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LDL-C Levels and Cardiovascular Risk

What is the best strategy to target LDL-C levels and improve cardiovascular outcomes?

Diabetic dyslipidemia predisposes patients to an increased risk of cardiovascular disease and death. There is well-established evidence between the risk of ischemic heart disease (IHD) and cholesterol in both diabetic and non-diabetic patients. However, this risk increases by twofold in patients with diabetes. The pathophysiological mechanism by which these patients develop dyslipidemia is of great concern. Diabetic dyslipidemia is characterized by elevated concentrations of triglycerides (TG) and low-density lipoproteins (LDL), with decreased concentrations of high-density lipoproteins (HDL). These abnormalities are not isolated one from another, but each of them has a metabolic link leading to atherogenic dysfunction in the vascular endothelium. These effects have prompted major disease-management guidelines to set targets for LDL-C levels when managing dyslipidemia in patients with diabetes. However, there is lack of a consensus when it comes to defining appropriate target levels in these patients. The most recent update to the American Heart Association guidelines focuses on managing dyslipidemia based on statin intensity without taking into consideration LDL-C levels. This leads to the question: do more or less stringent LDL-C levels improve cardiovascular disease outcomes and mortality?

In a recent cohort study done by Morton Leibowitz and colleagues, the use of statins and achieved LDL-C levels was assessed looking to establish a relationship and understand the risk of cardiovascular events in patients adherent to statin therapy with pre-existing ischemic heart disease (IHD). Participants in this observational study were ages 30-84 years with pre-existing ischemic heart disease (IHD). Those patients with uncontrolled metabolic abnormalities, such as fasting glucose higher than 300 mg/dL, abnormal serum thyrotropin levels (>6 mIU/L or <0.4 mIU/L), LDL-C greater than 130 mg/dL or triglycerides greater than 600 mg/dL, were excluded from the study. After taking into consideration the inclusion and exclusion criteria, 31,619 patients were part of the study and at least 80% were adherent to statin therapy one year prior to enrollment. The exposure of the study was defined by the first observed LDL-C level achieved after at least 1 year of statin use (low, moderate, or high intensity). The study outcome was defined as MACE. MACE was defined as the first occurrence of myocardial infarction (MI), unstable angina, stroke, percutaneous coronary intervention, coronary artery bypass grafting, or all-cause mortality during the study period.

After the intervention, analysis found 9,086 patients with an index LDL-C of <70 mg/dL (low); 16,782 patients had an index LDL-C of 70.1-100 mg/dL (moderate), and 5,751 patients had an index of 100.1-130 mg/dL (high). From that total study population, 9,035 patients experienced MACE. There were more MACE events in the low index LDL-C group when compared to the moderate index LDL-C group, 4,595 and 2,681, respectively (unadjusted HR 1.10; 95% CI, 1.05-1.15; P<0.001 vs adjusted HR 1.02; 95% CI 0.97-1.07; P=0.54). In the high index LDL-C group 1,759 MACE events were identified (unadjusted HR 0.87; 95% CI 0.83-0.92; P<0.001 vs adjusted HR 0.86; 95% CI 0.84-0.94; P<0.001 when compared to the moderate index LDL-C group). All patients were either on pravastatin, atorvastatin, simvastatin, or rosuvastatin, with the majority of patients taking simvastatin

Results from the study show that having a low LDL-C index (<70 mg/dL) did not reduce the risk of MACE when compared to those patients with a moderate LDL-C index (70.1-100 mg/dL). However, when comparing those patients with a moderate LDL-C index and a high LDL-C index, the risk of MADE was lower in the moderate index group. Therefore, these results show that having a more robust LDL-C goal (<70 mg/dL) in patients with IHD does not provide any benefits for all patients. However, certain limitations in this study limit its generalizability. For instance, the study population was restricted to patients who were only 80% adherent to statin therapy one year prior the LDL-C index measurement. Therefore, these findings cannot be applied to patients who have higher percentages of adherence. In conclusion, the use of statin therapy provides clear benefits in lowering LDL-C levels and preventing cardiovascular complications. Highlighting the benefits of utilizing statin dose strategies and maintaining LDL-C levels between 70.1-100 mg/dL, can help maximize health outcomes in patients with IHD.

Practice Pearls:

  • Patients with pre-existing ischemic heart disease (IHD) can benefit from statin therapy and moderate LDL-C index values.
  • Obtaining LDL-C levels of 70.1 mg/dL-100 mg/dL with statin therapy can help decrease cardiovascular disease risks.
  • Robust LDL-C levels (<70 mg/dL) provide no additional benefit in cardiovascular health outcomes.

Researched and prepared by Pablo A. Marrero-Núñez – USF College of Pharmacy Student Delegate – Doctor of Pharmacy Candidate 2017, reviewed by Dave Joffe, BSPharm, CDE

References:

Deedwania, Prakash C., Terje R. Pedersen, David A. Demicco, Andrei Breazna, D. John Betteridge, Graham A. Hitman, Paul Durrington, and Andrew Neil. “Differing Predictive Relationships between Baseline LDL-C, Systolic Blood Pressure, and Cardiovascular Outcomes.” International Journal of Cardiology 222 (2016): 548-56. Web.

Leibowitz, Morton, Tomas Karpati, Chandra J. Cohen-Stavi, Becca S. Feldman, Moshe Hoshen, Haim Bitterman, Samy Suissa, and Ran D. Balicer. “Association Between Achieved Low-Density Lipoprotein Levels and Major Adverse Cardiac Events in Patients With Stable Ischemic Heart Disease Taking Statin Treatment.” JAMA Internal Medicine JAMA Intern Med 176.8 (2016): 1105. Web.

Taskinen, Marja-Riitta, and Jan Borén. “New Insights into the Pathophysiology of Dyslipidemia in Type 2 Diabetes.” Atherosclerosis 239.2 (2015): 483-95. Web.