Future perspectives of the pharmacological management of diabetic dyslipidemia

ABSTRACT

Introduction: Diabetic dyslipidemia is frequent among patients with type 2 diabetes mellitus (T2DM) and is characterized by an increase in triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and small-dense (atherogenic) particles, and by a decrease in low high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo) A1 that are strongly related to insulin resistance. The increased flux of free fatty acids from adipose tissue to the liver aggravates hepatic insulin resistance and promotes all of aspects of the dyslipidemic state.

Areas covered: Statins are the first-line agents for treatment while other lipid-lowering drugs (ezetimibe, fibrate and proprotein convertase subtilisin/kexin type 9) or novel anti-diabetic agents (dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon like peptide-1 receptor agonist (GLP-1RA), sodium/glucose cotransporter 2 inhibitors (SGLT2is)) or nutraceuticals (berberine, omega 3 fatty acid, red yeast rice) can be used alone or in combination.

Expert commentary: In patients with T2DM, lipid abnormalities should be identified and treated as part of the overall diabetic treatment, in order to prevent cardiovascular disease. The choice of drugs to be used is mainly based on the lipid profile and on the characteristic lipoprotein abnormalities; the use of new drugs for the treatment of hyperglycemia and lipids alteration in these patients can improve diabetic dyslipidemia.

KEYWORDS:

• Dipeptidyl peptidase-4 inhibitors (DPP-4is)
• dyslipidemia
• ezetimibe
• fibrate
• glucagon like peptide-1 receptor agonist (GLP-1RA)
• nutraceutical
• proprotein convertase subtilisin/kexin type 9 (PCSK9)
• sodium/glucose cotransporter 2 inhibitors (SGLT-2is)
• statins
• type 2 diabetes mellitus

Article highlights

• The most common pattern of dyslipidemia in patients with type 2 diabetes mellitus (T2DM) is atherogenic dyslipidemia that includes a variety of quantitative and/or qualitative lipoprotein abnormalities as increase in triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and small-dense (atherogenic) particles, and decrease in low high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo) A1.

• Diabetic dyslipidemia is strongly related to insulin resistance. The increased flux of free fatty acids from adipose tissue to the liver aggravates hepatic insulin resistance and promotes all of aspects of the dyslipidemic state.

• In patients with T2DM, lipid abnormalities should be identified and treated as part of the overall diabetic treatment, in order to prevent cardiovascular disease. If the objectives of the lipid profile of patients with T2DM are not achieved with lifestyle changes, it will be necessary to resort to pharmacological treatment.

• Pharmacological management of diabetic dyslipidemia can be achieved by selecting the common (Statin, Ezetimibe, Fibrate) or innovative (Proprotein convertase subtilisin/kexin type 9 (PCSK9) and Nutraceutical) treatment. Hypoglycemic drugs as Glucagon like peptide-1 receptor agonist (GLP-1RA), Dipeptidyl peptidase-4 inhibitors (DPP-4is) and Sodium/glucose cotransporter 2 inhibitors (SGLT-2is) can improve diabetic dyslipidaemia although slightly.

• The diabetic dyslipidemia therapeutic choice must be aimed at managing metabolic complications and cardiovascular risk associated it. The diabetic dyslipidemia therapy must be personalized on the patient to scope of reduce the residual cardiovascular risk associated it.

Clinical trial information

Collaborative Atorvastatin Diabetes Study (CARDS, NCT00327418), Action to Control Cardiovascular Risk in Diabetes (ACCORD, NCT00000620), Heart Protection Study 2- Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRlVE, NCT00461630), Improved Reduction of Outcomes: Vytorin Efficacy International Trial study (IMPROVE-IT, NCT00202878), PROMINENT study (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts with diabeTes; NCT03071692), Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER, NCT01764633, NCT03080935, NCT02867813), safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY outcome study, (NCT01663402), Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG-TERM, NCT01507831), Efficacy and safety of Alirocumab vs Ezetimibe in Statin-intolerant patients, with a statin rechallenge arm (ODYSSEY ALTERNATIVE, NCT01709513), CLEAR Outcomes (NCT02993406), Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results-A Long Term Evaluation (LEADER, NCT01179048), Exenatide Study of Cardiovascular Event Lowering (EXSCEL, NCT01144338), Diabetes Therapy Utilization: Researching Changes in HbA1c, Weight and Other Factors Through Intervention with Exenatide ONce Weekly (DURATION, NCT00308139), FREEDOM-CVO trial (NCT01455896), SUSTAIN-6 CVOT (NCTOI 720,446), Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA, NCT01147250), HARMONY 1-8 trials (NCT00849056, NCT00849017, NCT00838903, NCT00838916, NCT00839527), EMPA-REG (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (NCT01131676), Canagliflozin Cardiovascular Assessment Study (CANVAS, NCT01032629), Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus (SAVOR-TIMI 53, NCT01107886), EXamination of cArdiovascular outcoMes with alogliptlN vs. standard of care (EXAMINE, NCT00968708), ANCHOR (NCTOI 047501)Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT, NCT01492361), A LongTerm Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh Cardiovascular Risk PatienTs With Hypertriglyceridemia (STRENGTH, NCT02104817).

Declaration of interest

AM Patti and RV Giglio have participated in clinical trials sponsored by AstraZeneca, Eli-Lilly and Novo Nordisk. M Rizzo has received grants and/or fees from Amgen, Astra Zeneca, Boehringer-Ingelheim, Eli-Lilly, Meda Pharma, Merck, Novo Nordisk, Roche, Servier. N Papanas has been an advisory board member of TrigoCare International, Abbott, AstraZeneca, Elpen, MSD, Novartis, Novo Nordisk, Sanofi-Aventis and Takeda; has participated in sponsored studies by Eli Lilly, MSD, Novo Nordisk, Novartis and Sanofi-Aventis; received honoraria as a speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elpen, Galenica, MSD, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi-Aventis, Takeda and Vianex; and attended conferences sponsored by TrigoCare International, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Pfizer and Sanofi-Aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.