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Abdulrahman Zafer Alsallam et al, 2020 ;4(2):473–476.

International Journal of Medicine in Developing Countries

Management of diabetic dyslipidemia: a brief review

Abdulrahman Zafer Alsallam1, Dhafer Mohammed Alyami2, Abdulmalik Abdullah Alshoshan3, Slwan Ali Alrabaei4, Almaha Ali Atafi4, Mohamad Theeb A Otaibi1, Abdullah Khalid Alshebili3

Correspondence to: Abdulrahman Zafer Alsallam

*Al-Maarfah University, Riyadh, Saudi Arabia.

Email: aalsallam2 [at] gmail.com

Full list of author information is available at the end of the article.

Received: 03 December 2019 | Accepted: 24 December 2019


ABSTRACT

Diabetic dyslipidemia can play a significant role in many pathogenic processes, particularly cardiovascular diseases. Consequently, it is essential to evaluate the therapeutic alternatives for the treatment of diabetic dyslipidemia. This review paper aims to explore the options of treatment of diabetic dyslipidemia in adults. A filtration procedure was used to remove duplicates, irrelevant publications. The online databases Ovid, Pubmed, and Google Scholar were used to perform a literature search for publications published between 2011 and 2019, without any date or language restrictions. We used a combination of relevant search terms “management’,” “diabetes’,” “diabetic dyslipidemia,” and resulting papers were then thoroughly screened. We independently identified publications and systematically screened titles, abstracts, and full texts of the collected publications. Among 30 articles initially selected based on the title and abstract, 24 articles were excluded. Finally, six articles were selected and included in the systematic review. Aggressive management of diabetic dyslipidemia was found mandatory and was observed to be strongly recommended by the current American guidelines. Controlling of diabetic dyslipidemia can significantly decrease the rate of cardiovascular ailments.


Keywords:

Diabetes mellitus, dyslipidemia, treatment.


Introduction

Risk minimization of cardiovascular diseases is considered the most critical perspective in treating diabetic patients [1]. There are multiple and additional risk factors other than increased blood glucose that results in the increasing incidence of cardiovascular diseases in diabetic patients [2]. One of the most significant factors is diabetic dyslipidemia [3]. Atherosclerotic cardiovascular disease is regarded as the most lethal disease in the developed countries [4]. In the United States, it is estimated that 2,000 deaths occur daily due to atherosclerotic diseases [5]. Additionally, diabetes is regarded as a major influencer on atherosclerotic diseases, in addition to being on the top of the list of lethal diseases globally [6]. Moreover, diabetic patients are at two to four increased risk of death from atherosclerotic diseases compared to non-diabetic peers [7]. Also, the rise in diabetes prevalence represents a public burden that needs urgent, as well as aggressive interventions to solve the problem [8]. Consequently, the main consequences arising from developing diabetic dyslipidemia are premature atherosclerosis, which is primarily because of an increase in apolipoprotein B, as well as pancreatitis, particularly if triglyceride level is above 1,000 mg/dl [9].


Data Search

The online databases Ovid, Pubmed, and Google Scholar were used to perform a literature search for publications published between 2011 and 2019, without any date or language restrictions. We used a combination of relevant search terms “management,” “diabetes, ” “diabetic dyslipidemia,” and resulting papers were then thoroughly screened. We independently identified publications and systematically screened titles, abstracts, and full texts of the collected publications. Among 30 articles, initially selected based on the title and abstract, 24 (nine Twenty articles were discussing either diabetes or dyslipidemia solely, while four articles were short editorials or poster presentations) articles were excluded. Finally, six articles were selected and included in the systematic review.


Discussion

The management of diabetic dyslipidemia has been exposed to major alterations in the past few years. However, Low-Density Lipoprotein (LDL) levels are constantly remaining the major target of dyslipidemia medications [10]. Also, the American diabetes association (ADA) recommendations in 2019 supported the use of high-intensity statin therapy for all diabetic subjects who have atherosclerotic cerebrovascular disease (ASCVD) or with 10-year cardiovascular risk greater than 20%. This recommendation is in parallel to lifestyle changes [11]. Furthermore, patients with diabetes who are aging forty years or older, who have an additional risk for atherosclerotic disease, such as hypertension, chronic kidney disease, familial hypercholesterolemia, or smoking, in addition to patients who are between 40 to 75 years old without any comorbidity except diabetes, and patients who are above 75-year old with diabetes, all should be managed utilizing moderate-intensity statin therapy, targeting a decrease in LDL level by 30% to 49% [12]. The most recent the American College of Cardiology (ACC) and American Heart Association (AHA) recommendations also supported the ADA guidelines. Diabetes was described as a strong predictor for ASVCD [13]. Also, the guidelines described a list of predictors that strengthen the risk of ASCVD, including the onset of diabetes of more than 10 years for type 2 diabetes, as well as the onset of type 1 diabetes of more than 20 years. Additionally, neuropathy, retinopathy, reduced brachial index, and increased albuminuria were all influencers for ASCVD. Also, moderate-intensity statins were recommended for patients aging between 40 and 75 years old [14]. As for diabetic patients who have a range of predictors for ASCVD or those who have atherosclerotic disease should be prescribed a high-intensity statin agent. The therapy should target the lowering of the LDL level by about 50% [15]. Yet, patients who are older than 75-year old should be continued on their therapy as long as their kidney and liver function is within the normal range [16]. In individuals who are aging between 40 and 75 years old who do not have ASCVD and their LDL level is below 190 mg/dl, should be evaluated using the pooled cohort equation to evaluate their risk. This calculator considers the patient’s age, race, comorbidities, and smoking habit to evaluate their risk of ASCVD in the future ten years [17]. In the case of ASCVD risk of greater than or equal 20%, LDL should be reduced by not less than 50%, where diabetic patients aging between 20 to 30 years old should take moderate-intensity statin [18]. Other pharmacological agents to treat dyslipidemia include statins, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors, cholesterol absorption inhibitors, fibrates, and niacin.

Statins

Statin is considered the treatment of choice to reduce LDL levels. The major mechanism of action for statins ids through the inhibition of HMG CoA reductase enzyme that inhibits the rate-limiting step in the cholesterol synthesis. Statins are mainly recommended by AHA and ADA guidelines to be prescribed in primary and secondary prevention of ASCVD, with its three dose ranges, high, moderate and low intensity [18,19]. By reducing circulating cholesterol levels in the blood, statins can improve the expression of LDL receptors, which aids in a further reduction in cholesterol level, and additional protection from ASCVD [3,8,9]. Additionally, statins can reduce triglyceride levels and improve HDL levels, but this is to a lower extent compared to a reduction of LDL [14,18]. In addition to the reduction of cholesterol levels, statins have an additional potential to reduce cardiovascular risk through its pleiotropic effect, which means that the drug has other actions away from its major mechanism of action. Through pleiotropic effect, statins can reduce vascular inflammation, reduce platelet aggregation, and improve plaque stabilization [4,6]. It is worth to mention that the pleiotropic effect is established with a high-intensity statin, which also can reduce LDL levels of about 15-20%. As for moderate-intensity statin, it has a lower pleiotropic effect compared to a high-intensity statin, with LDL reduction between 30% to 50 % [11].

Cholesterol absorption inhibitors (Ezetimibe)

Ezetimibe acts on LDL levels through inhibiting cholesterol absorption from the intestines. Ezetimibe is usually combined with statins for a synergistic effect on LDL reduction. Also, it can substitute statins in patients who do not tolerate statin therapy [13]. Some previous studies showed that Ezetimibe prescription combined with statin therapy in acute coronary syndrome patients who have acceptable LDL levels (below 130 mg/dl) can produce a significant reduction in LDL levels compared to placebo and low-intensity statins [12,14]. It is important to note that the proven benefit of statin/ezetimibe combination is only achievable with long-term administration [14,17]. Additionally, ezetimibe showed an additional reduction in primary events including unstable angina, cardiac revascularization, stroke, myocardial infarction, and cardiovascular death by 6.4%. This finding proves the privileges of the synergistic effect of ezetimibe when added to statin therapy [14,17].

Moreover, the role of ezetimibe in diabetic patients has been rigorously tested. Ezetimibe showed a 14% reduction in atherosclerotic risk in diabetic patients when used for primary prevention. Additionally, statin/ezetimibe combination decreased the risk of ischemic stroke when prescribed for secondary prevention [11,13].

Proprotein Convertase Subtilisin/Kexin Type 9 inhibitors (PCSK9 inhibitors)

The only two available agents in the recently approved PCSK 9 inhibitors class are Alirocumab and Evolocumab. PCSK 9 inhibitors proved to be effective medications, that can reduce the level of LDL when used solely or combined with statin therapy [18,19]. The novel PCSK9 inhibitors act through binding to PCSK9 protein to halt its attachment to LDL receptors, thus rendering them inactive and prevent LDL receptors to break down by lysosomes. In turn, the inhibition of PCSK9 protein will lead to improved production of LDL receptors, and consequently, a significant reduction in LDL levels [2,8]. A significant advantage of PCSK9 inhibitors is that they are administered every 2 to 4 weeks in an injectable form. This can have a significant positive impact on patient compliance and cholesterol control [2,5]. The approved indication for PCSK9 inhibitors is mainly in case of failure of a maximal tolerable dose of statin to reduce LDL below 70 mg/dl, either with or without ezetimibe combination. Also, PCSK9 inhibitors are uniquely adventitious in the case of homozygous and heterozygous familial hypercholesterolemia with LDL levels greater than 190 mg/dl [4,7,18].

Fibrates

Fibrates are another important pharmacological class that has a potential benefit in diabetic dyslipidemia. However, fibrates are mainly targeting triglyceride levels. Fibrates can reduce the level of triglyceride by up to 50% from baseline; this action is mainly through reducing the fatty acids formation. Another additional benefit of fibrate is through improving HDL levels which are considered a negative risk factor for ASCVD [6,14]. The benefit of fibrates on primary and secondary prevention of cardiovascular events has been thoroughly examined. Gemfibrozil, a potent fibrate, showed up to a 30% reduction in triglyceride level and up to 10% improvement in HDL compared with placebo, yet it has minimal effect on LDL level [11,13]. Additionally, the benefit of fibrates was extended to include nonfatal myocardial infarction and cardiovascular mortality. Fibrates reduced mortality in ASCVD patients by 4%. Although, the included patients were not in statin therapy and were considered low-risk patients in terms of low LDL levels [12,18]. Not only gemfibrozil was studied, but also fenofibrate benefit in diabetic patients was evaluated. Fenofibrate significantly reduced the incidence of macro and microvascular complications in type 2 diabetes. However, fenofibrate failed to reduce primary composite cardiovascular endpoints after long-term administration, which explains the higher recommendation of ADA and AHA for statins compared to fibrates in ASCVD patients [3,8,14].

Niacin

Another effective medication that can control high triglyceride levels is Niacin. Moreover, niacin can also improve low HDL levels, with minimal action on reducing LDL levels. In spite of these benefits, niacin failed to show any added benefit on cardiac basis even when combined statin [9,15,18]. Even in the case of high-risk patients, niacin failed to reduce the risk of atherosclerosis in high-risk patients who were already on simvastatin and ezetimibe synergistic combination [3,9]. Therefore, neither AHA nor ADA recommends a combination of both niacin and statin therapy as a treatment option to reduce ASCVD risk by controlling the lipid profile of diabetic dyslipidemia patients [10,13]. Another important consideration in addition to medications is lifestyle modifications. Physical activity and diet/caloric control can have a significant influence on ASCVD risk when matched with cholesterol-lowering medications [12,17,19].


Conclusion

Diabetic dyslipidemia is a common medical problem among diabetic patients which imposes a significant risk on ASCVD. Medications that treat hypercholesterolemia have an established role in primary and secondary prevention of ASCVD in diabetic dyslipidemia patients. Statins are the major pharmacological class with proven benefit, while PCSK-9 inhibitors have promising benefits that could be proved in the future years. Improving the level of knowledge of the general public about the privileges of controlling diabetic dyslipidemia will have a positive influence on the reduction of ASCVD burden, especially in the developing countries.


List of Abbreviations

ADA American Diabetes association
ASCVD Atherosclerotic cerebrovascular disease

Conflict of interest

Not applicable.


Funding

None.


Consent for publication

Not Applicable.


Ethical approval

Not applicable.


Author details

Abdulrahman Zafer Alsallam1, Dhafer Mohammed Alyami2, Abdulmalik Abdullah Alshoshan3, Slwan Ali Alrabaei4, Almaha Ali Atafi4, Mohamad Theeb A Otaibi1, Abdullah Khalid Alshebili3

  1. Al-Maarfah University, Riyadh, Saudi Arabia
  2. Tabuk University, Abha, Saudi Arabia
  3. Qassim University, Qassim Region, Saudi Arabia
  4. King Abdulaziz University, Jeddah, Saudi Arabia

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How to Cite this Article
Pubmed Style

Alsallam AZ, Alyami DM, Alshoshan AA, Alrabaei SA, Atafi AA, Otaibi MTA, Alshebili AK. Management of diabetic dyslipidemia: a brief review. IJMDC. 2020; 4(2): 473-476. doi:10.24911/IJMDC.51-1575410730


Web Style

Alsallam AZ, Alyami DM, Alshoshan AA, Alrabaei SA, Atafi AA, Otaibi MTA, Alshebili AK. Management of diabetic dyslipidemia: a brief review. https://www.ijmdc.com/?mno=76480 [Access: October 15, 2021]. doi:10.24911/IJMDC.51-1575410730


AMA (American Medical Association) Style

Alsallam AZ, Alyami DM, Alshoshan AA, Alrabaei SA, Atafi AA, Otaibi MTA, Alshebili AK. Management of diabetic dyslipidemia: a brief review. IJMDC. 2020; 4(2): 473-476. doi:10.24911/IJMDC.51-1575410730



Vancouver/ICMJE Style

Alsallam AZ, Alyami DM, Alshoshan AA, Alrabaei SA, Atafi AA, Otaibi MTA, Alshebili AK. Management of diabetic dyslipidemia: a brief review. IJMDC. (2020), [cited October 15, 2021]; 4(2): 473-476. doi:10.24911/IJMDC.51-1575410730



Harvard Style

Alsallam, A. Z., Alyami, . D. M., Alshoshan, . A. A., Alrabaei, . S. A., Atafi, . A. A., Otaibi, . M. T. A. & Alshebili, . A. K. (2020) Management of diabetic dyslipidemia: a brief review. IJMDC, 4 (2), 473-476. doi:10.24911/IJMDC.51-1575410730



Turabian Style

Alsallam, Abdulrahman Zafer, Dhafer Mohammed Alyami, Abdulmalik Abdullah Alshoshan, Slwan Ali Alrabaei, Almaha Ali Atafi, Mohamad Theeb A Otaibi, and Abdullah Khalid Alshebili. 2020. Management of diabetic dyslipidemia: a brief review. International Journal of Medicine in Developing Countries, 4 (2), 473-476. doi:10.24911/IJMDC.51-1575410730



Chicago Style

Alsallam, Abdulrahman Zafer, Dhafer Mohammed Alyami, Abdulmalik Abdullah Alshoshan, Slwan Ali Alrabaei, Almaha Ali Atafi, Mohamad Theeb A Otaibi, and Abdullah Khalid Alshebili. "Management of diabetic dyslipidemia: a brief review." International Journal of Medicine in Developing Countries 4 (2020), 473-476. doi:10.24911/IJMDC.51-1575410730



MLA (The Modern Language Association) Style

Alsallam, Abdulrahman Zafer, Dhafer Mohammed Alyami, Abdulmalik Abdullah Alshoshan, Slwan Ali Alrabaei, Almaha Ali Atafi, Mohamad Theeb A Otaibi, and Abdullah Khalid Alshebili. "Management of diabetic dyslipidemia: a brief review." International Journal of Medicine in Developing Countries 4.2 (2020), 473-476. Print. doi:10.24911/IJMDC.51-1575410730



APA (American Psychological Association) Style

Alsallam, A. Z., Alyami, . D. M., Alshoshan, . A. A., Alrabaei, . S. A., Atafi, . A. A., Otaibi, . M. T. A. & Alshebili, . A. K. (2020) Management of diabetic dyslipidemia: a brief review. International Journal of Medicine in Developing Countries, 4 (2), 473-476. doi:10.24911/IJMDC.51-1575410730