Updates on dyslipidemia in patients with diabetes

The main aim of diabetes management is to prevent atherosclerotic cardiovascular diseases (ASCVD) and microvascular complications. ASCVD, the major cause of diabetes-related mobility and mortality, greatly increases healthcare costs in patients with type 2 diabetes¹. Dyslipidemia often coexists with diabetes mellitus and is a significant risk factor for ASCVD, along with smoking, hypertension and chronic kidney disease. Dyslipidemia is involved in the progression of diabetic kidney disease² and diabetic retinopathy³. Patients with diabetes mellitus show atherogenic lipid profiles exhibiting elevated low-density lipoprotein cholesterol (LDL-C) levels with small dense LDL particles; decreased high-density lipoprotein cholesterol (HDL-C) levels; and hypertriglyceridemia (TG) due to insufficient insulin action. Furthermore, a retrospective cohort study identified an elevated LDL-C/HDL-C ratio as a potential independent risk factor for new-onset diabetes⁴. Therefore, abnormal lipid profiles must be managed to reduce the risk of cardiovascular (CV) events and microvascular complications.

A high LDL-C level is a strong risk factor for ASCVD in patients with and without diabetes mellitus. Numerous outcome trials have shown that cholesterol-lowering therapy using 3-hydroxy 3-methylglutaryl-coenzyme A reductase inhibitors (statins) reduces the relative risk of primary and secondary ASCVD events⁵. Furthermore, a recent randomized controlled trial showed that LDL-C control using statins reduced the risk of kidney events in patients with diabetic kidney disease⁶. In addition to statin therapy, proprotein convertase subtilisin/kexin type 9 inhibitors and ezetimibe therapies reduced CV event risk^7-9.

Although these LDL-C-lowering therapies can decrease the risk of ASCVD, the risk rate reduction is only 30–40%, suggesting the presence of residual risk factors, such as hypertriglyceridemia, low HDL-C levels and highly oxidized or small dense LDL particles. Interestingly, a recent prospective study showed the TG/HDL-C ratio to be correlated with an increased risk of major ASCVD events, suggesting that the TG/HDL-C ratio can be a parameter for assessing atherogenic dyslipidemia¹⁰. Furthermore, in addition to fasting hypertriglyceridemia, postprandial hypertriglyceridemia is a risk factor for CV events¹¹.

Several epidemiological, genetic and clinical studies have shown that a high TG level is a residual risk factor; however, neither the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial nor the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study reported reduced CV events in patients with type 2 diabetes¹². A meta-analysis of fibrate users in 11,590 patients with type 2 diabetes mellitus showed that fibrate use significantly reduced the risk of non-fatal myocardial infarction, but had no effect on the risk of overall or coronary mortality¹³. As evidenced in the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial, the use of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, to reduce TG also did not significantly mitigate CV events as an add-on statin in patients with diabetes¹⁴. In addition, the effects of TG-lowering therapy using N-3 unsaturated fatty acids are unclear. Although the Japan Eicosapentaenoic Acid Lipid Intervention Study (JELIS) and Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention (REDUCE-IT) showed that combination therapy with eicosapentaenoic acid and statins reduced residual CV risk, the Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH) trial was not able to confirm these results using a combination of eicosapentaenoic acid, docosahexaenoic acid and statins¹⁵. Nevertheless, a meta-analysis of 49 randomized controlled trials including 374,358 participants showed that TG-lowering therapy reduced major vascular events by 16% per 1-mmol/L TG, which is comparable with an LDL-C reduction of 20% per 1-mmol/L¹⁶. Furthermore, Mendelian randomization studies have shown that TG is a causal risk factor of CVD¹⁷, suggesting that the effect of TG-lowering therapy on CV risk is controversial. Currently, one report showed that the TG-lowering effect on small dense LDL particles is limited when LDL-C levels are tightly controlled, which might explain why TG-lowering therapy as an add-on to statins did not reduce ASCVD events¹⁸. Considering this finding, a subsequent analysis of the PROMINENT trial would show why CVD risk was not reduced by pemafibrate administration.

Several glucose-lowering medications have been reported to exert a beneficial effect on lipid metabolism. A meta-analysis of 48 randomized controlled trials showed that the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors decreased serum TG, and increased total cholesterol, HDL-C and LDL-C levels¹⁹. However, this slight increase in LDL-C levels on using an SGLT2 inhibitor was due to the decreased level of small dense LDL particles and the increased level of large buoyant LDL particles, contributing to the beneficial effect on ASCVD²⁰. Furthermore, TG reduction by empagliflozin administration is strongly associated with endothelial function recovery²¹. Glucagon-like peptide-1 receptor agonist (GLP-1 RAs) therapy also improved lipid profiles by decreasing the LDL-C (−0.08 to −0.16 mmol/L) and TG (−0.17 to −0.3 mmol/L) levels²². Tirzepatide, a dual glucose-dependent insulinotropic polypeptide, and GLP-1 RAs significantly reduced the TG (−19% to −24.8%) levels and increased the HDL-C levels (6.8% to 7.9%)²³. In addition, these medications have favorable effects on non-alcoholic fatty liver disease (NAFLD). NAFLD is a complication in >70% of patients with diabetes; type 2 diabetes promotes the progression to non-alcoholic steatohepatitis and severe fibrosis²⁴. A randomized study showed that dapagliflozin and pioglitazone had beneficial effects on NAFLD; they decreased the visceral fat area and increased the adiponectin levels in patients with diabetes²⁵. Furthermore, SGLT-2 inhibitors and GLP-1 RAs might decrease the incidence of NAFLD²⁶. Meanwhile, tirzepatide significantly reduced the liver fat content by 8.09%²⁷. These pleiotropic effects might be associated with the protective effects of SGLT-2 inhibitors and GLP-1 RAs against ASCVD.

Dyslipidemia in managed in daily clinical settings according to guidelines established in the USA, Europe and Japan^{28, 29}. Although all guidelines are based on similar concepts, the lipid management goals and therapeutic recommendations differ by area (Table 1). The American Diabetes Association standards of care in diabetes 2023 and the 2019 European Society of Cardiology/European Atherosclerosis Society guidelines recommend statin therapy, and have set more intensive LDL-C target levels than the Japan Atherosclerosis Society guidelines. The Japan Atherosclerosis Society guidelines do not mention the selection of medications, because there is little evidence in Asian populations. After achieving the target LDL-C levels, other lipid parameters, such as TG and HDL-C levels, must be considered. In the 2022 Japan Atherosclerosis Society guidelines, both fasting and postprandial TG goals were set. Similarly, the American Diabetes Association guidelines recommend intensive lifestyle therapy and optimization of glycemic control in patients with high TG and low HDL-C levels.

The present article briefly reviews the update on dyslipidemia in patients with diabetes regarding treatment evidence and lipid management goals based on major guidelines. Although LDL-C-lowering therapy provides robust evidence for ASCVD risk reduction, further evidence for achieving residual risk reduction is required.

KY has participated on advisory panels for AstraZeneca, Kowa Company and Novo Nordisk Pharma; and has received research grants from Abbott Diabetes care, Astellas Pharma, Bayer Yakuhin, Daiichi Sankyo Company, Eli Lily Japan, Kowa Company, Merck Sharp and Dohme, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Novo Nordisk Pharma, Ono Pharmaceutical, Pfizer, Shionogi, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical Company, and Takeda Pharmaceutical Company. The other authors declare no conflict of interest.

Approval of the research protocol: N/A.

Informed consent: N/A.

Registry and the registration no. of the study/trial: N/A.

Animal studies: N/A.