Cardiovascular disease (CVD) remains the predominant cause of morbidity and mortality globally. Amid rising CVD rates, Lipoprotein(a) [Lp(a)] has been recognized as a critical biomarker identifying individuals at an increased risk of atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (AS), independent of traditional risk factors. Lp(a) is a lipoprotein variant similar to LDL but includes apolipoprotein(a), which influences its pathogenic potential. Elevated Lp(a) levels are genetically determined and have been implicated in promoting vascular inflammation, atherogenesis, enhanced calcification, and thrombosis. Emerging antisense oligonucleotide (ASO)- and small interfering ribonucleic acids (siRNAs)- based therapies have been shown to lower Lp(a) concentrations, with ongoing trials underway to determine whether they reduce the risk of CVD. While guidelines on screening and management continue to evolve, the advent of specific Lp(a)-lowering therapies may transform CVD prevention and treatment. This review aims to consolidate the current knowledge on Lp(a) from its biological functions to its implications for clinical practice, focusing on its role as a biomarker and potential therapeutic target.

Hypertriglyceridemia (HTG), which arises from defects in triglyceride-rich lipoprotein (TRL) metabolism, is associated with increased morbidity and mortality from pancreatitis and atherosclerotic cardiovascular disease. Traditional therapies, including fibrates and omega-3 fatty acids, have shown limited efficacy in controlling triglyceride (TG) levels and cardiovascular risk. This review explores the role of emerging therapies that target TG and TRL metabolism via novel biochemical pathways.

Apolipoprotein C-III inhibitors appear most effective for patients with variants of severe HTG, particularly multifactorial and familial chylomicronemia syndromes, by enhancing TRL metabolism through both lipoprotein lipase-dependent and independent mechanisms. Angiopoeitin-like proteins 3 and 4 inhibitors appear most useful for mixed hyperlipidemia, with favorable effects across the entire spectrum of apoB-containing atherogenic lipoproteins. For patients with HTG and concomitant complications of insulin resistance, including metabolic associated steatotic liver disease and type 2 diabetes mellitus, fibroblast growth factor-21 analogs may provide significant benefit.

HTG is a diverse condition. Apolipoprotein C-III inhibitors, angiopoeitin-like proteins 3 and 4 inhibitors, and fibroblast growth factor-21 analogs represent significant advancements in the treatment of HTG, offering new hope for effectively managing this condition across its full spectrum of disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Quantitative and qualitative changes in plasma lipoprotein profiles are frequently associated with CKD and represent a significant risk factor for CVD in patients with CKD. Guidelines from the European Society of Cardiology and the European Atherosclerosis Society classify CKD as a condition with high or very high cardiovascular risk and set specific low-density lipoprotein cholesterol targets. Conventional lipid-lowering therapies (LLTs), such as statins, ezetimibe, and fibrates, can control CKD-associated dyslipidemia and, to some extent, prevent major atherosclerotic events in patients with CKD, but their use in clinical practice presents challenges because of the potential renal safety concerns. In recent years, novel therapies with the ability to lower both low-density lipoprotein cholesterol and triglycerides have been introduced to the market (e.g., proprotein convertase subtilisin/kexin type 9 inhibitors, bempedoic acid, lomitapide, volanesorsen) to improve our ability to control lipid abnormalities. However, their impact on kidney functionality has not been fully elucidated. The aim of this review was to examine the renal safety profiles of various LLTs, with special reference to novel medications, and to highlight important considerations and guidance for the use of these medications in overt CKD or in patients with some degree of renal function impairment. We underscore the lack of a comprehensive understanding of kidney safety, particularly for novel LLT therapies, and strongly emphasize the importance of future dedicated research to fully assess the safety and efficacy of these agents in patients with kidney abnormalities.

Hypertriglyceridemia is related to atherosclerotic cardiovascular risk and pancreatitis risk. The efficacy and safety of apolipoprotein C-III (APOC-III) inhibitors remains unclear.

To investigate the effects of APOC-III inhibitors on hypertriglyceridemia and its complications.

We systematically searched PubMed, Embase, and Cochrane Central databases from inception to May 2024 for randomized controlled trials (RCTs) comparing APOC-III inhibitors to placebo in patients with hypertriglyceridemia. We pooled percentage standardized mean difference (SMD) changes and risk ratio (RR) for continuous and binary outcomes, respectively, with 95 % confidence interval (CI). Subgroup analyses were performed with APOC-III inhibitors drugs doses (Olezarsen, Volanesorsen and Plozasiran), and primary and secondary hypertriglyceridemia.

10 RCTs with 1204 participants were included, of which 46 % were men. APOC-III inhibitors significantly reduced triglycerides (TG) (SMD: -60.56 %; 95 % CI -68.94 to -52.18; p < 0.00001), APOC-III (SMD: -75.44 %; 95 % CI -80.81 to -70.07; p < 0.00001) and non-HDL-c (SMD: -27.49 %; 95 % CI -34.16 to -20.82; p < 0.00001) levels. Consistent results were found for all subgroup analyses. APOC-III inhibitors were capable to normalize TG levels in patients with severe hypertriglyceridemia (RR: 7.92; 95 % CI 4.12 to 15.23; p < 0.00001). There was a significant increase in HDL-c (SMD: 43.92 %; 95 % CI 37.27 to 50.57; p < 0.00001) and LDL-c (SMD: 33.05 %; 95 % CI 9.08 to 57.01; p = 0.007) levels. There was a significant relative risk reduction in acute pancreatitis in the APOC-III inhibitors group (RR 0.17; 95 % CI 0.05 to 0.53; p = 0.007). Adverse events were similar in both groups.

APOC-III inhibitors improve TG levels and other lipid panel parameters, as well as reduce episodes of acute pancreatitis in patients with primary and secondary hypertriglyceridemia.

Limited data exist on the relation between long-term variability in blood lipid fractions and incident heart failure (HF) in the setting of type 2 diabetes mellitus (T2DM).

Among 9,443 participants with T2DM from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, with lipid measurements available at six time points (baseline, 4, 8, 12, 24, and 36 months), we assessed variability in total cholesterol (TC), LDL cholesterol, HDL cholesterol, and triglycerides (TG) across visits, using coefficient of variation (CV), SD, and variability independent of the mean. Cox proportional hazards models were employed to estimate adjusted hazard ratios (HRs) for incident HF.

During a median follow-up of 5.0 years, 345 participants developed HF. Participants in the highest quartile of CV of TC had a 68% higher relative risk of HF compared with those in the lowest quartile (adjusted HR [aHR] 1.68, 95% CI 1.22-2.30). Similarly, those in the highest quartile of LDL cholesterol CV had a 76% higher relative risk (aHR 1.76, 95% CI 1.27-2.42) of HF, while those in the highest quartile of HDL cholesterol CV had a 53% higher risk (aHR 1.53, 95% CI 1.13-2.06). For TG CV, participants in the highest quartile had a 49% higher risk of HF compared with the lowest quartile (aHR 1.49, 95% CI 1.09-2.04). Similar patterns were observed for other variability metrics.

Increased variability in TC, LDL cholesterol, HDL cholesterol, or TG is independently associated with a higher HF risk among individuals with T2DM.

Lipoprotein lipase regulates triglyceride hydrolysis and contributes to cellular uptake of triglyceride-rich lipoprotein remnants. Multiple pathways modulate lipoprotein lipase activity, which has prompted interest in the development of drugs that increase lipoprotein lipase activity as means to reduce risk for acute pancreatitis, atherosclerotic cardiovascular disease, and metabolic dysfunction-associated steatohepatitis through reduction of circulating triglycerides and remnant cholesterol. The authors provide an overview of the target populations for agents that lower triglycerides and remnant cholesterol through increased lipoprotein lipase activity, the drugs being developed for these indications, including apolipoprotein C-III and angiopoietin-like protein 3, 3/8, and 4 inhibitors, and the epidemiologic and genetic evidence supporting the use of these drugs for the prevention of atherosclerotic cardiovascular disease and acute pancreatitis. In addition, the authors provide a corresponding overview of fibroblast growth factor-21 analogues that share many characteristics with these novel triglyceride-lowering drugs. Apolipoprotein C-III inhibitors, angiopoietin-like protein 3, 3/8, and 4 inhibitors, and fibroblast growth factor-21 analogues have pronounced triglyceride-lowering and remnant cholesterol-lowering effects. In clinical trials, apolipoprotein C-III inhibitors have been shown to lower risk for acute pancreatitis in patients with severe hypertriglyceridemia and are approved for this indication, while fibroblast growth factor-21 analogues reduce hepatic steatosis and fibrosis in patients with metabolic dysfunction-associated steatohepatitis. It remains to be seen whether these novel drugs may lower risk for atherosclerotic cardiovascular disease as well.

Diabetes is associated with increased atherosclerotic cardiovascular disease (ASCVD) risk, a leading cause of morbidity and mortality. Disordered lipid metabolism is a major contributor to ASCVD risk in diabetes. Dyslipidemia in type 2 diabetes is characterized by hypertriglyceridemia, low high-density lipoprotein cholesterol and the presence of small, dense low-density lipoprotein particles. Statins have demonstrated longstanding benefit for reducing ASCVD risk in individuals with diabetes. Newer agents for add-on therapies to statins are now available for additional cardiovascular risk reduction. In this clinical overview, we review the pathogenesis of dyslipidemia in both type 1 and 2 diabetes and provide an update on the management of lipids in the individual with diabetes. We discuss the importance of appropriate risk stratification and individualized treatment selection and the need to avoid therapy inertia to mitigate cardiovascular risk. We also address lipid-related effects of glycemic-lowering therapies.

Guidelines focus on individuals with triglycerides between 2.3 and 5.6 mmol/L (200 and 499 mg/dL). The hypotheses that triglycerides across the full biological range and within this constrained range associated with cardiovascular risk were re-assessed.

Multivariable-adjusted hazard ratios for major cardiovascular events and death according to baseline triglycerides among 119 573 individuals with triglycerides across the full biological range from the Copenhagen General Population Study, among 27 757 individuals with baseline triglycerides between 2.3 and 5.6 mmol/L from the Copenhagen General Population Study and the Women's Health Study cohorts, and among 31 272 individuals with mild-to-moderate hypertriglyceridaemia from the PROMINENT, REDUCE-IT, and STRENGTH trials were calculated.

Increasing triglycerides across the full range (0.3 to 11.2 mmol/L) were associated with an increasing risk of major cardiovascular events (N = 12 241). In the cohorts, combined hazard ratios [95% confidence interval (triglyceride range in mmol/L)] for major cardiovascular events (N = 3928) from lowest to highest triglyceride quartile were 1.0 [referent (range: < 2.5)], 0.95 [0.87-1.04 (range: 2.5 to <3.0)], 1.04 [0.95-1.13 (range: 3.0 to <3.6)], and 1.13 [1.04-1.23 (range: ≥ 3.6)]. In the three contemporary trials, the corresponding hazard ratios (N = 4265 cardiovascular events) from lowest to highest quartile were 1.0 [referent (ranges for PROMINENT/REDUCE-IT/STRENGTH: < 2.6/2.0/2.2)], 1.01 [0.93-1.10 (ranges: 2.6 to <3.1/2.0 to <2.5/2.2 to <2.7)], 1.05 [0.96-1.14 (ranges: 3.1 to <3.9/2.5 to <3.1/2.7 to < 3.5)] and 1.09 [1.00-1.19 (ranges: ≥ 3.9/3.1/3.5)]. In neither cohorts nor trials were triglycerides across this range strongly associated with risk of cardiovascular or all-cause death.

Individuals with mild-to-moderate hypertriglyceridaemia may not express the same magnitude of cardiovascular risk as that observed across the full range of plasma triglycerides. Future triglyceride-lowering therapy trials may want to consider enrolment across a wider range of triglyceride levels if there is no prior history of pancreatitis nor excessive alcohol intake.

Genetic and epidemiological evidence indicates that triglyceride-rich lipoproteins are causal risk factors for atherosclerotic cardiovascular disease (ASCVD). Elevated levels of plasma triglyceride are common in patients who are diabetic or obese and contribute substantially to residual, ongoing risk of an ASCVD event in individuals on low-density lipoprotein (LDL)-lowering treatment. Hypertriglyceridaemia, therefore, presents a target for further intervention. Clinical trials have demonstrated that high-dose eicosapentaenoic acid (EPA) is effective in reducing ASCVD risk in patients on statin therapy, and it is now being incorporated into strategies using combination lipid-regulating treatment to manage aggressively those at highest risk. This review summarises the concepts underpinning the use of high-dose EPA alongside intensive LDL-lowering therapy, especially in the context of post-acute coronary syndrome. A practical implementation algorithm is presented setting out treatment options for combination therapy, and the place of high-dose EPA in ASCVD prevention in hypertriglyceridaemia.

Adequate lipid control has emerged as a key factor in the prevention and management of chronic kidney disease (CKD). Remnant cholesterol (RC), a lipoprotein with an established association with cardiovascular risk, has been investigated in the context of CKD. Given the conflicting results from recent studies, we performed this meta-analysis to summarize the existing evidence on the association between RC and CKD.

Medline, Cochrane Library and Scopus were searched until 16 September 2024. Double-independent study selection, data extraction and quality assessment were performed. Evidence was pooled using random-effects meta-analyses. We set as primary end-point of interest the association between RC and CKD.

Twelve studies (4 139 674 participants) were included. Participants with RC values in the highest quantile had significantly greater odds of CKD compared to those in the lowest quantile (Odds Ratio [OR] = 1.46, 95% confidence interval [CI] = 1.26-1.68). In a sensitivity analysis confined to subjects with type 2 diabetes (T2D), those in the higher RC quantile also exhibited significantly increased odds of CKD compared to those in the lowest quantile (OR = 1.46, 95% CI = 1.20-1.78). A significant inverse association was observed between RC and estimated glomerular filtration rate (Mean Difference [MD] = -1.43 mL/min/1.73 m2 for each 1 mmol/L increase in RC, 95% CI = [-2.67, -0.19]). Additionally, individuals with T2D-related CKD had a 24% increased risk of progression to end-stage renal disease for each 1 standard deviation increase in RC (Hazard Ratio [HR] = 1.24, 95% CI = 1.04-1.47).

RC is directly associated with higher risk for CKD. Beyond traditional lipid markers, greater emphasis should be placed on RC levels in individuals with or at risk for CKD.

To review existing and new evidence regarding the relationship between diabetes and dyslipidemia and to provide an update of the lipid biomarkers used to assess cardiovascular risk and the current guidelines reflecting these changes.

We conducted a literature review pertaining to diabetes and lipids using the MEDLINE/PubMed database. We reviewed articles in English and primarily published between 1994 and early 2025. Also included are guidelines published by professional organizations who are recognized nationally or internationally in the fields of diabetes, lipids, and cardiovascular disease.

Studies evaluating the relationship between diabetes and hypertriglyceridemia have provided practice-changing evidence. Lipid markers such as apolipoprotein B, non-high-density lipoprotein cholesterol, and lipoprotein (a), as well as the concept of lipid variability have emerged as treatment targets.

Over the past 30 years, non-low-density lipoprotein cholesterol lipid markers have been identified to further stratify individuals with diabetes who are at risk for future cardiovascular events. Treatment targets and pharmacological therapy have been studied and continue to be updated.

Fenofibrate is a serum lipid-modifying agent that is commonly used to treat dyslipidemia. This study aimed to compare the pharmacokinetics (PKs) and establish bioequivalence of two 145-mg fenofibrate formulations, AD-104 (test) and TRICOR® (reference). This randomized, open-label, two-sequence, two-period crossover study was conducted in healthy Korean participants. Forty participants were enrolled and received either the test or reference formulation during each period, with a 14-day washout between doses. Blood samples were collected pre-dose and up to 72 h post-dose. PK parameters were assessed using non-compartmental analysis with Phoenix WinNonlin®. Bioequivalence was determined if the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of the maximum plasma concentration (Cmax) and the area under the concentration-time curve from time zero to the last measurable plasma concentration (AUClast) were within the bioequivalence limits of 0.80 to 1.25. Thirty-eight participants completed the study and were included in the PK analysis. The GMR and 90% CIs for the Cmax and AUClast of the test compared to the reference formulation were 0.8643 (0.8283-0.9019) and 0.9930 (0.9631-1.0239), respectively, both within the bioequivalence limits. No serious adverse events were reported during the study. This study demonstrates that the test formulation is bioequivalent to the reference formulation in healthy Korean participants. Both formulations were safe and well-tolerated; therefore, AD-104 is expected to benefit Korean patients with dyslipidemia. Clinical Research Information Service No. is as follows: KCT0009332 (April 12, 2024).

In scenarios involving correlated endpoints, multivariate methods offer increased robustness for comparisons. However, understanding the individual contribution of each variable toward multivariate hypothesis rejection remains underexplored. Usually, this question is sidelined, and separate univariate analyses are performed. This paper addresses this gap by demonstrating the relative importance and contribution of variables toward the rejection of multivariate hypotheses, comparing it against a univariate approach using clinical trial data. Using the ACCORD lipid trial dataset, which includes lipid measurements of triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), we employed Hotelling's T2 multivariate statistic for two-group comparisons. We showcased the significance and relative importance of contributions through standardized discriminant function coefficients and partial F tests. Additionally, we investigated the impact of varying correlation levels on the significance of each variable's contribution in multivariate versus univariate approaches. Our results revealed significant lipid differences in a multivariate context at the 12th and 36th months. Across both follow-ups, TG exhibited the highest relative importance and contribution, followed by HDL and LDL. Notably, in the 36th month, the univariate approach rendered LDL's contribution insignificant for group separation, contrasting with the significant contribution identified in the multivariate approach. Furthermore, the significance likelihood of variable contributions in group separation within the multivariate approach increased with rising correlation levels. The simulation technique and the power analysis was also adopted to characterize the features of the proposed method. Our approach enables the evaluation of the relative importance and significance of each variable's contribution within the multivariate framework. This methodology holds promise for enhancing the interpretation of clinical trial analysis outcomes, particularly when dealing with multiple correlated endpoints.

Metabolic syndrome (MetS) is a complex cluster of interrelated metabolic disorders that significantly elevate the risk of cardiovascular disease, making it a pressing public health concern worldwide. Among the key features of MetS, dyslipidemia-characterized by altered levels of high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)-plays a crucial role in the disorder's progression. This review aims to elucidate the intricate interplay between HDL-C and TG within the context of lipid metabolism and cardiovascular health, while also addressing the detrimental impact of various cardiovascular risk factors and associated comorbidities. The dynamics of HDL-C and TG are explored, highlighting their reciprocal relationship and respective contributions to the pathophysiology of MetS. Elevated levels of TGs are consistently associated with reduced concentrations of HDL-C, resulting in a lipid profile that promotes the development of vascular disease. Specifically, as TG levels rise, the protective cardiovascular effects of HDL-C are diminished, leading to the increased accumulation of pro-atherogenic TG-rich lipoproteins and low-density lipoprotein particles within the vascular wall, contributing to the progression of atheromas, which can ultimately result in significant ischemic cardiovascular events. Ultimately, this paper underscores the significance of HDL and TG as essential targets for therapeutic intervention, emphasizing their potential in effectively managing MetS and reducing cardiovascular risk.

To summarize studies analyzing whether remnant cholesterol should be a target for prevention of atherosclerotic cardiovascular disease (ASCVD).

There is a growing body of evidence from epidemiologic and Mendelian randomization studies implicating remnant cholesterol as a causal risk factor for ASCVD. However, the results of randomized controlled trials, particularly those conducted in the current high-intensity statin era, have been inconsistent. Most recently, the PROMINENT trial failed to show a beneficial effect of 0.4 mg/day of pemafibrate on the risk of ASCVD. In the Copenhagen General Population Study (CGPS), which mimics PROMINENT, the estimated hazard ratio for ASCVD was 1.05 (0.96-1.14) when absolute changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B were combined, whereas the hazard ratio for ASCVD in PROMINENT was 1.03 (0.91-1.15). Further trials are warranted to ascertain the efficacy of novel remnant cholesterol- and triglyceride-lowering agents in the prevention of ASCVD. To reduce ASCVD, active agents need to reduce total atherogenic cholesterol (LDL and remnant cholesterol) and apolipoprotein B.

Hypertriglyceridemia is an independent risk factor for cardiovascular diseases. In previous trials, apolipoprotein C-III (APOC3) inhibition through the antisense oligonucleotides volanesorsen, olezarsen, and plozasiran reduced triglyceride levels. However, the three medications' safety and efficacy have yet to be compared.

A network meta-analysis was performed to compare multiple doses of the three medications to each other through the placebo. Randomized controlled trials (RCTs) were retrieved by searching PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane until November 22nd, 2024. The mean difference (MD) and 95% confidence interval (CI) were used for continuous outcomes. The risk ratio (RR) and 95% CI were used for dichotomous outcomes.

Ten RCTs with a total of 1,129 patients were included. volanesorsen 300 mg once weekly showed the most significant percent reduction in triglyceride levels (MD = -91.0%, 95% CI: (-109.2%; -72.8%); P < 0.01). Only plozasiran once monthly, regardless of the dose, showed a non-significant percent reduction in triglycerides. This finding should be taken cautiously as the data were derived from a phase 1 trial with a small sample size. All the regimens significantly reduced APOC3 levels compared to placebo, with plozasiran 100 mg monthly and volanesorsen 300 mg once weekly showing the most significant reduction (MD range: -92.8% to -88.5%; P < 0.01). None of the treatments showed a statistically significant difference in overall adverse events rate compared to the placebo.

APOC3 antisense oligonucleotide inhibitors effectively reduced triglyceride and APOC3 levels in hypertriglyceridemia with an acceptable safety profile. However, the results should be interpreted cautiously due to the small sample size. Further research is needed to confirm the beneficial effects of APOC3 inhibitors and show strong evidence of the impact of each regimen.

The triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) index, calculated as TG divided by HDL-C, has been suggested as a predictor of cardiovascular disease (CVD). We investigated the association between the TG/HDL-C index and CVD events in type 2 diabetes mellitus (T2DM) patients with retinopathy and hyperlipidemia but no known CVD, enrolled in the EMPATHY study, which compared intensive and standard statin therapy (targeting LDL-C levels < 70 mg/dL and ≥ 100 to < 120 mg/dL, respectively). A total of 4665 patients were divided into high (TG/HDL-C ≥ 2.5, n = 2013) and low (TG/HDL-C < 2.5, n = 2652) TG/HDL-C index groups. During a median follow-up of 36.8 months, 260 CVD events occurred. The high TG/HDL-C index group had higher CVD risk than the low group (HR 1.89, 95% CI 1.45-2.47, p < 0.001). This association remained consistent across subgroups. A trend toward interaction between TG/HDL-C index and statin treatment allocation for CVD risk was observed (p for interaction = 0.062). Intensive statin treatment reduced CVD risk in the high TG/HDL-C group but not in the low group. In conclusion, a TG/HDL-C index ≥ 2.5 was associated with higher CVD risk in T2DM patients with retinopathy and hyperlipidemia without a history of CVD. The TG/HDL-C index may identify patients who benefit from intensive statin treatment.

This review aims to examine the evidence on the benefits and risks of lipid-lowering drugs in patients with liver disease. Elevated liver enzyme levels often lead to cautious discontinuation of these drugs, potentially withholding from patients their benefit in reducing cardiovascular disease morbidity and mortality. Using a literature search of PubMed, we examine the efficacy and safety profiles of various lipid-lowering agents, including statins, ezetimibe, bempedoic acid, PCSK9 inhibitors, fibrates, and icosapent ethyl, focusing particularly on their potential side effects related to liver health. A major challenge in the assessment of drug-induced hepatotoxicity is the fact that it relies heavily on case reports rather than real-world evidence. There is currently a lack of robust evidence on lipid-lowering therapy in people with pre-existing liver disease. Nevertheless, we have attempted to summarize the available data for all the drugs mentioned in order to provide guidance for the treatment of patients with liver dysfunction. This review highlights the need for further research to optimize treatment strategies for patients with coexisting liver and cardiovascular disease.

Low levels of high-density lipoprotein cholesterol (HDL-C) are clearly associated with atherosclerotic cardiovascular disease (ASCVD), but the risk curve is not well defined, especially at very high and low HDL-C levels. Current proportional hazards prediction models assume inverse linearity of effect, which may not accurately represent risk at these levels.

Clinical inattention to risk associated with low HDL-C may derive from randomized controlled trials (RCTs) aimed at raising HDL-C, though most failed to reduce ASCVD events when combined with statin-based therapy. However, these prior trials enrolled patients with HDL-C levels largely in the 35-45 mg/dL range.

Mounting post hoc evidence from RCTs as well as new genetic and observational data suggest that very low HDL-C (less than 30 or 35 mg/dL) may signal a further increase in incident cardiovascular events. Moreover, when HDL-C exceeds 90 mg/dL, monotonic reduction of ASCVD risk appears to reverse. Because a pervasively agnostic view of the importance of both very low and high levels of HDL-C now exists, consideration should be given to incorporating nonlinear effects of HDL-C into future risk prediction models such that very low HDL-C and/or very high HDL-C levels could be considered as new risk-enhancing factors to promote more optimal risk stratification.

When revision of the U.S. Cholesterol Guideline recommences, consideration should be directed to whether HDL-associated risk matches the assumptions of current statistical models. Thus, it may be both timely and opportune to revisit the "HDL hypothesis" based on evolving scientific evidence.

The ACCORD trial showed that intensive glucose-lowering therapy has a limited impact on renal function decline. We aimed to identify subgroups in the ACCORD population that might derive renal benefits from intensive glucose-lowering therapy.

The primary renal outcome included a ≥50% decline in baseline estimated glomerular filtration rate or end-stage renal disease (ESRD). Using the causal tree model, we employed internal cross-validation to identify five pivotal variables influencing the renal efficacy of intensive glycaemic control. These variables were integrated into the model-based recursive partitioning approach, yielding a visualizable tree model that depicted benefitting subgroups.

Node 4, characterized by no cardiovascular history, systolic blood pressure (SBP) ≤142.67 mm Hg, and triglycerides ≤172 mg/dL, showed significantly reduced hazards of the composite renal outcome (fully adjusted hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.49-0.89; p = 0.006) and doubling of serum creatinine (fully adjusted HR 0.59, 95% CI 0.36-0.98; p = 0.041). Node 7 (no cardiovascular history and SBP 142.67-154 mm Hg) showed reduced hazards of the primary renal outcome (fully adjusted HR 0.67, 95% CI 0.49-0.93; p = 0.016) and ESRD (fully adjusted HR 0.35, 95% CI 0.17-0.74; p = 0.0057). Encouragingly, neither node 4 nor node 7 displayed elevated cardiovascular risk or hypoglycaemic events.

Through innovative machine learning, we identified ACCORD subgroups benefitting significantly from intensive glycaemic therapy for renal outcomes, without increased cardiovascular or hypoglycaemic risks.

Despite extensive research on pharmacokinetic interactions between hydroxymethylglutaryl-CoA reductase inhibitors (statins) and fibrates, the underlying pharmacodynamic mechanisms contributing to the increased risk of rhabdomyolysis remain unclear. This study aimed to determine the differences among statins or fibrates in terms of their susceptibility to rhabdomyolysis. The data mining of FDA Adverse Event Reporting System (FAERS) suggested the association of both statins and fibrates with rhabdomyolysis and the add-on effect of their combinations. In rats, their administration was associated with outliers in creatine phosphokinase and myoglobin levels and a larger distribution of data than in the control. Additionally, co-administration of cerivastatin increased the gemfibrozil concentration in skin and muscle tissues by more than two-fold without an increase in systemic exposure to gemfibrozil, suggesting that an alteration in the pharmacokinetics of gemfibrozil might contribute to an increased risk of rhabdomyolysis when cerivastatin and gemfibrozil are co-administered. Taken together, caution is uniformly needed in combination therapy with statins and fibrates because of the increased risk of rhabdomyolysis.

Complications of diabetes mellitus have significant impacts on morbidity, mortality, quality of life, and health costs for individuals. Setting and achieving glycemic targets to prevent these complications is a top priority when managing diabetes. However, patients often already have complications when diagnosed with diabetes mellitus. Therefore, methods to prevent disease progression become a crucial component of diabetes management. The purpose of this article is to review glycemic targets and methods of screening and managing diabetes-related complications.

A PubMed review of the literature pertaining to diabetes mellitus, glycemic targets, microvascular complications, and macrovascular complications was conducted. We reviewed articles published between 1993 and 2024. Guidelines published by nationally recognized organizations in the fields of diabetes, nephrology, and cardiology were referenced. Public health statistics obtained by the Center for Disease Control and Prevention and the National Kidney Foundation were used.

Achieving glycemic targets and screening for diabetes-related complications at appropriate intervals remains the key factor for early detection and intervention. An algorithmic approach to glycemic management based on individual risk factors is beneficial in choosing pharmacotherapy.

The consequences of diabetes-related complications can be detrimental. However, achieving and maintaining glycemic targets combined with diligent screening, reduction of risk factors, and prompt treatment can halt disease progression.

High-density lipoprotein (HDL) exhibits multiple metabolic protective functions, such as facilitating cellular cholesterol efflux, antioxidant, anti-inflammatory, anti-apoptotic and anti-thrombotic properties, showing antidiabetic and renoprotective potential. Diabetic kidney disease (DKD) is considered to be associated with high-density lipoprotein cholesterol (HDL-C). The hyperglycemic environment, non-enzymatic glycosylation, carbamylation, oxidative stress and systemic inflammation can cause changes in the quantity and quality of HDL, resulting in reduced HDL levels and abnormal function. Dysfunctional HDL can also have a negative impact on pancreatic β cells and kidney cells, leading to the progression of DKD. Based on these findings, new HDL-related DKD risk predictors have gradually been proposed. Interventions aiming to improve HDL levels and function, such as infusion of recombinant HDL (rHDL) or lipid-poor apolipoprotein A-I (apoA-I), can significantly improve glycemic control and also show renal protective effects. However, recent studies have revealed a U-shaped relationship between HDL-C levels and DKD, and the loss of protective properties of high levels of HDL may be related to changes in composition and the deposition of dysfunctional particles that exacerbate damage. Further research is needed to fully elucidate the complex role of HDL in DKD. Given the important role of HDL in metabolic health, developing HDL-based therapies that augment HDL function, rather than simply increasing its level, is a critical step in managing the development and progression of DKD.

Atherogenic dyslipidemia with increased triglycerides, low high-density lipoprotein cholesterol levels and increased small dense low-density lipoprotein (LDL) particles is a major risk factor contributing to the increased cardiovascular (CV) risk in patients with type 2 diabetes (T2D). This is regarded as a residual risk after achieving target levels of LDL cholesterol.

This article reviews the novel therapies to reduce triglycerides in patients with T2D. These were identified by a PubMed search and mainly focus on pemafibrate and the drugs targeting apolipoprotein C3 (apoC3) and angiopoietin-like 3 (ANGPTL3).

Current therapies to reduce triglycerides in patients with T2D include fibrates and omega-3 fatty acids but these are often not sufficient and the evidence for CV benefits is limited. Pemafibrate was effective in reducing triglycerides in patients with T2D but did not reduce CV events in the PROMINENT study. Inhibitors of apoC3 are effective in reducing triglycerides even in familial chylomicronaemia syndrome and olezarsen and plozasiran in this group are being studied in patients with combined hyperlipidemia. The ANGPTL3 inhibitor evinacumab has been approved for homozygous familial hypercholesterolemia, and other ANGPTL3 inhibitors may prove to be useful to reduce triglycerides in T2D.

Patients with type 2 diabetes mellitus (T2DM) managed in both hospital and out-ofhospital settings usually have a high/very high cardiovascular risk, with a high burden of cardiovascular disease. All this justifies that the reduction of low-density lipoprotein cholesterol is the main therapeutic goal in T2DM. However, residual cardiovascular risk is very prevalent in T2DM, and is usually associated with atherogenic dyslipidemia and hyperlipoproteinemia(a); therefore, it is also necessary to reverse these lipoprotein abnormalities to achieve effective cardiovascular prevention. Given the considerable armamentarium of lipid-lowering drugs currently available, the Cardiovascular Disease Working Group of the Spanish Diabetes Society has considered it appropriate to carry out a narrative review and update of the effectiveness of these lipid-lowering drugs in the population with T2DM taking into account their effect on the lipoprotein profile and their potential impact on glycemic control.

Lipid-lowering therapies are well established for the treatment of cardiovascular disease (CVD). Historically monotherapy studies have been performed, but the introduction of statins has led to these drugs being recognized as baseline therapies and to the investigation of combination therapy of both older and newer medications with them.

Surrogate marker studies have shown additive effects on LDL-C, triglycerides and HDL-C of combination therapies with statins and these have extended to lipoprotein (a). Imaging studies have often shown benefits paralleling lipid studies. However, outcome studies have failed to show added benefits with niacin or fibrates while confirming the benefits of ezetimibe, bempedoic acid and proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors and icosapent ethyl.

Combination therapy for LDL-C in dual combinations is well validated. Data for intervention on triglycerides is limited to icosapent ethyl, but this may exert effects independent of lipids. New drugs targeting triglycerides through apolipoprotein C3 and angiopoietin-like peptides are in development. Studies on combination therapy raising HDL-C have generally disappointed, though cholesterol ester transfer protein (CETP) inhibition remains a target. Lipoprotein (a) is recognized as a CVD risk factor and effective therapies are in development but results on CVD events are lacking.

High triglyceride (TG) levels are associated with increased atherosclerotic cardiovascular disease (ASCVD) risk in the general population. Yet, the role of TG in familial hypercholesterolemia (FH) remains understudied. This research aims to evaluate the link between TG levels and ASCVD prevalence in adult patients with FH.

This cross-sectional analysis, derived from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH), involves categorizing patients into tertiles based on their TG concentrations.

In our study of 1772 adults with heterozygous FH (HeFH), aged 51 ± 15 years at registration and diagnosed at 44 ± 16 years, TG concentrations in the 1st (80 mg/dL), 2nd (124 mg/dL), and 3rd (200 mg/dL) tertiles revealed varying ASCVD prevalence (18.0%, 28.5% and 28.5%, respectively). Adjusted for ASCVD risk factors, TGs ≥116 mg/dL were linked to higher ASCVD risk than levels <116 mg/dL (OR: 1.37, 95% CI 1.05-1.80, P = .02).

A notable association with ASCVD is evident in FH patients, even at relatively low TG levels, starting from 116 mg/dL (1.31 mmol/L).

Hypertriglyceridemia (HTG) is associated with a residual risk of atherosclerotic cardiovascular disease. Extremely elevated triglyceride (TG) concentrations, particularly due to familial chylomicronemia syndrome (FCS), pose a risk for acute pancreatitis. Standard therapies with statins, fibrates, omega-3 fatty acids, and niacin may be insufficient to reduce elevated TG levels and improve clinical outcomes in patients with HTG. Novel antisense oligonucleotides and small interfering ribonucleic acids target the key modulators of TG-rich lipoprotein catabolism. Among apolipoprotein C-III (apoC-III) inhibitors, olezarsen and plozasiran appear to be safer alternatives for volanesorsen regarding the risk of drug-induced thrombocytopenia in patients with FCS or severe HTG. After the failure of vupanorsen, a new angiopoietin-like protein 3 (ANGPTL3) inhibitor, zodasiran, demonstrated the potential to decrease TG levels in patients with moderate HTG. Meanwhile, the fibroblast growth factor 21 (FGF21) analog, pegozafermin, became another candidate for the treatment of severe HTG. This comprehensive review outlines pharmacological targets in TG-rich lipoprotein metabolism, discusses international guidelines, and summarizes the latest evidence from clinical trials to provide insight into the current and emerging treatment options for primary HTG.

Background: Hypertriglyceridemia has serious health risks such as cardiovascular disease, type 2 diabetes mellitus, nephropathy, and others. Fenofibrate is an effective hypolipidemic drug, but its benefits for ameliorating disorders associated with hypertriglyceridemia failed to be proven in clinical trials. Methods: To search for possible causes of this situation and possibilities of their favorable influence, we tested the effect of FF monotherapy and the combination of fenofibrate with silymarin on metabolic disorders in a unique model of hereditary hypertriglyceridemic rats (HHTg). Results: Fenofibrate treatment (100 mg/kg BW/day for four weeks) significantly decreased serum levels of triglyceride, (-77%) and free fatty acids (-29%), the hepatic accumulation of triglycerides, and the expression of genes encoding transcription factors involved in lipid metabolism (Srebf2, Nr1h4. Rxrα, and Slco1a1). In contrast, the hypertriglyceridemia-induced ectopic storage of lipids in muscles, the heart, and kidneys reduced glucose utilization in muscles and was not affected. In addition, fenofibrate reduced the activity of the antioxidant system, including Nrf2 expression (-35%) and increased lipoperoxidation in the liver and, to a lesser extent, in the kidneys and heart. Adding silymarin (micronized form, 600 mg/kg BW/day) to fenofibrate therapy increased the synthesis of glycogen in muscles, (+36%) and reduced hyperinsulinemia (-34%). In the liver, it increased the activity of the antioxidant system, including PON-1 activity and Nrf2 expression, and reduced the formation of lipoperoxides. The beneficial effect of combination therapy on the parameters of oxidative stress and lipoperoxidation was also observed, to a lesser extent, in the heart and kidneys. Conclusions: Our results suggest the potential beneficial use of the combination of FF with SLM in the treatment of hypertriglyceridemia-induced metabolic disorders.

Dyslipidemia is a major risk factor for cardiovascular disease, and its impact may be exacerbated when accompanied by metabolic dysfunction-associated steatotic liver disease (MASLD). The simultaneous management of these conditions poses multiple challenges for healthcare providers. Insulin resistance has been implicated in the pathogenesis of both dyslipidemia and MASLD, necessitating a holistic approach to managing dyslipidemia, glucose levels, body weight, and MASLD. This review explores the intricate pathophysiological relationship between MASLD and dyslipidemia. It also examines current guidance regarding the use of lipid-lowering agents (including statins, ezetimibe, fibrates, omega-3 polyunsaturated fatty acids, and proprotein convertase subtilisin/kexin type 9 inhibitors) as well as glucose-lowering medications (such as pioglitazone, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors) in patients with MASLD, with or without metabolic dysfunction-associated steatohepatitis (MASH), and dyslipidemia. Additionally, the review addresses the potential of emerging drugs to concurrently target both MASLD/MASH and dyslipidemia. Our hope is that a deeper understanding of the mechanisms underlying MASLD and dyslipidemia may assist clinicians in the management of these complex cases.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Tirzepatide is a novel dual glucose-dependent insulinotropic peptide (GIP)-glucagon-like peptide 1 (GLP-1) receptor agonist being evaluated for the treatment of various metabolic disorders. We performed a meta-analysis of randomized data on the effects of tirzepatide on serum lipid levels.

We systematically searched the PubMed and ClinicalTrials.gov databases for relevant data from randomized controlled clinical trials. All articles were screened, reviewed, and extracted by at least two independent authors, with conflicts resolved by consensus. Four hundred and thirty-three records were identified in the initial literature search; 18 of them were identified for full-text review, and 14 of those were systematically reviewed and included in the analysis. The meta-analysis was performed using an inverse variance random-effects model.

Fourteen articles that reported data from 13 randomized controlled clinical trials were included in the review. Nine trials had a low risk of bias, two had a moderate risk, and two had a high risk of bias. The pooled analysis showed that tirzepatide was efficacious at improving all lipid markers, including cholesterol and triglycerides. Moreover, a clear dose response trend was visible across results from groups taking 5, 10, and 15 mg of tirzepatide.

There is growing evidence to support the use of tirzepatide in patients with metabolic diseases such as type 2 diabetes mellitus, metabolic syndrome, and obesity. Our results demonstrate that tirzepatide significantly improves all aspects of patient metabolism and might be superior in this regard to conventional agents such as insulin formulations or traditional GLP-1 agonists.

Cardiovascular diseases (CVD) prevention does not only mean effective fight against the existing and well-recognized cardiovascular risk factors, but also against their complications, including micro- and macrovascular complications. Only then we might comprehensively reduce CVD burden and cardiovascular and cause-specific morbidity and mortality. In relation to obesity, prediabetes and especially diabetes, we recognize a number of potential dangerous non-cardiovascular complications, such as neuropathy, nephropathy and retinopathy. The latter's prevalence is even 30-40% and may appear in as many as 15% of patients with prediabetes. If not treated well it might result in the need for eye surgery or even vision loss. Fenofibrate has had a long history of evidence suggesting its preventive role in primary and especially secondary prevention of retinopathy, what has been investigated since the FIELD trial 19 years ago. Thus, given the obesity (the prevalence of 30% in Poland) and diabetes (10% which is predicted to be doubled in next 25 years) epidemic, we should look for the effective methods not only to optimize fasting blood glucose and haemoglobin A1C, but also atherogenic dyslipidaemia and their complications, including retinopathy. In this Position Paper by the Polish Lipid Association (PoLA) we have reviewed the current stage of knowledge on possible mechanisms by which fenofibrate may contribute to retinopathy prevention, available data on safety and efficacy, to finally recommend administering fenofibrate in prevention of this dangerous diabetic complication, which significantly affects quality of life and disability-adjusted life-years (DALY). This intervention - well-recognized and already in common use in diabetic patients - may significantly improve population health in Poland and worldwide.

An association between obesity, metabolic abnormalities and clinical hypertrophic cardiomyopathy (HCM) expression has been reported. We investigated whether managing dyslipidaemia with fibrates could affect the clinical expression of HCM.

We screened patients who used fibrates between 2010 and 2017 from a nationwide database. After excluding patients with a history of HCM, we identified fibrate-user group (n = 412 823). We then constructed a 1:1 matched cohort of fibrate-naïve participants (n = 412 823). After a 1 year lag period, we identified the incident HCM cases for the following 5 years.

During a median follow-up period of 3.96 years, we identified 454 incident clinical HCM cases. After adjusting for covariates, fibrate use was associated with a lower risk of clinical HCM expression [hazard ratio (HR) 95% confidence interval (CI): 0.763 (0.630-0.924)]. In subgroup analyses, fibrate use was associated with a reduced risk of clinical HCM expression in patients with a body mass index ≥25 kg/m2 and those with abdominal obesity [HR (95% CI): 0.719 (0.553-0.934) and 0.655 (0.492-0.872)], but not in those without obesity. Fibrate use was also associated with lower risks of incident clinical HCM in patients with triglyceride levels ≥150 mg/dL and those with metabolic syndrome [HR (95% CI): 0.741 (0.591-0.929) and 0.750 (0.609-0.923)], but not in their counterparts. Regarding lifestyle behaviours, fibrate use appeared to provide more prognostic benefits in patients who currently smoked, consumed alcohol or did not engage in regular physical activities.

The use of fibrates is associated with a lower incidence of clinical HCM expression. This association was also more prominent in those with obesity, unhealthy metabolic profiles and poor lifestyle behaviours.

The Royal College of Physicians of Thailand (RCPT) published a Clinical Practice Guideline on Pharmacologic Therapy of Dyslipidemia for Atherosclerotic Cardiovascular Disease (ASCVD) Prevention in 2016. The availability of newer classes of medications for dyslipidemia, supported by extensive clinical research findings, indicates a significant need for the updating of the existing clinical practice guideline.

To serve as guidelines on the management of dyslipidemia for Thai adults.

The RCPT Dyslipidemia Guidelines Committee was established with representatives from selected professional societies to revise the 2016 Guideline by critically reviewing the latest evidence. Meetings were conducted from August to December 2023, culminating in a public hearing that engaged various stakeholders in January 2024. The final Thai version received approval in April 2024, while the English translation was completed in October 2024.

Lifestyle modifications and statins remain the cornerstone of therapy for dyslipidemia in adults across various clinical settings. Emerging evidence regarding newer classes of lipid-lowering medications indicates that these treatments are effective in lowering LDL-cholesterol levels and reducing atherosclerotic cardiovascular events. This suggests that they may serve as an add-on therapy for individuals who cannot achieve target levels or who are at high risk for future cardiovascular events. The Thai CV Risk Score is recommended due to its specificity for the Thai population.

The 2024 updated clinical practice guidelines establish a framework, provide recommendations, and serve as a comprehensive resource for the contemporary management of dyslipidemia in adults, with the goal of preventing ASCVD in Thailand.

Diabetes mellitus (DM) affects 537 million people as of 2021, and is projected to rise to 783 million by 2045. This positions DM as the ninth leading cause of death globally. Among DM patients, cardiovascular disease (CVD) is the primary cause of morbidity and mortality. Notably, the prevalence rates of CVD is alarmingly high among diabetic individuals, particularly in North America and the Caribbean (46.0%), and Southeast Asia (42.5%). The predominant form of CVD among diabetic patients is coronary artery disease (CAD), accounting for 29.4% of cases. The pathophysiology of DM is complex, involving insulin resistance, β-cell dysfunction, and associated cardiovascular complications including diabetic cardiomyopathy (DCM) and cardiovascular autonomic neuropathy (CAN). These conditions exacerbate CVD risks underscoring the importance of managing key risk factors including hypertension, dyslipidemia, obesity, and genetic predisposition. Understanding the genetic networks and molecular processes that link diabetes and cardiovascular disease can lead to new diagnostics and therapeutic interventions. Imeglimin, a novel mitochondrial bioenergetic enhancer, represents a promising medication for diabetes with the potential to address both insulin resistance and secretion difficulties. Effective diabetes management through oral hypoglycemic agents (OHAs) can protect the cardiovascular system. Additionally, certain antihypertensive medications can significantly reduce the risk of diabetes-related CVD. Additionally, lifestyle changes, including diet and exercise are vital in managing diabesity and reducing CVD risks. These interventions, along with emerging therapeutic agents and ongoing clinical trials, offer hope for improved patient outcomes and long-term DM remission. This study highlights the urgent need for management strategies to address the overlapping epidemics of DM and CVD. By elucidating the underlying mechanisms and risk factors, this study aims to guide future perspectives and enhance understanding of the pathogenesis of CVD complications in patients with DM, thereby guiding more effective treatment strategies.

Individuals with diabetes face increased risk of atherosclerotic cardiovascular disease (ASCVD), in part due to hyperlipidemia. Even after LDL cholesterol-lowering, residual ASCVD risk persists, part of which may be attributed to elevated remnant cholesterol. We describe the impact of elevated remnant cholesterol on ASCVD risk in diabetes.

Preclinical, observational, and Mendelian randomization studies robustly suggest that elevated remnant cholesterol causally increases risk of ASCVD, suggesting remnant cholesterol could be a treatment target. However, the results of recent clinical trials of omega-3 fatty acids and fibrates, which lower levels of remnant cholesterol in individuals with diabetes, are conflicting in terms of ASCVD prevention. This is likely partly due to neutral effects of these drugs on the total level of apolipoprotein B(apoB)-containing lipoproteins. Elevated remnant cholesterol remains a likely cause of ASCVD in diabetes. Remnant cholesterol-lowering therapies should also lower apoB levels to reduce risk of ASCVD.

Diabetic nephropathy (DN) is the most common cause of end-stage kidney disease (ESKD). Remnant cholesterol has been investigated as a predictor for the progression of DN in type 1 diabetes mellitus patients, as well as the incidence of DN in type 2 diabetes mellitus (T2DM) patients. This study aimed to evaluate the longitudinal relationship between baseline remnant cholesterol and kidney outcomes using a Chinese T2DM with biopsy-confirmed DN cohort.

We included 334 patients with T2DM and biopsy-confirmed DN during 2010-2019 West China Hospital T2DM-DN cohort. Remnant cholesterol was defined by Martin-Hopkins equation. Patients were divided into four groups based on the median (IQR) remnant cholesterol concentration at the time of renal biopsy. The kidney outcome was defined as ESKD, which was defined as the need for chronic kidney replacement therapy or estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2. The relationship between remnant cholesterol and kidney outcome was analyzed using the Kaplan‒Meier method and Cox regression analysis.

The mean age was 51.1 years, and 235 (70%) were men. During follow-up, a total of 121 (36.2%) patients reached ESKD. The Kaplan‒Meier analysis showed that patients in the highest quartile (quartile 4) group had lower cumulative renal survival (log-rank test, p = 0.033) and shorter median renal survival time [34.0 (26.4-41.6) vs. 55.0 (29.8-80.2) months] than patients in the lowest quartile (quartile 1) group. By univariate analysis, the high remnant cholesterol group was associated with a higher risk of progression to ESKD. Moreover, the risk of progression to ESKD in the highest quartile was still 2.857-fold (95% CI 1.305-6.257, p = 0.009) higher than that in the lowest quartile, and one-SD increase of remnant cholesterol was associated with a higher risk (HR = 1.424; 95% CI 1.075-1.886, p = 0.014) of progression to ESKD, after adjusted for confounding factors.

High remnant cholesterol is independently associated with a higher risk of ESKD in patients with T2DM-DN, and it may be a new noninvasive marker of ESKD.

Calculated remnant cholesterol has the advantages of being economical and clinically accessible. Moreover, to our knowledge, there are no longitudinal cohort studies for investigating the risk of progression of T2DM-DN to ESKD. In our study, higher remnant cholesterol was associated with a higher risk of ESKD in patients with T2DM-DN, and it may be a new noninvasive predictor of ESKD.