Atherogenic Dyslipidemia in Diabetes Mellitus: A Literature Review of Pathophysiology and Potential Drugs for Treatment

Atherogenic Dyslipidemia in Diabetes Mellitus: A Literature Review of Pathophysiology and Potential Drugs for Treatment
Raphael de Magalhães Cipriano ^a, Thayná Nara Costa Silva ^a, João Pedro Mores Artifon ^a, Larissa Gomes Melo Matos ^a, Artur de Tassis Cabral Fernandes ^a, Mariana da Costa Portugal Duarte ^b, Rodrigo Oliveira Moreira ^d,e, Humberto Batista Ferreira ^a,f

a Faculdade Ciências Médicas de Minas Gerais (FCM-MG). Belo Horizonte - MG, Brazil.

b Felício Rocho Hospital. Belo Horizonte. MG, Brazil.

d Centro Universitário Presidente Antônio Carlos Juiz de Fora (UNIPAC/JF). Juiz de Fora - MG, Brazil.

e Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione (IEDE). Rio de Janeiro - RJ, Brazil.

f Universidade Federal de Minas Gerais (UFMG). Belo Horizonte - MG, Brazil.

*Correspondence to Raphael de Magalhães Cipriano, Faculdade Ciências Médicas de Minas Gerais (FCM-MG). Belo Horizonte - MG, Brazil.

Copyright
© 2025 Raphael de Magalhães Cipriano. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 02 January 2025

Published: 17 January 2025

DOI: https://doi.org/10.5281/zenodo.14677416

Abstract

INTRODUCTION: Dyslipidemic in diabetic patients is an important factor in the increase of cardiovascular risk. The use of statins reduces mortality and cardiovascular risk, mainly by decreasing LDL levels. AIMS: Review the cardiovascular risk in diabetic, the therapies used, their benefits and risks. METHODS: The present review was conducted using the PICOs a search strategy. By means of a literature search in CENTRAL (MEDLINE) via Pubmed and EMBASE databases. RESULTS AND DISCUSSION: The studies included in the review presented as outcomes to statin use the reduction of overall mortality between 10-14% in primary prevention with risk factors for cardiovascular events. A 25% reduction in all-cause relative risk was noted, and a trend toward a near 22% reduction in the number of fatal and nonfatal strokes. In 7 other clinical trials, a 30% reduction in the number of fatal acute infarctions was estimated. CONCLUSION: Secondary prevention is well established in diabetic patients using statins, its risks and benefits are balanced with additional gain in longer life to the patient and low risk of complications. In primary prevention there is a need for stratification of patients so that we achieve the greatest individual benefit.

Keywords: Diabetes; Hypercholesterolemia; Cardiovascular Risk; Statins.

Introduction
Dyslipidemia is a cumulative risk factor alongside other metabolic disorders in patients with diabetes mellitus (DM) that increases cardiovascular risk. In this patient group, atherogenesis is accelerated by quantitative and qualitative characteristics of cholesterol patterns, suggesting higher cardiovascular risk (CVR).¹.

According to the World Health Organization (WHO) and the International Diabetes Federation, it is estimated that by 2045 there will be approximately 630 million people aged 20 to 70 diagnosed with type 2 diabetes mellitus (DM). Complications associated with poor disease control are significant determinants in the costs of public and private healthcare.².

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality among patients with DM, occurring up to 14.6 years earlier. Approximately two-thirds of deaths in these patients are due to cardiovascular diseases (CVD).3

At the diagnosis of DM, dyslipidemia is found in 75-82% of patients. Therefore, an  individualized  and  intensive  approach,  both  pharmacological  and non-pharmacological, is necessary.

Clinically, the impact of dyslipidemia on cardiovascular outcomes was established following evaluations from the "Coronary Drug Project" study. Elevated levels of Low Density Lipoprotein (LDL) were established as a direct predictor of risk for mortality and morbidity outcomes related to CVD.

In diabetic patients, the approach to dyslipidemia has been intensively modified with the aim of achieving increasingly challenging reductions, due to gains in life expectancy, cost savings to healthcare systems worldwide, and prevention of cardiovascular events through lowering levels of low-density lipoprotein cholesterol (LDL-C).

The aim of this study is to review cardiovascular risk (CVR), especially in patients with DM, the therapies used, their benefits, and risks.

Methodology

The exploratory review was conducted using an evidence-based review method and aimed to answer the following question: The use of statins is able to prevent cardiovascular outcomes associated with dyslipidemia, and pharmacological therapies are effective and safe?

The search strategy was constructed based on the PICOs framework:

? P (population): population at increased risk of dyslipidemia;

?  I (intervention): pharmacological therapy for dyslipidemia;

?  C (comparator): placebo;

?  O (outcomes): cholesterol control, cardiovascular outcomes, adverse events, and serious adverse events;

? S (studies): randomized clinical trials, literature reviews, systematic reviews, and cohort studies published from 2000 to 2021;

A review was conducted in the CENTRAL (MEDLINE) database via PubMed and EMBASE, using keywords to search for scientific articles evaluating the treatment of dyslipidemia. Double-blind, randomized, controlled clinical trials, systematic reviews, literature reviews, and meta-analyses on dyslipidemia treatment published from 1990 to 2022 were selected.

The sample size calculation was not conducted, as this is a narrative review.

As research instruments, databases available in major methodological references were used.

The search strategy will be adapted to the equivalent language of other reference databases in possible databases.

-      LILACS (Latin American and Caribbean Health Sciences Literature);

-          MEDLINE (Medlars On Line)

-          The Cochrane Central Register of Controlled Trials (CENTRAL);

-          PUBMED

The sampling consisted of a two-stage analysis; in the first stage, a simple random sample of studies that meet the eligibility criteria according to the Jadad scale will be conducted. In the second stage, studies that allowed the evaluation of the desired objectives were included.

The data will be stored in the Access 2013 program, Microsoft Corporation®USA. For statistical analysis, the SPSS 21.0 program, IBM®SPSS Statistics, will be used.

With the method adopted for this research, no risks for patients were identified.

Results

In this review, 6 articles were included, encompassing systematic reviews, clinical trials, and literature reviews. Based on the reading of these articles, we organized Table I to highlight aspects such as: article authorship, study design, main data obtained regarding samples/location, participant characteristics, and the main results of the respective articles, focusing primarily on the comparison of cardiovascular outcomes based on the therapeutic approach studied by the authors.

Table I. Main results of the meta-analyses included in this revie

Author	Study design	Sample / Location	Participants' characteristics	Main results
C Baigent et al.4	Systematic Review	Meta-analyses of individual participant data from randomized trials involving at least 1000 participants and at least 2 years of treatment duration comparing more versus less intensive statin regimens.	169,138 patients, of whom 87,903 were women and 25,920 had a diagnosis of diabetes. 41% of the sample did not have established cardiovascular disease.	In trials comparing more aggressive therapy versus less intensive statin therapy, the weighted mean reduction in LDL at 1 year was 0.51 mmol/L. Compared to less intensive regimens, more intensive regimens resulted in a highly significant 15% additional reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13%, coronary revascularization of 19%, and ischemic stroke of 16%.
Paul M Ridkeret al.5	Clinical Trial	Randomized clinical trial of 17,802 apparently healthy men and women.	17,802 apparently healthy men and women.	Median follow-up of 1.9 years (maximum, 5.0). The use of Rosuvastatin reduced LDL levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary endpoint were 0.77 and 1.36 per 100 years of follow-up in the rosuvastatin and placebo groups, respectively, with corresponding rates of 0.17 and 0.37 for myocardial infarction, 0.18 and 0.34 for stroke, 0.41 and 0.77 for revascularization or unstable angina, 0.45 and 0.85 for the combined endpoint of myocardial infarction, stroke, or death from cardiovascular causes, and 1.00 and 1.25 for death from any cause. Consistent effects were observed in all evaluated subgroups. The rosuvastatin group did not have a significant increase in myopathy or cancer but had a higher incidence of physician-reported diabetes.
Rory Collins et al.6	Systematic Review	Review comprising 308 articles that analyze the main aspects of cholesterol reduction and cardiovascular risk reduction, as well as the profile of side effects.	(The original table did not include the characteristic of patients)	Reducing LDL cholesterol by 2 mmol/L with an effective low-cost statin regimen (e.g., atorvastatin 40 mg per day for 5 years in 10,000 patients) would typically prevent major vascular events from occurring in about 1000 high-risk patients (i.e., 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (i.e., 5% absolute benefit) who are at higher risk but have not yet had a vascular event (primary prevention). Since statin therapy further reduces the risk of vascular events during each year it is taken, longer therapy would yield even greater absolute benefits. The only adverse events definitively shown to be caused by statin therapy — that is, adverse effects of statins — are myopathy (specifically defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase) and diabetes.
James A. Blument hal et al.7	Randomized Clinical Trial	Voluntary sample of 160 older sedentary adults with cardiovascular disease (CVD) followed at an academic tertiary care medical center.	Patients over 60 years old enrolled in the ILLUMINATE trial between December 2011 and March 2016.	The prevalence of obesity, central obesity, and lipids were elevated at 13%, 11%, and ≥20%, respectively, and 70% of the children had at least one cardiometabolic risk factor. Most correlations between obesity and central obesity indicators were moderate to strong (0.40 < r < 0.96). Obesity was positively, but weakly associated with C-reactive protein in both sexes and with homeostasis model assessment of insulin resistance only in girls (all r < 0.3, P < 0.05). Obesity indicators were not related to interleukin-6 concentrations and lipids (P > 0.05). Overall, obesity indicators explained a maximum of 8% of the variability in cardiometabolic risk factors.
Richard Kones et al.8	Non-systematic Literature Review	516 randomized clinical trials, cohort studies, and prospective studies.	Heterogeneous and multivariate analysis not amenable to individual comparison. Heterogeneous profiles.	In primary prevention, traditional risk factors used in combination to generate global scores do not predict risk sufficiently, nor do they adequately discriminate between those who will have cardiovascular events and those who will not. Defining the best approach to cardiovascular prevention cannot currently be based solely on hard endpoint data but partly on evidence-based synthesis using inductive reasoning.
Rory Collins et al.6	Systematic Review	Review comprising 308 articles that analyze the main aspects of cholesterol reduction and cardiovascular risk reduction, as well as the profile of side effects.	Figure 1