxS. This classification was associated with significant differences in terms of HbA1c values and GLT total DDD between profiles. Thus, patients in profiles 1 and 2 presented with the lowest HbA1c values (median: 6.5%) though they received the lightest GLT (median GLT DDD: 0.75). Patients in profiles 3 to 5 presented with intermediate values of HbA1c (median: 7.3% and GLT DDD (median: 1.31). Finally, patients in profile 6 had the highest HbA1c values (median: 8.4%) despite receiving the highest GLT DDD (median: 2.28). Other metabolic differences were found between profiles. CONCLUSIONS: This study identified 6 groups among patients ≥75 years with type 2 diabetes by latent profile analysis, based on age at diabetes diagnosis, insulin sensitivity, absolute and residual ß-cell function. Intensity and choice of GLT should be adapted on this basis in addition to other existing recommendations for treatment individualisation.

[HDL-C/apoA-I]: A multivessel cardiometabolic risk marker in women with T2DM.

AIMS: Although women have higher high-density lipoprotein cholesterol (HDL-C) than have men, their HDL particles are also prone to become small, dense, and dysfunctional in case of type 2 diabetes mellitus (T2DM). To assess the vascular risk related to HDLs of different sizes/densities without direct measurement, we adjusted HDL-C to its main apolipoprotein (apoA-I) as [HDL-C/apoA-I]. This ratio estimates HDL sizes and provides indices as to their number, cholesterol load, and density. METHODS: We stratified 280 Caucasian T2DM women according to [HDL-C/apoA-I] quartiles (Q) to determine how they are segregated according to cardiometabolic risk, ß-cell function, glycaemic control, and vascular complications. Five parameters were derived from combined determination of HDL-C and apoA-I: HDL size, HDL number, cholesterol load per particle (pP), apoA-I pP, and HDL density. RESULTS: An adverse cardiometabolic profile characterized QI and QII patients whose HDLs were denser and depleted in apoA-I, whereas QIII patients had HDLs with characteristics closer to those of controls. QIV patients had HDLs of supernormal size/composition and a more favourable phenotype in terms of fat distribution; insulin sensitivity (64% vs 41%), metabolic syndrome, and ß-cell function (32% vs 23%); exogenous insulin (44 vs 89 U·d-1 ); and glycaemic control (glycated haemoglobin, 56 vs 61 mmol·mol-1 ), associated with lower prevalence of microvascular/macrovascular complications: all-cause microangiopathy 47% vs 61%; retinopathy 22% vs 34%; all-cause macroangiopathy 19% vs 31%; and coronary artery disease 6% vs 24% (P < .05). CONCLUSION: [HDL-C/apoA-I] can stratify T2DM women according to metabolic phenotype, macrovascular and coronary damage, ß-cell function, microangiopathic risk, and retinopathy. This ratio is a versatile and readily available marker of cardiometabolic status and vascular complications in T2DM women.

The mixed benefit of low lipoprotein(a) in type 2 diabetes.

BACKGROUND: Lipoprotein(a) (Lp(a)), a variant low-density lipoprotein (LDL), is a major genetic risk factor for cardiovascular disease. It is unknown whether an inverse relationship exists between Lp(a) and ß-cell function (BCF), as for LDL-cholesterol (LDL-C) lowering by statins. We therefore assessedthe cardiometabolic phenotype of 340 men with type 2 diabetes mellitus (T2DM) in relation to Lp(a), focusing on BCF and hyperbolic product [BxS], which adjusts BCF to insulin sensitivity and secretion. METHODS: Two groups were analyzed according to Lp(a) quartiles (Q): a (very-)low Lp(a) (Q1;n = 85) vs a normal-to-high Lp(a) group (Q2-Q4;n = 255). RESULTS: In the overall cohort, mean Lp(a) was 52 nmol.L-1. Median Lp(a) was 6 nmol.L-1 (Q1) vs 38 nmol.L-1 (Q2-Q4). There were no differences between groups regarding age; education; diabetes duration; body mass index; body composition and smoking. Q1 had significantly worse glycemic control, higher systolic blood pressure, more severe metabolic syndrome, and more frequent hepatic steatosis. Insulin sensitivity was significantly lower (- 37%) in Q1, who also had lesser hyperbolic product (- 27%), and higher [BxS] loss rate (+ 15%). Q1 also had higher frequency (+31%) and severity (+20%) of atherogenic dyslipidemia. Microangiopathy and neuropathy were higher in Q1 (+ 34% and + 48%, respectively), whereas Q2-Q4 patients had increased macroangiopathy (+ 51%) and coronary artery disease (CAD; + 94%). CONCLUSIONS: Low Lp(a) appears both beneficial and unhealthy in T2DM. It is associated with unfavourable cardiometabolic phenotype, lesser BCF, poorer glycemic control, and increased microvascular damage despite being linked to markedly reduced CAD, suggesting that Lp(a)-related vascular risk) follows a J-shaped curve.

How to transform a metabolic syndrome score into an insulin sensitivity value?

BACKGROUND: The metabolic syndrome (MetS) predicts cardiovascular risk and incident type 2 diabetes mellitus. The presence of a MetS is defined by the clustering of ≥3 out of 5 cardiometabolic criteria (hyperglycemia; hypertension; enlarged waist; low high-density lipoprotein-cholesterol; and hypertriglyceridemia), each of which is connected with insulin resistance. It is not known whether the severity of MetS, ranked from the sextet of scores range [0/5 to 5/5], is linearly related to reduced insulin sensitivity (IS) and/or lesser hyperbolic product across the glycemic spectrum. PATIENTS AND METHODS: A total of 839 adults (54 normoglycemic; 785 with abnormal glucose homeostasis, among whom 711 type 2 diabetes mellitus) had insulin sensitivity assessed together with their cardiometabolic phenotype. RESULTS: There was a significant gradient according to interval-scale MetS score in insulinemia; body mass index; (visceral) fat; hepatic steatosis; and macroangiopathy. There was an inverse linear relationship between increasing MetS scores and decreased insulin sensitivity, allowing to define an insulin resistance-predicting linear equation: IS (%) = [-15.1 × MetS score] + 109.4 (R(2) = 0.221). For each MetS category, mean IS values did not significantly differ between groups of patients across the glycemic spectrum. The hyperbolic product (ß-cell function × IS) and/or its loss rate were inversely related to MetS severity. CONCLUSION: Insulin sensitivity is linearly and inversely related to MetS severity across the 6 scores. This novel way to exploit information intrinsic to the MetS criteria provides an easy and low cost means to quantify insulin sensitivity across the glycemic spectrum. Moreover, a higher MetS score is associated with lesser residual insulin secretion, and faster B-cell function loss. Copyright © 2015 John Wiley & Sons, Ltd.

Sflt-1 in heart failure: relation with disease severity and biomarkers.

Soluble fms-like tyrosine kinase-1 (sFlt-1) is an endogenous inhibitor of endothelial growth factors, such as placental growth factor (PlGF), which modulates cardiovascular (CV) remodeling. We determine sFlt-1 levels in patients with heart failure (HF) and its relationship to adverse cardiovascular (CV) events and biomarkers of cardiovascular risk. Levels of sFlt-1 and PlGF levels were also determined in healthy volunteers and patients with type 2 diabetes mellitus (T2DM). SFlt-1 and PlGF were clearly increased in HF patients in comparison to T2DM patients or healthy subjects (p < 0.01). Concentration of sFlt-1 was related to HF severity (p < 0.001) and was correlated to NT-proBNP (ρ = 0.37, p < 0.01), soluble ST2 (ρ = 0.52, p < 0.01), Galectin-3 (ρ = 0.38, p < 0.01), aldosterone (ρ = 0.25, p = 0.01) and PTH(1-84) (ρ = 0.38, p < 0.01). Furthermore, sFlt-1 levels were associated to long-term CV risk. These results suggest a potential role of sFlt-1 in HF and its potential role as biomarker of CV risk.

Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global case-control study in 13 countries.

BACKGROUND: Microvascular renal and retinal diseases are common major complications of type 2 diabetes mellitus. The relation between plasma lipids and microvascular disease is not well established. METHODS AND RESULTS: The case subjects were 2535 patients with type 2 diabetes mellitus with an average duration of 14 years, 1891 of whom had kidney disease and 1218 with retinopathy. The case subjects were matched for diabetes mellitus duration, age, sex, and low-density lipoprotein cholesterol to 3683 control subjects with type 2 diabetes mellitus who did not have kidney disease or retinopathy. The study was conducted in 24 sites in 13 countries. The primary analysis included kidney disease and retinopathy cases. Matched analysis was performed by use of site-specific conditional logistic regression in multivariable models that adjusted for hemoglobin A1c, hypertension, and statin treatment. Mean low-density lipoprotein cholesterol concentration was 2.3 mmol/L. The microvascular disease odds ratio increased by a factor of 1.16 (95% confidence interval, 1.11-1.22) for every 0.5 mmol/L (≈1 quintile) increase in triglycerides or decreased by a factor of 0.92 (0.88-0.96) for every 0.2 mmol/L (≈1 quintile) increase in high-density lipoprotein cholesterol. For kidney disease, the odds ratio increased by 1.23 (1.16-1.31) with triglycerides and decreased by 0.86 (0.82-0.91) with high-density lipoprotein cholesterol. Retinopathy was associated with triglycerides and high-density lipoprotein cholesterol in matched analysis but not significantly after additional adjustment. CONCLUSIONS: Diabetic kidney disease is associated worldwide with higher levels of plasma triglycerides and lower levels of high-density lipoprotein cholesterol among patients with good control of low-density lipoprotein cholesterol. Retinopathy was less robustly associated with these lipids. These results strengthen the rationale for studying dyslipidemia treatment to prevent diabetic microvascular disease.