Abstract
Cardiovascular diseases are the leading cause of global mortality, accounting for roughly one-third of all deaths. Dyslipidemia is a key risk factor for atherosclerotic cardiovascular disease (ASCVD) and often coexists with diabetes, which exacerbates ASCVD risk. Despite the comprehensive management of dyslipidemia in patients with diabetes through pharmacological and non-pharmacological approaches, many individuals struggle to meet lipid targets through lifestyle changes alone. Therefore, pharmacological interventions are essential. Pharmacotherapy options for dyslipidemia in patients with diabetes, including those currently under development, have gained attention, particularly regarding their impact on cardiovascular outcomes. In this narrative review, we explore the data on cardiovascular outcomes related to established and emerging pharmacotherapy in the management of dyslipidemia in diabetes, such as statins, ezetimibe, bempedoic acid, PCSK9 inhibitors, icosapent ethyl, inclisiran, other lipid-lowering agents (fibrates, bile acid sequestrants, niacin), and novel medications such as antisense nucleotides and cholesterol ester transfer protein inhibitors. We aim to provide a summary that will help navigate the extensive evidence base on cardiovascular outcomes trials of these agents. We found that statins, particularly atorvastatin, showed the strongest and most consistent evidence on cardiovascular outcomes in patients with diabetes, with high-intensity statin therapy associated with significant reductions in major adverse cardiovascular events (MACE). Therefore, clinicians should prioritize statin therapy as the first-line pharmacotherapy for managing dyslipidemia in patients with diabetes to optimize cardiovascular outcomes. Studies also showed that the duration of statin therapy is the strongest predictor of MACE, followed by the achieved LDL cholesterol level and statin intensity. Additional lipid-lowering agents, such as ezetimibe or PCSK9 inhibitors, should be considered for patients who do not achieve target LDL cholesterol levels or for those who are statin-intolerant.
Plain Language Summary
Cardiovascular complications, such as stroke and heart attack, are the leading cause of death among people with diabetes. This group often has high cholesterol, which has unique features and heavily contributes to these complications. In recent years, additional medications have become available to manage high cholesterol. This review looked at the current cholesterol-lowering drugs and how they help reduce cardiovascular complications in people with diabetes. Statins, especially atorvastatin, have the strongest and most consistent evidence of benefit, with different doses leading to varying levels of risk reduction. Although statins can cause new-onset diabetes or worsen existing diabetes, their benefits outweigh the risks. The combination of ezetimibe and a statin, particularly with a moderate-dose statin, can effectively lower cardiovascular risk as an alternative to high-dose statins. Bempedoic acid and PCSK9 inhibitors also reduce cardiovascular risk and are reserved for patients who do not respond to the initial therapies. More research is necessary to confirm that inclisiran lowers cardiovascular risk, while fibrates show inconsistent results regarding risk reduction.
Keywords
Introduction
The prevalence of diabetes has continued to rise globally, with the estimated number of patients living with diabetes increasing from 693 million in 2045 to approximately 1.3 billion by 2050.1,2 Atherosclerotic cardiovascular disease (ASCVD) is the most prevalent cause of morbidity and mortality in patients with diabetes. 3 Among the significant risk factors for ASCVD, dyslipidemia is a key contributor to the increased risk of ASCVD in this cohort. 4
Atherosclerosis is a complex pathology that has been linked to various mechanisms in the context of diabetes. The key contributing factors include the pro-atherogenic effects of hyperglycemia, oxidative stress and inflammatory processes that lead to endothelial dysfunction and increased vascular permeability.5,6 Insulin resistance in diabetes stimulates hormone-sensitive lipase, which releases free fatty acids from the adipose tissue (lipolysis) and increases hepatic triglycerides (Tg) and very low-density lipoprotein (VLDL) production.7,8 Furthermore, it reduces lipoprotein lipase enzyme activity, which decreases VLDL clearance. 9 The low-density lipoprotein (LDL) levels are typically normal or slightly elevated in patients with diabetes. However, due to hypertriglyceridemia, the LDL composition is abnormal, emerging as small dense LDL (sdLDL).10,11 High-density lipoprotein (HDL) facilitates the transfer of excess cholesterol, inhibits oxidation, reduces inflammation and improves endothelial function. 12 A low HDL is typically seen in patients with diabetes, which independently predicts cardiovascular disease. In addition, diabetes-induced vascular inflammation modifies HDL particles and impairs its anti-atherogenic properties.12,13 In patients with type 1 diabetes (T1D) with diabetic ketoacidosis, absolute insulin deficiency reduces lipoprotein lipase enzyme activity, leading to a reduction in the catabolism of chylomicrons and VLDL, causing hypertriglyceridemia and low LDL levels. 14 Overall, serum lipid abnormalities are commonly seen in patients living with diabetes, irrespective of insulin resistance or insulin deficiency.
There is growing interest in examining whether lipid-lowering treatment in diabetes is associated with cardiovascular outcomes. In this narrative review, we explore the cardiovascular outcomes data on established and emerging pharmacotherapy in the management of dyslipidemia in diabetes, such as statins, ezetimibe, bempedoic acid (BA), Proprotein Convertase Subtilisin/Kexin Type 9 inhibitors (PCSK9i), icosapent ethyl (IPE), inclisiran, other lipid-lowering agents (fibrates, bile acid sequestrants, niacin), and novel medications such as antisense nucleotides and cholesterol ester transfer protein inhibitors. This review aims to provide a summary that will help navigate the extensive evidence base on cardiovascular outcomes trials of these agents. It is beyond the scope of this review to discuss non-pharmacological interventions such as the Mediterranean diet or other alternative therapies, cost-effectiveness, patient selection and preferences, treatment optimization, or the management of adverse effects, as numerous guidelines and articles provide this information.
We conducted a comprehensive literature search of PubMed from inception to May 2025 for the terms “dyslipidemia,” “diabetes,” and “cardiovascular outcomes.” The search was limited to English-language articles that examined humans and involved adult populations (⩾19 years). We supplemented this search by screening the reference lists of retrieved articles. We prioritized evidence from systematic reviews, meta-analyses, randomized clinical trials (RCTs), and observational studies, with emphasis on studies reporting cardiovascular outcomes in patients with diabetes. Following title and abstract screening, full texts were reviewed for relevance to dyslipidemia management and cardiovascular outcomes in adults with diabetes. Of the 655 records initially identified, the majority were excluded at the full-text stage for 1 or more predefined reasons. Common reasons for exclusion included: (i) study populations not focused on adults with diabetes or not reporting diabetes-specific data; (ii) pediatric or adolescent cohorts; (iii) studies reporting surrogate or intermediate outcomes only (eg, lipid parameters, imaging markers, endothelial function, or metabolic indices) without clinical cardiovascular endpoints; (iv) insufficient or unclear reporting of cardiovascular outcomes in diabetes subgroups within mixed populations; (v) articles without original data synthesis (eg, editorials, commentaries, opinion pieces); and (vi) publications limited to protocols, baseline characteristics, or methodological descriptions without outcome data. After applying these criteria, 25 studies reporting cardiovascular outcomes in adults with diabetes were retained for narrative synthesis. All articles were appraised by authors against the SANRA (Scale for the Assessment of Narrative Review Articles) domains: (1) Justification of article importance, (2) Concrete aims formulated, (3) Literature search described in detail, (4) Key statements supported by references, (5) Appropriate scientific reasoning and (6) Relevant data presented appropriately. 15
Guidelines for Managing Dyslipidemia in Diabetes
The management of dyslipidemia is considered a fundamental component of risk reduction to improve cardiovascular outcomes in patients with diabetes. Therefore, most guidelines recommend obtaining a lipid profile at the onset of diabetes diagnosis as part of the initial medical assessment and advocate implementing lifestyle modifications and pharmacotherapy to mitigate the risk of developing ASCVD.16,17
Tables 1 and 2 provide an overview of the approved medications for managing dyslipidemia in diabetes, the mechanism of action of the drugs, recommended doses, and crucial clinical considerations such as LDL targets and adverse effects. Table 1 focuses on statins, with additional information from the National Institute for Health and Care Excellence (NICE) UK, the American Diabetes Association (ADA), and the European Society of Cardiology (ESC). Table 2 highlights the approved non-statin agents used in diabetes as adjunctive pharmacotherapy to achieve the desired target, as an option for patients with statin intolerance, and for primary and secondary prevention. Supplemental Table 1 provides additional details on the impact of each pharmacotherapy on lipid profiles, main cautions and contraindications, drug interactions, and primary adverse effects. Figure 1 illustrates an example of a treatment algorithm for managing dyslipidemia in diabetes. While this section summarizes the similarities and differences among the guidelines, it is not intended to replace them; readers are encouraged to review the NICE, 18 ADA, 16 and ESC 17 guidelines for further information and specific clinical applications.
Features of Approved Medications for Dyslipidemia in Diabetes: Statins.
Bold indicates the recommended statins for each guideline.
Abbreviations: ADA, American Diabetes Association; ASCVD, atherosclerotic cardiovascular disease; CK, creatine kinase; ESC, European Society of Cardiology; LFT, liver function tests; NICE, National Institute for Health and Care Excellence UK; TOD, target organ damage.
Unless stated otherwise, dosage is administered orally.
For very high and high-risk individuals. No dose recommendation is stated in the guideline.
Features of Approved Medications for Dyslipidemia in Diabetes: Non-Statins.
Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CK, creatine kinase; EPA, eicosapentaenoic acid; LFT, liver function tests; PCSK9i, PCSK9 inhibitors; PPAR-alpha, peroxisome proliferator-activated receptors alpha; SC, subcutaneously; URTI, upper respiratory tract infection.
Unless stated, dosage is administered orally.
An example of a treatment algorithm in managing dyslipidemia in diabetes. Factors such as patient adherence, cost barriers, and individualized LDL thresholds, should be considered when managing dyslipidemia in diabetes. Colored boxes represent specific recommendations from each guideline. aPrimary prevention. bSecondary prevention. cHigh cardiovascular risk. dVery-high cardiovascular risk. eConsider referring to a specialist in a dedicated lipid clinic for suspected Familial Hyperlipidemia; requirement of a genetic diagnosis or apheresis service. Inclisiran, PCSK9i and IPE may be limited to specialists only (please refer to local guidelines).
The NICE guidelines employ the QRISK3 tool, a predictive algorithm that estimates cardiovascular risk over the next 10 years, in patients with diabetes aged 25 to 84 years. The QRISK3 tool is not recommended for high cardiovascular-risk individuals (T1D, estimated GFR < 60 mL/min/1.73 m2, albuminuria, familial hypercholesterolemia, or other inherited lipid metabolism disorders). The guidelines recommend atorvastatin 20 mg as the preferred statin therapy for primary prevention in patients with type 2 diabetes (T2D) with a 10-year QRISK3 score of ⩾10% (Table 1, Figure 1). Atorvastatin may be considered for older patients (⩾85 years) and for those with a QRISK3 <10% who prefer to take statins. Atorvastatin 20 mg is recommended as primary prevention for patients with T1D (>40 years of age, have had diabetes for >10 years, have established nephropathy, or have other pre-existing cardiovascular risk factors). Consideration for atorvastatin may apply to younger patients with T1D (18-40 years) and diabetes with a duration of >10 years. Atorvastatin 80 mg is the preferred drug for secondary prevention, irrespective of cholesterol level (Table 1, Figure 1). To achieve the LDL target of ⩽2 mmol/L, the dose may be increased to the maximum tolerated level of the high-intensity statin therapy, alongside lifestyle modification and assessment of adherence and timing. 18
For primary prevention, the ADA recommends moderate-intensity statin therapy in all patients with diabetes (aged 40-75 years) without ASCVD (Table 1, Figure 1). 16 Statin therapy may be initiated in younger patients (20-39 years) with diabetes and additional ASCVD risk factors. High-intensity statins are indicated in patients with diabetes (aged 40-75 years) with ⩾1 ASCVD risk factor. Older patients with diabetes over 75 years may continue statin therapy or be initiated on a moderate-intensity statin following a discussion on the potential risks and benefits. For secondary prevention, high-intensity statins are indicated in patients with diabetes (all ages) with ASCVD (Figure 1).
The ESC recommends high-intensity statins in very high-cardiovascular-risk or high-cardiovascular-risk patients (Table 1, Figure 1). 17 The former is defined as patients with T2D with severe target organ damage (TOD), a history of established ASCVD, or a 10-year cardiovascular risk ⩾ 20% (SCORE2-Diabetes predictive model). High-cardiovascular risk individuals are defined as patients with T2D, with a SCORE2-Diabetes risk of 10 to <20% without severe TOD or established ASCVD.
These guidelines may generally differ in the initial recommended dose of statins, target cholesterol levels, preferred cholesterol subtype measurements, and the definition of very high-risk individuals. However, most guidelines agree that a second or third-line medication may be considered, such as ezetimibe, PCSK9i, BA, IPE, and long-acting small interfering RNA (siRNA, eg, inclisiran), as an adjuvant to statin therapy or if statins are contraindicated or not tolerated.
NICE recommends ezetimibe 10 mg daily for patients who have been on a maximally tolerated, high-intensity statin for 3 months and have not achieved a non-HDL cholesterol reduction of >40% (primary and secondary prevention; Figure 1). If statin intolerance is confirmed, ezetimibe monotherapy may be an option. If the target is not achieved with ezetimibe alone, a combination of ezetimibe 10 mg and BA 180 mg can be considered (Figure 1). For primary prevention, patients who do not achieve the non-HDL cholesterol target reduction despite maximally tolerated lipid-lowering therapy, including those with intolerance or contraindications, should be referred to a specialist lipid management clinic. For secondary prevention, injectable therapies (PCSK9i/inclisiran) should be considered if non-HDL cholesterol remains > 2.5 mmol/L. PCSK9i (alirocumab and evolocumab) are recommended only for patients with high or very high risk of cardiovascular disease (CVD) in cases of primary hypercholesterolemia or mixed dyslipidemia. Inclisiran is an option in primary hypercholesterolemia or mixed dyslipidemia, if there have been any cardiovascular events, and LDL cholesterol remains persistently elevated at ⩾2.6 mmol/L despite maximum tolerated doses of other lipid-lowering treatments. IPE is also reserved for patients with established CVD who are on statin therapy and have fasting Tg ⩾ 1.7 mmol/L and LDL between 1.04 and ⩽2.6 mmol/L (Table 2). 18
In contrast to NICE, for primary prevention, the ADA recommends BA in patients with diabetes (age 45-75 years), with or without ASCVD risk factors, who are statin intolerant (Figure 1). For those on maximum tolerated high-intensity statins, ezetimibe or PCSK9i may be added if the LDL goal is not achieved. For secondary prevention, following a maximally tolerated high-intensity statin, ezetimibe, or PCSK9i may be added to reach the LDL target. For those who are statin-intolerant, other options include PCSK9i, BA, or a combination of PCSK9i with inclisiran. IPE may be considered for patients with ASCVD who are on a maximally tolerated statin, have controlled LDL levels, and elevated Tg from 1.7 to 5.6 mmol/L (Table 2). 16
Similar to NICE, the ESC recommends a combination of a statin and ezetimibe if the target LDL is not reached in patients with diabetes (Figure 1). In patients with statin intolerance (even after re-challenge), ezetimibe monotherapy may be considered (Figure 1), and a PCSK9i may be added to ezetimibe if the target LDL is not achieved. PCSK9i is recommended for patients with diabetes at a very high CVD risk, with persistently elevated LDL, despite a maximum tolerated statin, in combination with ezetimibe or in statin-intolerant patients. IPE may be considered for patients with hypertriglyceridemia (Tg 1.7-5.6 mmol/L) already on a statin. The ESC did not provide any recommendation on the use of BA or inclisiran in patients with diabetes (Table 2). 17
Statins: Mode of Action and Pleiotropic Benefits
HMG-CoA reductase enzyme is the enzyme that catalyzes the rate-limiting step in cholesterol synthesis. By competitively inhibiting this enzyme, statin therapy reduces hepatic cholesterol levels, which in turn increases the expression of hepatic LDL receptors that clear LDL cholesterol from the circulation. In addition to this primary mechanism, statins also inhibit the release of triglyceride-rich lipoproteins and the synthesis of apolipoprotein B-100 from the liver, which may explain their effectiveness in lowering LDL cholesterol in patients without functioning LDL receptors, such as those with homozygous familial hypercholesterolemia. 19
In addition to the clinical benefits associated with reductions in LDL cholesterol, statin therapy also demonstrates an LDL cholesterol-independent (pleiotropic) effect by reducing the isoprenylation of signaling molecules (Ras, Rho, and Rac) within the cholesterol biosynthetic pathway. These effects lead to the upregulation of nitric oxide synthase, stabilization of atherosclerotic plaque, reductions in proinflammatory cytokines and reactive oxygen species, decreased platelet aggregation, and the development of cardiac hypertrophy fibrosis. 20
Clinical studies of statins in diseases unrelated to LDL have demonstrated associations between their pleiotropic effects and improvements in creatinine function, a reduction in the incidence of pneumonia and venous thromboembolism (VTE), decreased inflammation in rheumatoid arthritis, and a lower risk of hip fractures in postmenopausal women.21 -26 In a post hoc analysis of 690 patients (The CARE Study) with moderate chronic renal insufficiency (Modification of Diet in Renal Disease – Glomerular Filtration Rate (MDRD-GFR)) less than 60 mL/min/1.73 m2, the rate of renal function decline was slower in the pravastatin group compared to the placebo group, particularly in those with proteinuria (P = .07 in those with MDRD-GFR less than 50 mL/min/1.73 m2 and P = .0001 in those with MDRD-GFR less than 40 mL/min/1.73 m2). 21 In the JUPITER trial, there was a 19% reduction in the incidence of pneumonia prior to cardiovascular events in the rosuvastatin group compared to placebo (HR 0.81, 95% CI 0.67-0.97). 22 The rosuvastatin group also had lower rates of symptomatic VTE (HR 0.57, 95% CI 0.37-0.86, P = .007), provoked VTE (HR 0.52, 95% CI 0.28-0.96, P = .03), and deep vein thrombosis (HR 0.45, 95% CI 0.25-0.79, P = .004). No significant differences were observed in the rates of unprovoked VTE (P = .09) and pulmonary embolism (P = .42). 23 Data from observational studies demonstrated an odds ratio of 0.43 (95% CI 0.25-0.75) for statin use and hip fracture and 0.69 (95% CI 0.55-0.8) for non-spine fractures. However, the meta-analysis of clinical trials did not support these findings. 24 In an RCT, compared with placebo, atorvastatin reduced the rheumatoid arthritis disease activity score (between-group difference of −0.52; 95% CI, −0.87 to −0.17; P = .006) and demonstrated a higher proportion of patients achieving the EULAR (European League Against Rheumatism) response criteria (OR 3.9, 95% CI 1.42-10.72, P = .005). 26
Even with these indirect clinical trials, precisely quantifying the contribution of statin pleiotropic effects to any clinical outcome remains challenging. Regulatory authorities require that a new lipid-lowering agent be tested alongside the standard of care, which is a statin. This means that statins will be included in both treatment groups. Furthermore, the extent of statin-induced isoprenoid inhibition correlates with the degree of LDL reduction, making it difficult to further isolate the pleiotropic effects. 20
Statins: Cardiovascular Outcomes in Diabetes
Numerous clinical trials demonstrated the positive impact of statins on cardiovascular outcomes in patients with or without coronary artery disease.27,28 Similar findings have also been observed in patients with diabetes. A meta-analysis of 14 RCTs involving 18 686 patients with diabetes was conducted to evaluate cardiovascular outcomes based on diabetes type, lipid profile, and other factors. The study included 1466 patients with T1D, 17 220 with T2D, and 71 370 patients without diabetes. With a mean follow-up of 4.3 years, the use of statins in patients with diabetes resulted in a 9% proportional reduction in all-cause mortality (P = .02) and a 21% proportional reduction in major vascular events (P < .0001) for each 1 mmol/L reduction in LDL cholesterol. There were proportional reductions of 22%, 25%, and 21% in myocardial infarction or coronary death (P < .001), coronary revascularization (P < .0001), and stroke (P = .0002), respectively, in patients with diabetes. These proportional effects were observed regardless of baseline characteristics or prior history of vascular disease. 29
More recently, another meta-analysis evaluated the cardiovascular outcomes in 24 primary and secondary prevention studies (including 17 RCTs) involving statins usage in more than 2 million patients with diabetes. The inclusion criteria included statins usage of ⩾ 1 year duration in patients with diabetes and studies with a control group (non-statins users) in patients with diabetes. There was a 20% (P = .006) and 25% (P < .0001) reduction in cardiovascular disease events for primary and secondary prevention, respectively, in patients with diabetes using statins compared to non-users. While there was no difference in the risk of all-cause mortality, the risk of ischemic stroke was reduced by 17% (P = .02) and 26% (P < .0001), respectively. 30
Different statin intensities contribute to varying cardiovascular outcomes and cholesterol levels in patients with diabetes. A systematic review and network meta-analysis of 42 RCTs involving 11 698 patients with T2D and T1D was conducted to compare the efficacy of different statin intensities on the level of non-HDL cholesterol (primary outcome) compared to placebo. Secondary outcomes include changes in LDL cholesterol and TC, three-point major cardiovascular events (non-fatal stroke, non-fatal myocardial infarction, and death from cardiovascular diseases), and discontinuation due to adverse events. Statins were categorized into high, moderate, and low intensity based on the percentage reduction in LDL cholesterol: >40%, 31% to 39%, and 20% to 30%, respectively. Compared to placebo, high-intensity and moderate-intensity rosuvastatin demonstrated a non-HDL cholesterol reduction of −2.31 mmol/L (95% credible interval −3.39 to −1.21) and −2.27 mmol/L (95% credible interval −3.0 to −1.49), while high-intensity simvastatin and atorvastatin reduced the non-HDL cholesterol by −2.26 mmol/L (95% credible interval −2.99 to −1.51) and −2.2 mmol/L (95% credible interval −2.69 to −1.7), respectively. High-intensity atorvastatin group had the largest reduction in non-HDL cholesterol of −1.98 mmol/L (95% credible interval −4.16 to 0.26) in patients with diabetes and high cardiovascular risk (n = 4670). In contrast, high-intensity simvastatin and rosuvastatin were the most effective statins in reducing LDL cholesterol with a reduction of −1.93 mmol/L (95% credible interval −2.63 to −1.21) and −1.76 mmol/L (95% credible interval −2.37 to −1.15), respectively. Data from 4 studies demonstrated a reduction in non-fatal myocardial infarctions with moderate-intensity atorvastatin (RR 0.57, 95% CI 0.43-0.76) compared to placebo. 31
The duration of statin therapy in diabetes may be more critical than the dose intensity. In a population-based cohort study, using propensity score matching, 8554 patients with T2D on moderate or high-intensity statins were compared to 383 patients with T2D on low-intensity statins. Major adverse cardiovascular events (MACE) included ischemic heart disease (IHD), ischemic stroke (IS), or cardiovascular death. There were 861 MACE with a median follow-up of 41.9 months. Compared to patients with T2D in the low-intensity statin group, those in the moderate or high-intensity statin group had lower MACE (HR 0.72, P = .027). Lower LDL cholesterol was also associated with a lower cardiovascular risk in the moderate and high-intensity groups. Compared to patients taking statins for less than 6 months, the risk of MACE was significantly reduced in groups taking statins for 18 to 24 (aHR 0.7, P = .009), 24 to 30 (aHR 0.71, P = .023), 30 to 36 (aHR 0.63, P = .009), and ⩾36 months (aHR 0.64, P = .002), respectively. The strongest predictor of MACE was statin duration, followed by achieved LDL cholesterol levels and statin intensity, with explainable log-likelihood proportions of 2.55%, 2.18%, and 0.95%, respectively. 32
Impact of Statins on Glycemic Control in Patients With Diabetes
It is proposed that statins increase new-onset diabetes (NOD) by reducing insulin secretion and increasing insulin resistance. β-cell toxicity is a consequence of higher LDL concentrations in the pancreas due to an increase in LDL receptor expression. By upregulating the mitochondrial carrier gene expression, statins alter the metabolism of branched-chain amino acids, increasing short-chain acyl carnitines, which are associated with insulin resistance. 33
In the WOSCOPS (The West of Scotland Coronary Prevention Study) trial, 6595 men (mean age 55.2 years) with a mean baseline LDL and TC of 5.0 and 7.0 mmol/L, respectively, without diabetes, were randomized to either placebo or pravastatin. In 5974 men with post-randomization glucose measurements, 139 transitioned from normoglycemia to overt diabetes. Predictors of this transition include body mass index (BMI), log Tg, glucose, and pravastatin therapy. There was a 30% reduction in the hazard of progression to diabetes with pravastatin (P = .042). 34 The JUPITER trial involved 17 802 healthy men and women with LDL cholesterol < 3.4 mmol/L and hs-CRP of ⩾2 mg/L, randomized to either rosuvastatin or placebo. Rosuvastatin reduced the incidence of major cardiovascular events in this group, with a higher physician-reported NOD (270 in the rosuvastatin vs 216 in the placebo group, P = .01). 35
A sizeable collaborative meta-analysis of 13 statins RCTs involving 91 140 participants demonstrated a 9% increase in the incidence of NOD. However, the absolute number was small, with 255 participants needing to be on statins for 4 years for an extra case of diabetes, while 5.4 vascular events were prevented within the same period. 36 More recently, a meta-analysis of statin therapy RCTs from the Cholesterol Treatment Trialists’ (CTT) Collaboration group was published. The aim was to provide further insight into diabetes-related adverse events and the impact of statin therapy on diabetes treatment and glycemic control. There were 19 eligible trials involving 123 940 participants over the 4-year duration, with 16 trials (n = 117 437) comprised of participants with and without diabetes and 3 trials (n = 6503) consisting of participants with diabetes only. Compared to placebo, low to moderate-intensity and high-intensity statins contributed to a 10% and 24% increase in risks of worsening glycemia, respectively, without any difference in the diabetes medications escalation between groups. Similar to previous studies, low to moderate-intensity statins and high-intensity statins demonstrated a 10% and 36% proportional increase of NOD, respectively, and the majority were in participants who were already close to the diabetes diagnosis threshold. Although there was a slight increase in the worsening of glycemic control with statins, the authors concluded that it had been taken into account as part of the overall cardiovascular risk reduction with statins. 37
Achieving a target LDL cholesterol of <1.8 mmol/L in patients with diabetes often requires a high-intensity statin. However, high-intensity statin is associated with diabetes progression. In a retrospective primary prevention study, 80 110 men with diabetes, with 21 294 propensity score matching pairs, were followed up over a mean duration of 6 years. The group with a strict LDL cholesterol target ( ⩽1.8 mmol/L) following statin initiation was compared to the group with a more lenient target of >1.8 to 2.58 mmol/L. There was no difference in MACE (6.1% vs 5.8%), microvascular complications (22.3% vs 21%), and total mortality (14.4% vs 15%) between groups, with OR of 1.06 (P = .17), 1.02 (P = .31), and 0.97 (P = .2), respectively. However, diabetes progression was higher in the strict LDL target group (66.7%) compared to the lenient target group (64.1%) with an OR of 1.12 (P < .001). 38
Overall, although statin therapy causes a moderate increase in the rate at which patients are diagnosed with NOD or worsening glycemic control among those with diabetes, the mean changes in glycemia are small. While the current ADA guideline acknowledges the increase in the incidence of T2D with statins, especially in those with diabetes risk factors, 16 there are no recommendations to screen for NOD or diabetes progression. The benefits of using statin therapy in patients who are at increased risk of developing diabetes or have already developed it outweigh the risks.
Clinicians must stay constantly aware of potential adverse events linked to even the most effective cardiovascular preventive therapies. Any patients at risk of diabetes and cardiovascular disease, in whom statins are indicated, must be counseled on strategies to prevent diabetes, such as lifestyle modifications, aiming for weight reduction, and an increase in physical activity. 39 Clinicians may also consider pravastatin or pitavastatin in this at-risk group, due to a lower tendency for NOD. In patients with diabetes at risk of progression, pioglitazone may be a suitable choice due to its effectiveness in reducing NOD, improving lipid profile, and reducing cardiovascular risk. 40
Pitavastatin: Risk of New-Onset Diabetes (NOD) and Impact on Glycemic Control
Pitavastatin is the most recent statin that has garnered some interest in the management of hyperlipidemia in diabetes. 41 It is the third most potent statin after rosuvastatin and atorvastatin, with the ability to reduce LDL cholesterol by 44% at 4 mg daily. 42 To evaluate the cardiovascular outcomes in high-risk individuals, 664 participants with hypercholesterolemia plus 1 or more risk factors for atherosclerotic disease (including 76% with diabetes) were randomized to receive either pitavastatin 2 mg or atorvastatin 10 mg per day, with a follow-up period of 240 weeks. The primary outcome was a composite of cardiovascular death, sudden death of unknown origin, nonfatal MI, nonfatal stroke, transient ischemic attack, or heart failure requiring hospitalization. The secondary outcome was a composite of the primary outcome plus clinically indicated coronary revascularization for stable angina. There was no difference in the LDL cholesterol reduction between the 2 groups. There were 9 (2.9%) participants who reached the primary outcome in the pitavastatin group compared to 25 (8.1%) participants in the atorvastatin group (HR 0.37, P = .01). The pitavastatin group had a lower cumulative 5-year incidence of the primary outcome compared to the atorvastatin group (2.9% vs 8.1%, P = .006). The secondary outcome was also lower in the pitavastatin group (4.5%) compared to the atorvastatin group (12.9%; HR 0.34, P < .001). 43
To date, this is the only published cardiovascular outcome RCT of pitavastatin in participants with diabetes, and it has not been confirmed in subsequent RCTs. A larger double-blind RCT, with fewer patient dropouts and clearly adjudicated endpoints, is needed to support or refute the conclusion of cardiovascular protection with pitavastatin.
Compared to other statins, pitavastatin is associated with a lower risk of NOD. In a real-world, multicenter, comparative, retrospective, observational study, 11 396 participants (new pitavastatin users) were compared to 76 338 participants who were new users of atorvastatin or rosuvastatin. Following propensity score matching, the incidence of NOD 180 days after the start date was 21.7 and 27.8 per 1000 person-years in the pitavastatin group compared to the combined atorvastatin and rosuvastatin group (HR 0.72, 95% CI 0.59-0.87). In further subgroup analyses, pitavastatin was associated with lower NOD risk than atorvastatin (HR 0.69, 95% CI 0.54-0.88) or rosuvastatin (HR 0.74, 95% CI 0.55-0.99). Lower risk of NOD was also associated with pitavastatin compared to moderate-intensity atorvastatin and rosuvastatin groups (HR 0.78, 95% CI 0.62-0.98). There was no difference in the risk of NOD between atorvastatin and rosuvastatin (HR 1.08, 95% CI 0.9-1.29) or between the pitavastatin group and high-intensity combined atorvastatin and rosuvastatin group (HR 0.78, 95% CI 0.55-1.12). 44
Statins are an essential pharmacotherapy for dyslipidemia in patients with diabetes. There is a wealth of evidence supporting the immediate clinical benefits of statins as well as their pleiotropic actions and positive cardiovascular outcomes. It is worth noting that different statin intensity contributes to different cardiovascular outcomes and cholesterol levels in patients with diabetes. When choosing a statin intensity and LDL target, clinicians need to consider the impact of statin intensity on patients’ progression of diabetes. With a low risk of NOD, pitavastatin is a suitable option for patients at risk of diabetes. In contrast to other statins such as atorvastatin and rosuvastatin, larger datasets with more robust study designs are needed to establish the cardiovascular outcomes of pitavastatin in patients with diabetes.
Ezetimibe: The Effectiveness of Combination Therapies on Cardiovascular Outcomes in Diabetes
Ezetimibe significantly reduces LDL and non-HDL cholesterol by inhibiting the absorption of intestinal and biliary cholesterol. 45 Most of the studies with ezetimibe in patients with diabetes involve combination with a statin (statin-ezetimibe). A meta-analysis of 17 RCTs compared the effectiveness of statin versus statin-ezetimibe treatment in patients with T2D, with changes in lipid concentrations as the primary endpoints. The combination treatment demonstrated a greater reduction in LDL cholesterol compared to statin monotherapy with a standard difference in means of 0.691 (95% CI 0.534-0.847). Compared to monotherapy, greater improvement in HDL cholesterol was also seen in combination treatment, with a standard difference in means of 0.28 (95% CI 0.106-0.453). There were significant reductions in TC, Tg, and apo B in combination therapy compared to monotherapy, with standard differences in means of 0.56 (95% CI 0.3-0.751), 0.296 (95% CI 0.122-0.469), and 0.471 (95% CI 0.226-0.716), respectively. 46
Until recently, there has been no study on primary cardiovascular prevention in patients with diabetes with the statin-ezetimibe combination. Data from the Korean National Health Insurance were included in a retrospective cohort study involving 412 245 participants with diabetes. The statin intensity (low, moderate, or high) was based on the American Heart Association/American College of Cardiology (AHA/ACC) guidelines 2018. The primary (composite of MI, stroke, or all-cause death) and secondary outcomes (the incidence of each component of the composite outcome) were evaluated using propensity score matching. The ezetimibe-moderate-intensity statin group had lower LDL cholesterol than the high-intensity statin group (P < .001). However, Tg were lower in the high-intensity statin group (P < .001). The primary outcome was lower in the ezetimibe-moderate-intensity statin group compared to the high-intensity statin group (HR 0.85, 95% CI 0.74-0.98, P = .029), with a reduction in stroke (HR 0.7, 95% CI 0.52-0.93, P = .014). There was no difference in MI (P = .079) and all cause of death (P = .637) between these 2 groups. There was also no difference in the outcomes between the ezetimibe-low-intensity statin and high-intensity statin groups. Based on this study, the addition of ezetimibe to moderate-intensity statins may be considered as a primary prevention strategy in patients with diabetes. 47
The landmark cardiovascular outcome study of ezetimibe is the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) trial. This study included 18 144 participants with acute coronary syndrome, randomized to ezetimibe-simvastatin (ES) or placebo-simvastatin. The ES group had significantly lower LDL cholesterol and a 2% absolute risk reduction in the primary composite endpoint (cardiovascular death, major coronary event, or stroke) after a median 6-year follow-up. 48 Further analyses evaluated the outcome and stratified it based on the presence of baseline diabetes in 4933 participants. The ES group had lower LDL cholesterol compared to the placebo-simvastatin group, irrespective of diabetes status. In participants with diabetes, the ES group demonstrated a 5.5% absolute risk reduction in the 7-year primary outcome compared to the placebo-simvastatin group (40% vs 45.5%; HR 0.85, 95% CI 0.78-0.94). In contrast, there was no difference between ES and the placebo-simvastatin group in participants without diabetes, with an absolute primary outcome reduction of 0.7% (HR 0.98, 95% CI 0.91-1.04). The number needed to treat with ES in participants with diabetes to prevent 1 event over 6 years was 18. Myocardial infarction and ischemic stroke contributed to 24% and 39% relative risk reduction in participants with diabetes with ES compared to the placebo-simvastatin group. Participants were also stratified based on secondary prevention risk scores using the TIMI Risk Score for Secondary Prevention tool. In participants with diabetes, the risk reduction of the primary outcome with ES over placebo-simvastatin was consistent across all the risk strata. However, in participants without diabetes, at high-risk strata, there was an 18% reduction in the primary outcome with ES compared to placebo-simvastatin, while no significant difference was seen in moderate and low-risk strata in this group. It was concluded that there was a significant benefit of adding ezetimibe to statins in patients with diabetes and high-risk patients without diabetes with coronary artery disease. 49
Unlike the IMPROVE-IT trial, which used a similar dose of simvastatin in both comparison groups, the RACING (Randomized Comparison of Efficacy and Safety of Lipid-Lowering with Statin Monotherapy vs Statin/ezetimibe Combination for High-risk Cardiovascular Disease) trial assessed the effects of adding ezetimibe to a moderate-intensity statin regimen (EMS), compared to the use of a high-intensity statin (HS) alone. There was no difference in the 3-year composite cardiovascular outcomes in patients with ASCVD between the EMS and the HS groups, demonstrating the non-inferiority of combination therapy. 50 Further subgroup analyses were conducted in participants with diabetes (n = 1398) with ASCVD. 51 Similar to the main trial results, there was no difference in the rate of the primary outcome in the EMS group compared to the HS group (10% vs 11.3%, HR 0.89, 95% CI 0.64-1.22, P = .46). However, compared to the HS group, participants in the EMS group had a lower rate of medication discontinuation or dose reduction (5.2% vs 8.7%, P = .014), maintained a lower median LDL cholesterol level at 1, 2, and 3 years (P < .001) and had a higher proportion of participants with LDL cholesterol below 1.8 mmol/L at 1, 2 and 3 years (P < .001). This trial supported the use of ezetimibe in combination with a moderate-intensity statin as an alternative to high-dose statin in patients with diabetes and ACSVD.
There is strong evidence supporting the benefit of the ezetimibe-statin combination in reducing the composite cardiovascular outcome in patients with diabetes. Although high-intensity statin is recommended for individuals with ASCVD, issues such as treatment inertia, lack of efficacy, poor adherence, side effects, and cost have resulted in many not reaching the target LDL cholesterol levels in practice. Therefore, it may be beneficial to reconsider the strategy and evaluate the combination of ezetimibe and moderate-intensity statin as a primary option for both primary and secondary prevention. 52
Bempedoic Acid (BA) in Patients With Diabetes
BA is a novel agent that is converted to its active form, bempedoyl-CoA, in the liver. This active form inhibits the enzyme adenosine triphosphate (ATP)-citrate lyase, crucial in the cholesterol biosynthesis pathway. Inhibiting cholesterol synthesis in the liver leads to the upregulation of LDL receptors, which further reduces LDL particles in the blood. It is available as an oral tablet at a dose of 180 mg daily. Studies have demonstrated that combining BA with statin and/or ezetimibe significantly reduces LDL cholesterol, apo B, and hs-CRP in individuals at risk of ASCVD or with familial heterozygous hypercholesterolemia. 53 BA is currently approved for use as an adjuvant to the maximally tolerated statin therapy in individuals with ASCVD, those with heterozygous familial hypercholesterolemia, or individuals who are intolerant to or have contraindications to statins.
An updated meta-analysis and systematic review of 11 trials, including the results from the CLEAR trials involving 18 315 participants, was conducted to evaluate the impact of BA on MACE. There was a 13% reduction in MACE in the BA group compared to placebo (6 trials, n = 17 511; OR 0.86, 95% CI 0.79-0.95) over a median follow-up of 87 weeks. BA was also associated with a reduction of MI, unstable angina, and coronary revascularization with the OR of 0.76 (95% CI 0.64-0.88), 0.69 (95% CI 0.54-0.88), and 0.81 (95% CI 0.71-0.92), respectively. Compared to control, BA reduces LDL cholesterol, TC, non-HDL cholesterol, and apo B lipoprotein at 12 weeks by a mean difference of −22.42%, −16.5%, −20.3%, and −19.5%, respectively. Statin-naive participants experienced a greater reduction in LDL cholesterol at 12 weeks with BA (mean difference −24.13%). However, when BA was used in conjunction with statins, the reduction in LDL cholesterol varied depending on the intensity of the statin therapy. In combination with ezetimibe, BA was associated with an LDL cholesterol reduction of −19.03%. There was a higher risk of gout (OR 1.55, 95% CI 1.27-1.9) in association with BA, while there was no increase in the risk of new-onset diabetes (OR 0.94, 95% CI 0.82-1.06), compared to placebo. 54
The only published study of BA in patients with diabetes was the CLEAR Outcomes study. This was a multicenter, randomized, double-blind, placebo-controlled trial across 32 countries, including 1250 primary care and outpatient services. Participants with an LDL cholesterol of ⩾2.59 mmol/L, irrespective of cardiovascular disease status, unwilling or unable to take the guideline-recommended dose of statin, were randomly assigned to BA or placebo. There were 13 970 participants, including 6373 with diabetes, 5796 with prediabetes, and 1801 without diabetes, followed up over a median of 3.4 years. Participants with diabetes had an absolute risk reduction of 2.4% in MACE with BA (HR 0.83, 95% CI 0.72-0.95) compared with placebo. The proportion of new-onset diabetes was similar between BA and placebo (11.1% vs 11.5%, respectively), and there was no difference in glycated hemoglobin A1c (HbA1c) at 12 months or at the end of the study between participants with pre-diabetes and those without diabetes. The benefits of BA in improving the cardiometabolic profile, coupled with its proven clinical effectiveness, make it a viable therapeutic option for individuals both with and without diabetes. 55 However, clinicians need to be aware of the higher prevalence of cholelithiasis and gout in the BA compared to placebo. Furthermore, the absolute risk reduction in cardiovascular outcomes with BA is modest at best, compared to statin monotherapy. Other non-statin therapies showed cardiovascular benefits when used alongside a maximally tolerated statin in participants with stable atherosclerotic cardiovascular disease. This study offers patients with diabetes an additional option for those who are unable to tolerate statins to help reach the LDL cholesterol target and reduce cardiovascular risk.
BA lowers the risk of cardiovascular outcomes in patients with diabetes compared to placebo. When compared to statins, the effect is only modest at best, and clinicians should be aware of potential side effects. In practice, clinicians may consider BA in patients with diabetes and high ASCVD risk who do not reach their LDL targets on the maximum dose of statin and ezetimibe. BA may also be considered in statin-intolerant patients.
PCSK9 Inhibitors (PCSK9i) in Patients With Diabetes
PCSK9i are monoclonal antibodies that inhibit the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 regulates circulating LDL cholesterol by recycling the LDL receptors on the liver cell surface. When PCSK9 binds to the LDL receptor, it leads to the internalization and degradation of the receptor in lysosomes, reducing the number of receptors available on the cell surface. Inhibiting PCSK9 results in raised numbers of LDL receptors on the cell surface, which enhances the uptake of LDL cholesterol. Alirocumab and evolocumab are the currently approved PCSK9i available in the market as a fortnightly or monthly subcutaneous injection. 56
The landmark cardiovascular outcome studies for PCSK9i were FOURIER (Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease) and ODYSSEY OUTCOMES (Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome).57,58 Both were randomized, placebo-controlled, secondary prevention trials involving approximately 28% to 29% of participants with diabetes, with relatively short median follow-up periods of 2.2 and 2.8 years, respectively. The FOURIER trial included participants with stable atherosclerotic cardiovascular disease, while ODYSSEY focused on those who had acute coronary syndrome between 1 and 12 months prior. The FOURIER trial demonstrated a reduction in the primary composite cardiovascular endpoint (HR 0.85, 95% CI 0.79-0.92, P < .001) and the secondary composite endpoint (HR 0.8, 95% CI 0.73-0.88, P < .001) with evolocumab. However, no effect on cardiovascular mortality was observed (P = .62), likely due to the study’s short duration. 57 The ODYSSEY trial demonstrated a reduction in the primary composite cardiovascular endpoint (HR 0.85, 95% CI 0.78-0.93, P < .001) and all-cause mortality (HR 0.85, 95% CI 0.73-0.98) with alirocumab. Both studies also showed approximately a 25% to 27% reduction in ischemic stroke. 58
A comprehensive systematic review and meta-analysis of PCSK9i in patients with diabetes included 38 randomized controlled trials, encompassing 46 833 patients and 42 770 comparators, with a mean study duration of 36.4 weeks. The median proportion of participants with diabetes was 21.5%. The comparator groups consisted of placebo in 30 trials, ezetimibe in 12 trials, and high-dose statins in 2 trials. The objective was to assess the effects of PCSK9i on the incidence of new diabetes, diabetes parameters, LDL cholesterol levels, and MACE in patients with diabetes. PCSK9i was not associated with an increased risk of NOD, compared to placebo or any other comparators (OR 1.0, 95% CI 0.94-1.07). PCSK9i was associated with a mean difference in LDL cholesterol of −1.36 mmol/L (95% CI −1.07 to −1.65) in participants with diabetes and −1.73 mmol/L (95% CI −1.61 to −1.84) in all participants. Compared to placebo, PCSK9i was associated with a significant reduction in MACE in participants with (OR 0.82, 95% CI 0.74-0.91) and without diabetes (OR 0.73, 95% CI 0.64-0.84). There was no difference in all-cause mortality in participants with (OR 0.53, 95% CI 0.08-3.67) and without diabetes (OR 0.39, 95% CI 0.1-1.47). This was explained by the low event rates in each group, compared to placebo. Although participants with and without diabetes experienced similar reductions in cardiovascular risk, the higher baseline MACE risk in individuals with diabetes suggested that PCSK9i may be cost-effective for this group. 59
A retrospective study was conducted at a single tertiary center involving 237 participants to evaluate the real-world effectiveness of PCSK9i in reducing LDL cholesterol levels and their impact on cardiovascular outcomes over 18 months of follow-up. All-cause cardiovascular events were defined as a composite of any scheduled coronary procedure, acute coronary syndrome, aortic dissection, cerebral ischemic events, new or worsening peripheral vascular disease, peripheral vascular intervention, new or intervention to carotid artery disease, hemodialysis requirement, and heart failure decompensation. MACE was defined as any non-fatal MI, stroke, or cardiovascular death. Participants with diabetes accounted for 26.2%; more than half (51.1%) of the total participants were on concomitant lipid-lowering medications, and 97.5% were on PCSK9i for secondary prevention. At 3 months, 61.2% and 44.1% of participants reached the LDL target < 1.8 mmol/L and <1.4 mmol/L, respectively. At this follow-up, participants with diabetes had a numerically higher proportion of reaching the LDL targets compared to participants without diabetes (<1.4 mmol/L: 51% vs 41.5%; <1.8 mmol/L: 69.4% vs 58.5%, P = .119). At 12 months, this trend became significantly more in participants with diabetes compared to those without diabetes (<1.4 mmol/L: 58.8% vs 30.1%; <1.8 mmol/L: 70.6% vs 49.6%, P = .003). There was a higher risk of cardiovascular outcomes in participants with uncontrolled diabetes (HbA1c > 54 mmol/mol) compared to participants without diabetes (HR 5.1, 95% CI 2.2-12.4, P < .001), while no difference in MACE was seen between participants with and without diabetes (P = .212). This was the first real-world study to demonstrate superior LDL cholesterol reduction in patients with diabetes treated with PCSK9i compared to those without diabetes. However, a significant portion continued to have cardiovascular disease complications, suggesting the importance of managing other risk factors, such as optimizing glycemic control. 60
These studies offered further insights into the use of PCSK9i in patients with diabetes. Although there is no evidence to suggest that PCSK9i raises the risk of NOD, most clinical studies involving PCSK9i enrolled patients on background statin therapy, which could obscure its effects on glucose metabolism. The LDL reduction appears to be similar across groups, as seen in the real-world study. Despite the positive results for MACE in randomized controlled trials, the real-world evidence emphasizes the importance of managing factors that influence cardiovascular outcomes, such as poorly controlled diabetes. Due to cost, clinicians may consider PSCK9i as a secondary prevention strategy in patients with diabetes who do not reach the target LDL level despite maximum dose therapy.
Icosapent Ethyl (IPE) in Patients With Diabetes
IPE is a highly purified and stable ethyl ester of eicosapentaenoic acid (EPA), an omega-3 fatty acid. It effectively treats hypertriglyceridemia through various mechanisms, including the enhancement of lipoprotein lipase activity and the promotion of beta-oxidation of fatty acids in mitochondria, reducing hepatic triglyceride synthesis. Additionally, icosapent ethyl exhibits anti-inflammatory properties and contributes to improvements in endothelial function. 61
IPE is the only omega-3 fatty acid therapy that has been proven to have cardiovascular benefits. The REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention) trial was a placebo-controlled phase 3b RCT. This study involved administering 2 g of IPE twice daily or placebo to 8179 participants who either had established cardiovascular disease or diabetes along with at least 1 additional cardiovascular risk factor. Other inclusion criteria included fasting Tg and LDL cholesterol of 1.69 to 5.63 mmol/L and 1.06 to 2.59 mmol/L, respectively, on a stable dose of statin for 4 weeks. The majority (70.7%) were enrolled as secondary prevention, and 59% of participants in each intervention group had diabetes at baseline. The primary endpoint was a composite of cardiovascular death, non-fatal MI, non-fatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint was a composite of cardiovascular death, non-fatal MI, or non-fatal stroke. At 1 year, the IPE group had a larger reduction in Tg (−18.2% vs +2.2%) and a smaller elevation in LDL cholesterol (3.1% vs 10.2%) compared to placebo. At a median follow-up of 4.9 years, the primary endpoint occurred in 17.2% in IPE compared 22% in the placebo group (HR 0.75, 95% CI 0.68-0.83, P < .001), while the secondary endpoint accounts for 11.2% in IPE compared to 14.8% in placebo group ( HR 0.74, 95% CI 0.65-0.83, P < .001). More participants in the IPE group were hospitalized for atrial fibrillation or flutter (3.1% vs 2.1%, P = .004), while no difference in bleeding events was seen between groups (P = .06). 62
In contrast to REDUCE-IT, the subsequent STRENGTH (Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) trial did not demonstrate a reduction in composite MACE with omega-3 fatty acids added to statin therapy in patients at high cardiovascular risk. STRENGTH was an RCT involving 13 078 statin-treated participants at high cardiovascular risk, randomized to receive either 4 g/day of omega-3 CA (carboxylic acid formulation of EPA and DHA (docosahexaenoic acid)) or corn oil as a comparator. The primary endpoint (similar to REDUCE-IT) occurred in 1384 participants. An interim analysis indicated a low probability of clinical benefit, leading to premature discontinuation of the trial. 63
High-dose purified EPA was used as the active oil in REDUCE-IT, while a combination of EPA and DHA was used in the STRENGTH trial. There is an inverse relationship between omega-3 fatty acid levels and all-cause and cardiovascular mortality, and the differences in the active oils used in these studies may explain the results. Another factor that may contribute to the difference in results is the comparator oil. Mineral oil was used in REDUCE-IT, while corn oil was used in the STRENGTH trial. Mineral oil may be pro-inflammatory, negatively impact lipid profiles, and interfere with the absorption of statins and fat-soluble vitamins, all of which could partly explain the observed reduction in MACE in the icosapent ethyl group. Nonetheless, the U.S. Food and Drug Administration (FDA) concluded that the effects of mineral oils were unlikely to account for the significant benefit observed. 64
The evidence for cardiovascular protection from IPE is inconsistent, primarily due to variations in study design. However, IPE is currently included as part of the therapy that can be considered in patients with diabetes (with ASCVD or other cardiovascular risk factors) and hypertriglyceridemia in addition to statin therapy. 16
Inclisiran in Patients With Diabetes
Inclisiran is a small interfering RNA that inhibits the production of PCSK9 protein by inducing the degradation of PCSK9 mRNA. It has been approved in Europe for adults with primary hypercholesterolemia or mixed dyslipidemia at a dose of 284 mg subcutaneously on day 1, day 90, and every 6 months. 65
The only available data involving inclisiran and patients with diabetes was published recently as part of the post hoc analyses of the ORION-9, 10, and 11 phase 3 placebo RCTs. These pooled analyses included high cardiovascular risk participants with elevated LDL cholesterol despite maximally tolerated statins, in addition to either having heterozygous familial hypercholesterolemia (HeFH), existing ASCVD, or ASCVD risk equivalent. A total of 3658 participants were stratified by glycemic status. Inclisiran reduced the LDL cholesterol in participants with normoglycemia, pre-diabetes and diabetes with a placebo-corrected change in LDL from baseline to day 510 of −47.6% (95% CI −51.9 to −43.3, P < .001), −51.6% (95% CI −55 to −48.3, P < .001) and −51.9% (95% CI −55.7 to −48.1, P < .001), respectively. Irrespective of diabetes status, compared to placebo, inclisiran reduced other lipoprotein parameters, including TC (P = .02), apo B (P < .001), non-HDL cholesterol (P = .04), remnant cholesterol (P = .009), and lipoprotein (a) (P < .001). This report indicated that inclisiran achieved a significant and sustained reduction in cholesterol levels across all diabetes strata. 66
The assessment of inclisiran’s effect on cardiovascular outcomes is limited, as this study was not designed to evaluate MACE. However, the ongoing ORION-4, VICTORION-1 PREVENT, and VICTORION-2 PREVENT trials aim to fill this gap by examining the long-term effects of inclisiran on cardiovascular mortality, myocardial infarction, and stroke in a high-risk group. 67
Other Lipid-Lowering Therapies Less Commonly Used in Diabetes
Fibrates
Fibrates, such as fenofibrate, activate the peroxisome proliferator-activated receptor alpha (PPAR-alpha), which increases lipoprotein lipase, induces the synthesis of HDL, reduces apolipoprotein C production from the liver, and enhances triglyceride-rich particle clearances. Additional action through fatty acid oxidation via the action of acyl CoA synthetase and other enzymes further diminishes Tg synthesis. The overall effect is a reduction in plasma Tg and very low-density lipoprotein levels. 68
Landmark cardiovascular clinical trials on fibrates did not demonstrate any reduction in cardiovascular mortality in patients with diabetes. The FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study included 9795 patients, randomized to receive either placebo or fenofibrate over a 5-year period. Metabolic syndrome (defined as the presence of T2D with 2 other clinical features) was present in 83.4% and 83.7% of patients allocated to fenofibrate and placebo, respectively. Fenofibrate demonstrated a trend in the reduction of the 5-year CVD risk from 14.5% to 13.1% (absolute risk reduction 1.4%), with adjusted HR 0.89 (P = .052), in patients with metabolic syndrome. There was no difference between fenofibrate and placebo for CVD risk reduction in patients without metabolic syndrome in this study (P = .375). 69 The ACCORD (Action to Control Cardiovascular Risk in Diabetes) Lipid included 5518 patients with T2D, HbA1c ⩾ 7.5%, low HDL, and hypertriglyceridemia, randomly assigned to simvastatin-placebo or simvastatin-fenofibrate group, over 4.7 years. The primary outcome includes major cardiovascular events, including nonfatal MI, nonfatal stroke, or death from cardiovascular causes. There was no difference in the primary outcome (2.2% annual cardiovascular event rates in fenofibrate vs 2.4% in placebo) with an adjusted HR 0.92 (95% CI 0.79-1.08, P = .32). 70
A systematic review of the effects of fibrates on cardiovascular outcomes, including 18 clinical trials, 45 058 patients, 2870 major cardiovascular events, 4552 coronary events, and 3880 deaths, was published in 2010. There was a 10% and 13% RR reduction for major cardiovascular events (P = .048) and coronary events (P < .0001), respectively, in favor of fenofibrate. There was no difference in the effect of fenofibrate on the risk of all-cause mortality (P = .92), cardiovascular mortality (P = .59), sudden death (P = .19), stroke (P = .69), or non-vascular mortality (P = .063). A subset analysis in patients with coronary events demonstrated benefit in patients with high Tg, while baseline HDL did not affect the outcomes.71,72
In the PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes) trial, 10 497 patients with T2D (66.9% pre-existing cardiovascular disease), with mild to moderate hypertriglyceridemia and low HDL cholesterol, were randomized to pemafibrate or placebo for 3.4 years. Pemafibrate reduces Tg, VLDL cholesterol, and remnant cholesterol by approximately 26%, while apolipoprotein C-III was reduced by 28%. No difference was seen in the primary end point (composite nonfatal MI, ischemic stroke, coronary revascularization, or death from cardiovascular causes), which occurred in 572 and 560 patients in the pemafibrate and placebo group, respectively, with a HR 1.03 (95% CI 0.91-1.15). 73
A recent large, observational, real-world, population-based study evaluated the impact of fenofibrate on cardiovascular risk in 110 723 patients with diabetes who had Tg levels of 1.69 mmol/L without ASCVD, comparing those on statin and fenofibrate therapy to an equal number of controls on statin monotherapy over 4 years. The incidence of primary outcome: new MI, stroke, both MI and stroke, and all-cause mortality was lower in the combination statin-fenofibrate group by 12.2%, 9.9%, 10.3%, and 28.4% (Kaplan-Meier log-rank test, P < .001 for each comparison), respectively. The group also demonstrated that the association between fenofibrate and lower risk of ASCVD was only observed in participants with LDL cholesterol > 2.07 mmol/L. 74
Due to inconsistent data regarding cardiovascular outcomes, the recommendation to use fibrates in managing dyslipidemia in diabetes has been reduced. 16 However, fenofibrate monotherapy or fenofibrate-simvastatin combination therapy continues to play a role in patients with diabetes and retinopathy, independent of Tg levels, as demonstrated in the ACCORD EYE trial. 75 Fibrates also continue to play a role in the prevention of pancreatitis in individuals with moderate to severe hypertriglyceridemia (between 5.6 and 11.3 mmol/L). 76
Bile Acid Sequestrants (BAS) and Niacin
BAS (cholestyramine, colestipol, colesevelam) reduce LDL cholesterol levels by 15% to 18% by forming an insoluble complex with bile acids in the intestine, therefore, inhibiting cholesterol absorption. Additionally, the reduction of the bile acid pool resulted in increased bile acid synthesis, which competes with cholesterol synthesis in the liver. 77 Due to the absence of cardiovascular outcome benefits78,79 and an increase in gastrointestinal adverse effects, 80 BAS is not recommended in the management of dyslipidemia in patients with diabetes.
Niacin inhibits a crucial enzyme in hepatocyte triglyceride synthesis known as diacylglycerol acyltransferase-2. This inhibition leads to increased intracellular degradation of hepatic apo B, which reduces the secretion of VLDL and LDL particles. 81 Several meta-analyses and systematic reviews showed no effect on MACE, cardiovascular mortality, and all-cause mortality with niacin.82 -84 In addition to the high risk of withdrawal and adverse effects, 84 the use of niacin is currently not recommended in patients with diabetes.
The Effects of Sodium-Glucose Co-transporter-2 Inhibitors (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1a) on Lipids in Diabetes
In individuals with diabetes, SGLT2i decrease the risk of all-cause mortality, major cardiovascular events, and hospitalization for heart failure by up to 38%, 20%, and 39%, respectively. 85 Similarly, in individuals with high or very-high cardiovascular risk (with or without diabetes), GLP-1a reduce the incidence of MACE, cardiovascular death, non-fatal stroke, and non-fatal MI by 13%, 12%, 14%, and 13%, respectively. 86
The impact of these 2 pharmacotherapies on lipid parameters is of interest. A recent meta-analysis of 60 randomized placebo-controlled trials (58 with T2D) included 147 130 participants and examined the effects of SGLT2i on lipid profiles. The results showed a modest increase in TC by 0.09 mmol/L (95% CI 0.06-0.13), LDL cholesterol by 0.08 mmol/L (95% CI 0.05-0.1), and HDL cholesterol by 0.06 mmol/L (95% CI 0.05-0.07), while Tg were lowered by 0.1 mmol/L (95% CI 0.06-0.14). Dose and ethnicity contributed to slight differences in effect sizes, with no differences seen across SGLT2i types. Only 13 trials reported lipid-lowering therapy at baseline, and none reported changes in existing lipid-lowering treatments during the study. These minor variations are unlikely to impact clinical outcomes, as they fall within the laboratory’s established accuracy and precision limits, and most individuals with diabetes are on a treatment or monitoring plan for hyperlipidemia. 87
In a recent systematic review and network meta-analysis, 76 randomized placebo-controlled trials involving 39 246 participants with T2D compared the effectiveness of GLP-1a on glycemic control, body weight, and lipid profile. All GLP-1a, including several novel drugs, were included in this study. Compared with placebo, PEG (polyethylene glycol)-Loxenatide was the only GLP-1a to increase HDL cholesterol, with a mean difference of 0.16 mmol/L (95% CI 0.0-0.31). Semaglutide was the only GLP-1a that effectively lowered LDL cholesterol with a mean difference of −0.16 mmol/L (95% CI −0.3 to −0.02) and TC with a mean difference of −0.48 mmol/L (95% CI −0.84 to −0.11). ITCA 650 (exenatide in an osmotic mini-pump) and tirzepatide reduce Tg with a mean difference of 1.59 mmol/L (95% CI −2.86 to −0.32) and −0.89 (95% CI −1.64 to −0.13), respectively. 88
Although not among the approved pharmacotherapies for hyperlipidemia in diabetes, both SGLT2i and GLP-1a have demonstrated modest lipid-lowering effects. While the primary strength of these agents lies in their cardiorenal protection, the additional positive impact on lipid profiles is welcome.
Future Pharmacological Treatments
Several novel pharmacotherapies are being developed for the management of dyslipidemia. Despite the limited data on cardiovascular outcomes, the ongoing research and its potential implications are noteworthy.
Apo C III is an important regulator of Tg metabolism as it inhibits lipoprotein lipase. 89 Volanesorsen is a second-generation antisense nucleotide that binds to Apo C III mRNA, reducing its expression and effectively decreasing Apo C III and Tg by 70% to 80% in participants with familial chylomicron syndrome (FCS).90,91 However, due to significant thrombocytopenia, further studies are necessary to prove its safety and cardiovascular benefits. 89 To date, no cardiovascular outcome study has been published for volanesorsen. It has received conditional approval from the European Medicines Agency (EMA) for treating adults with FCS while the FDA advisory committee has voted in favor of approving volanesorsen.
Angiopoietin-like protein 3 (ANGPLT3) inhibits lipoprotein lipase and endothelial lipase, raising Tg, LDL cholesterol, and HDL cholesterol levels. Evinacumab is a fully human monoclonal antibody targeting ANGPLT3, resulting in an almost 50% reduction in LDL cholesterol in participants with homozygous familial hypercholesterolemia.92,93 Adverse events that need to be considered include hepatotoxicity, injection site reaction, hepatic fat accumulation, and high cost. 94 In a small, open-label trial, 12 patients with homozygous familial hypercholesterolemia (HoFH) received evinacumab in addition to their stable, maximum-tolerated-dose lipid-lowering therapy. Over 3.5 years of follow-up, no cardiovascular events occurred in the evinacumab group, while 13 events were reported in the control group (incidence per 1000 person-years: 0% vs 59.5%, respectively; adjusted likelihood P = .053). These results are encouraging; however, they are limited by the small sample size (due to the rarity of the condition) and the borderline significance. 95 Evinacumab is currently approved by the FDA and EMA to treat HoFH.
Cholesterol ester transfer protein (CETP) inhibitors reduce the transfer of cholesterol esters from HDL cholesterol to triglyceride-rich lipoproteins, increasing HDL cholesterol and decreasing non-HDL cholesterol. 96 In the REVEAL trials, anacetrapib demonstrated a reduction in the composite primary endpoint of coronary death, MI, or coronary revascularization, with no difference in secondary endpoints. 97 However, the developer of anacetrapib did not pursue regulatory approval after further review of its clinical profile and it was discontinued. Another CETP inhibitor, obicetrapib, is currently in a phase 3 cardiovascular outcome study (estimated completion November 2026) in patients with ASCVD who are not adequately controlled despite maximally tolerated lipid-lowering therapy. 98 Further research is needed to evaluate its role in patients with diabetes.
Lifestyle Interventions and Cardiovascular Outcomes in Diabetes
Lifestyle interventions are a vital part of managing dyslipidemia in diabetes. Following Mediterranean-style dietary patterns, using DASH (Dietary Approaches to Stop Hypertension) meal plans, and increasing physical activity, with the aim of losing 5% to 10% body weight, have been shown to lower LDL cholesterol and triglycerides and raise HDL cholesterol. 99 However, there is insufficient evidence to show that lifestyle changes and weight loss improve cardiovascular outcomes.
The Look AHEAD trial remained the main study evaluating this relationship. Intensive lifestyle intervention (ILI) was compared to standard diabetes support and education (DSE) in 5145 participants with overweight/obesity and T2D. ILI includes a low-calorie diet (target: 1200-1800 kcal/day), increased physical activity (target: 175 minutes per week of moderate-intensity activity), and aims for at least 7% weight loss. Over a median of 9.6 years of intervention, no significant differences in all-cause cardiovascular mortality and morbidity were observed. 100 A further intention-to-treat analysis of the Look AHEAD study with a median follow-up of 16.7 years demonstrated no difference in mortality between groups. 101 In a more recent analysis of the same cohort, participants who experienced any diabetes remission during 12 years of follow-up in the Look AHEAD trial had a 40% lower rate of the composite incidence of CVD (HR 0.6, 95% CI 0.47-0.79) and a 33% lower rate of chronic kidney disease (CKD; HR 0.67, 95% CI 0.52-0.87) compared to participants without remission. 102
Although lifestyle interventions did not produce a significant decrease in all-cause mortality, their neutral effect on death rates, combined with improvements in healthy life years, physical and psychological outcomes, and overall quality of life, support continued recommendations for lifestyle changes in diabetes management.
Conclusion
The relationship between dyslipidemia and diabetes poses a significant challenge in clinical practice, especially given the growing burden of cardiovascular disease in this patient group. CVD remains the leading cause of death worldwide, and patients with diabetes face an increased risk due to the inherent pathophysiological changes associated with their condition. 103 The evidence highlights the complex nature of dyslipidemia in diabetes, where traditional lipid profiles often do not accurately reflect the underlying atherogenic risk. For example, although LDL levels may appear normal or only slightly raised, the presence of sdLDL particles and hypertriglyceridemia indicates a significant rise in cardiovascular risk. 14 This emphasizes the need for clinicians to adopt a more nuanced view when assessing lipid profiles in diabetes, recognizing that conventional measures may conceal substantial atherogenic potential.
Statins demonstrate a clear benefit in reducing cardiovascular events 29 , yet adherence remains a challenge. 104 Patient’s beliefs of low cardiovascular risk, potential harm of statin, possible side effects, cost and poor communication and trust with healthcare experts are the main domains contributing to non-adherence to statin. 105 Clinicians must stay vigilant in monitoring clinical symptoms of adverse events, conducting additional blood tests such as creatine kinase (CK) and liver profile as recommended by local guidelines, while ensuring ongoing lipid profiles and assessment of cardiovascular risk. This ensures that patients receive personalized treatment strategies that take into account individual tolerability and preferences. Clinicians should stay informed about updates to current clinical guidelines, including differences such as ASCVD risk assessments, dose titration, and treatment targets, and recognize the benefits of long-term statin therapy for cardiovascular outcomes.
In line with current guidelines, due to strong evidence of cardiovascular event reduction, we recommend a statin for primary prevention in most patients with diabetes who exceed the cardiovascular risk threshold or have a high cardiovascular risk at baseline. Atorvastatin 20 mg is a good first-choice, as it meets guideline recommendations for a moderate-intensity statin (ADA) or a high-intensity statin (NICE), is relatively inexpensive, and is readily available. For secondary prevention, a high-intensity statin (eg, atorvastatin 80 mg) should be initiated (Figure 1). We strongly recommend addressing any potential statin-induced myopathy systematically. We do not recommend measuring CK in asymptomatic patients. A CK level below 5 times the upper limit of normal reduces the likelihood of statin-induced myopathy, and other causes of muscle pain should be investigated. 18 Options for statin-intolerant patients include switching to a different statin within the same intensity class, switching to a lower-intensity statin, reducing the statin dose, offering nondaily statin dosing, or switching to ezetimibe.16,18 In patients with diabetes and high ASCVD risk who are intolerant to a high-dose statin, we recommend a combination of ezetimibe and a moderate-intensity statin, as highlighted by the RACING trials and the observational cohort study.47,50,51 We recommend adding ezetimibe to patients with diabetes who did not achieve the target LDL/non-HDL reduction with the maximum-tolerated dose of a statin, as highlighted by the IMPROVE-IT trial and NICE guidelines (Figure 1).18,49 BA is an option for statin-intolerant patients (ADA) or in combination with ezetimibe if target LDL/non-HDL reduction is not achieved (NICE).16,18 However, we caution clinicians on the modest absolute cardiovascular risk reduction for BA in addition to a higher prevalence of cholelithiasis and gout as highlighted in the CLEAR outcomes study. We recommend referral to a lipid specialist for any patient who does not achieve the target LDL/non-HDL reduction despite the maximum tolerated dose, or who experiences significant adverse effects from these first-line agents (Figure 1). Among patients with diabetes, PCSK9i has the strongest evidence of reducing cardiovascular events 57 - 59 compared with inclisiran and IPE. Due to cost, PCSK9i is reserved as a secondary prevention in patients with diabetes. 18 However, in other jurisdictions, PCSK9i may be used for primary prevention in addition to a maximally tolerated statin. 16 Given the lack of cardiovascular benefit in patients with diabetes, we do not recommend the use of fibrates, except in the setting of diabetes retinopathy. Finally, we strongly recommend that clinicians incorporate lifestyle interventions into patient care, as they remain central to diabetes management.
Furthermore, there is an urgent need for more research into the effectiveness of these treatments in specific groups, such as older adults, women, ethnically diverse populations, and individuals with multiple health conditions. To date, evidence suggests a reduction in cardiovascular outcomes with lipid-lowering therapies in the elderly population (⩾75 years old) used as a secondary prevention strategy. However, no difference is observed in the population without pre-existing CVD (primary prevention).106,107 Additional data are also required on the role of primary prevention with newer agents (PCSK9i, IPE, and BA) in the elderly population. The cardiovascular risk for women changes significantly with age, pregnancy, and the onset of menopause. 108 However, women and ethnic minorities remained underrepresented in clinical trials for lipid-lowering therapies.108,109 Additionally, women are also underscreened and undertreated compared to men.110,111 Clinical trials that include a wider range of participants will be vital in ensuring treatment guidelines are relevant to the diverse patient groups that clinicians encounter in practice.
Furthermore, research into the economic implications of new treatments is necessary, as understanding their cost-effectiveness will be crucial for integrating them into standard care pathways. Collaboration among researchers, clinicians, and policymakers can promote innovative studies that enhance understanding of dyslipidemia management in diabetes.
Several methods can be employed to improve access, including pricing regulation such as external reference pricing (ERP) and internal reference pricing (IRP), as well as the use of multidisciplinary health technology assessment (HTA). Effective reimbursement policies, such as public insurance programs and universal health coverage, enable the public health system to support medication costs. Additionally, allocating government funds and establishing public-private partnerships will benefit both eligible patients and the involved sectors. Streamlining regulatory processes reduces duplication and accelerates the release of medications to the market, potentially passing on the cost savings to patients. 112
In summary, pharmacological interventions play a crucial role in managing dyslipidemia in diabetes. Lipid-lowering therapy has been shown to not only improve lipid profiles in patients living with diabetes but also to decrease cardiovascular event rates. Among the pharmacotherapies for patients with diabetes, statins have the most consistent evidence on cardiovascular outcomes, are generally safe and inexpensive. Studies have indicated that the duration of statin therapy is the strongest predictor of MACE, followed by the achieved LDL cholesterol level and statin intensity. In the latter’s case, a combination of ezetimibe and a moderate-dose statin is as effective as high-intensity statin therapy. This may help address the challenges of not reaching target LDL cholesterol levels in practice, such as poor adherence, side effects, and cost. To date, BA, PCSK9i, and IPE are available as alternative treatments for patients with diabetes, while future pharmacotherapies in development also show promise. Ongoing research is essential to optimize treatment strategies and explore the long-term effects of these pharmacotherapies.
Supplemental Material
sj-docx-1-end-10.1177_11795514261422310 – Supplemental material for Dyslipidemia in Diabetes: Navigating a Complex Landscape for Improved Cardiovascular Outcomes
Supplemental material, sj-docx-1-end-10.1177_11795514261422310 for Dyslipidemia in Diabetes: Navigating a Complex Landscape for Improved Cardiovascular Outcomes by Roshaida Abdul Wahab and Wan Aizad Wan Mahmood in Clinical Medicine Insights: Endocrinology and Diabetes
Footnotes
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References
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