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Understanding Diabetes and Dyslipidemia: Management Strategies and Risk Reduction

Explore the definition, pathophysiology, and management options for diabetic dyslipidemia, including statin therapy and non-statin interventions. Learn about the residual cardiovascular risk in diabetic patients and the importance of non-HDL cholesterol in predicting coronary heart disease. Findings from research studies and recommendations for reducing cardiovascular risk in individuals with diabetes.

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Understanding Diabetes and Dyslipidemia: Management Strategies and Risk Reduction

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  1. Diabetes and DyslipidemiaResidual Burden F. Hosseinpanah Obesity Research Center Research Institute for Endocrine sciences ShahidBeheshtiUniversity of Medical Sciences January 30, 2019 Ghazvin

  2. Agenda • Definition and pathophysiology of diabetic dyslipidemia • Statin therapy in diabetic patients • Non statin therapy (ezetimibe, PCSK9 inhibotors and highly purified omega 3) in individuals with diabetes mellitus • Conclusions

  3. Diabetic Dyslipidemia • In patients with type 2 diabetes mellitus, triglycerides are often elevated, HDL-C is often decreased, and LDL-C may be elevated, borderline, or normal. • LDL particules are small and dense. Thus, the LDL-C concentration may be misleading because there will be more LDL particles for any cholesterol concentration • The prevalence of DD reported in various studies varied between 35 and 56%and is strongly associated with increased cardiovascular risk Atherosclerosis 2015. 239: 483-95

  4. Chylo Pathophysiology of dyslipidemia The core features of the phenotype are underpinned by insulin resistance and result in abnormal metabolism and quantity of TG rich lipoproteins(TRLs) derived either from the intestine (as chylomicrons) or the liver (as very low-density lipoprotein [VLDL]) VLDL Chylo Remnant VLDL Remnant IDL TG Rich LP

  5. Remnant cholesterol = total cholesterol – (HDL cholesterol + LDL cholesterol) • Non HDL= Total cholesterol – HDL cholesterol Remnant cholesterol combined with LDL cholesterol

  6. Statin therapy and blood pressure control decrease CHD risk to a greater extent than targeting glucose lowering Number of CV events prevented by different interventions Per 4 mmHg lower SBP Per 0.9% lower HbA1c Per 1 mmol/l lower LDL-C 0 -5 -10 -15 CV events prevented Sattar. Diabetologia 2013;56:686–95

  7. Efficacy of cholesterol-lowering therapy in diabetic patients in 14 RCT of statins : meta analysis • Aim of study: • Although statin therapy reduces the risk of occlusive vascular events in people with DM • There is uncertainty about the effects on particular outcomes and whether such effects depend on the type of diabetes, lipid profile, or other factors. • Methods: • Data from 18686 individuals with diabetes (1466 type 1 and 17,220 type 2) in the context of a further 71,370 without diabetes in 14 randomised trials of statin therapy. • Estimates effects on clinical outcomes per 1.0 mmol/L reduction in LDL cholesterol Lancet 2008, Jan 12;371(9607):117-25

  8. Results • After 5 years, 42(95% CI 30–55) fewer people with diabetes had major vascular events per 1000 allocated statin therapy

  9. Key message • Statin therapy safely reduces the 5-year incidence of major coronary events, coronary revascularization, and stroke by about a fifth per mmol/L reduction in LDL cholesterol, largely irrespective of initial lipid profile or other baseline characteristics • Conclusion: Statin therapy should be considered for all diabetic individuals who are at sufficiently high risk of vascular events

  10. CHD events occur in patients treated with statins 19.4 12.3 10.2 8.7 6.8 5.5 Residual Cardiovascular Risk in Major Statin Trials 28.0 Placebo Statin Patients Experiencing Major CHD Events, % 15.9 13.2 11.8 10.9 7.9 4S1 LIPID2 CARE3 HPS4 WOSCOPS5 AFCAPS/ TexCAPS6 N 4444 9014 4159 20 536 6595 6605 Secondary High Risk Primary 4HPS Collaborative Group. Lancet. 2002;360:7-22. 5Shepherd J, et al. N Engl J Med. 1995;333:1301-1307. 6 Downs JR, et al. JAMA. 1998;279:1615-1622. 14S Group. Lancet. 1994;344:1383-1389. 2LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 3Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.

  11. Patients With Diabetes Have Particularly High Residual CVD Risk After Statin Treatment *CHD death, nonfatal MI, stroke, revascularizations †CHD death, nonfatal MI, CABG, PTCA ‡CHD death and nonfatal MI §CHD death, nonfatal MI, stroke ║CHD death, nonfatal MI, resuscitated cardiac arrest, stroke (80 mg versus 10mg atorvastatin) 1HPS Collaborative Group. Lancet. 2003;361:2005-2016. 2Sacks FM, et al. N Engl J Med. 1996;335:1001-1009. 3LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4Shepherd J, et al. Lancet. 2002;360:1623-1630. 5Sever PS, et al. Lancet. 2003;361:1149-1158. 6Shepherd J, et al. Diabetes Care. 2006;29:1220-1226.

  12. Residual risk ? • Elevated Triglyceride level • Role of TG rich lipoproteines • Beyond LDL, non HDL may be a better predictor

  13. To determine if non-HDL cholesterol is a more useful predictor of coronary heart disease (CHD) risk than LDL cholesterol and if VLDL cholesterol is an independent predictor of CHD risk • All subjects aged >30 years and free of CHD at baseline, followed for incident CHD (618 men, 372 women) Am J Cardiol 2006;98:1363–1368

  14. Within non–HDL-C levels, no association was found between LDL-C and the risk for CHD In contrast, a strong positive and graded association between non–HDL-C and risk for CHD occurred within every level of LDL Non–HDL-C Is Superior to LDL-C in Predicting CHD Risk Relative CHD Risk ≥190 160-189 <160 <130 130-159 ≥160 Non–HDL-C, mg/dL LDL-C, mg/dL .

  15. When the analysis was repeated within triglyceride levels (<200 vs>200 mg/dl), the risk pattern did not change significantly

  16. Key message • The results from this study support the conclusions that VLDL cholesterol is an independent predictor of CHD risk and that non-HDL cholesterol overall appears to be a better predictor of CHD risk than LDL cholesterol. • These conclusions appear to be valid for the entire population and when TG levels are either ≥200 or< 200 mg/dl

  17. Long-term and short-term relationships of triglycerides to risk after ACS were examined in the dal-OUTCOMES trial and atorvastatin arm of the MIRACL (Myocardial Ischemia Reduction with Acute Cholesterol Lowering) trial, respectively J Am CollCardiol 2015;65:2267–75

  18. Key message • Among patients with ACS treated effectively with statins, fasting triglycerides predict long-term and short-term cardiovascular risk. • Triglyceride-rich lipoproteins may be an important additional target for therapy.

  19. Sample size: 9795 Type 2 diabetic participants aged 50–75 years • Primary outcome: coronary events (coronary heart disease death or non-fatal myocardial infarction) • Prespecified subgroup analyses : total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke, and coronary and carotid revascularisation) • Length of F/U: 5 years • Lipids to qualify for the study were: cholesterol 116–251 mg/dl, and chol/HDL>4.0 or TG 89–444 mg/dl. Lancet 2005; 366: 1849–61

  20. Lipid changes

  21. FIELD: Primary and Secondary End Points 11% Reduction P = .035 Placebo Fenofibrate 21% Reduction P = .003 11% Reduction P = .16 24% Reduction P = .01 Event Rate (%) 19% Increase P = .22 Total CVD Events† (Secondary End Point) CHD Events* (Primary End Point) Nonfatal MI CHD Death Coronary Revascularization *Nonfatal MI and CHD death. †CHD events, stroke, CVD death, revascularizations. Keech A, et al. Lancet. 2005;366:1849-1861.

  22. Key messages • Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularizations. • The higher rate of starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit.

  23. Randomized, placebo-controlled, double-blind clinical trial conducted in 77 clinical sites in the U.S. and Canada • Sample size: 5518 patients with type 2 diabetes • Mean follow-up : 4.7 years. N Engl J Med 2010; 362: 1563–74.

  24. Baseline characteristics

  25. Lipid Values

  26. Fenofibrate Placebo (N=2765) (N=2753) Rate Rate N of N of (%/yr) (%/yr) HR (95% CI) P Value Events Events Primary Outcome: Major Fatal or Nonfatal 291 2.24 310 2.41 0.92 (0.79 - 1.08) 0.32 Cardiovascular Event Primary outcome

  27. Prespecified Primary and Secondary Outcomes

  28. Subgroup analysis

  29. Subgroup analysis

  30. Key message • ACCORD Lipid trial does not support use of the combination of fenofibrate and simvastatin, compared to simvastatin alone, to reduce CVD events in the majority of patients with T2DM who are at high risk for CVD

  31. IMPROVE-IT

  32. Patients: age ≥50 years, ACS (Recent 10 days), LDL-C between 50mg/dL and 100 - 125 mg/dL 18,144 9,067 9,077 Simvastatin40 mg + Placebo Simvastatin40 mg + Ezetimibe 10 mg CV mortality Major CV event (death from CAD, MI, stroke or revascularization more than 30 days after randomization) Nonfatal stroke

  33. Result Primary Outcome CV mortality, major CV event, or nonfatal stroke 34.7% vs. 32.7% (HR 0.94; 95% CI 0.89-0.99; P=0.016; NNT 50) Secondary Outcomes All-cause mortality, major CV event , or nonfatal stroke 40.3% vs. 38.7% (HR 0.95; 95% CI 0.90-1.00; P=0.03) CV mortality, nonfatal MI, urgent coronary revascularization ≥30 days 18.9% vs. 17.5% (HR 0.91; 95% CI 0.85-0.98; P=0.02) CV mortality, nonfatal MI, unstable angina hospitalization, any revascularization ≥30 days, nonfatal stroke 36.2% vs. 34.5% (HR 0.95; 95% CI 0.90-1.00; P=0.04)

  34. Key message • IMPROVE-IT is the first trial to show that adding a non-statin lipid-modifying agent in concert with a statin improves CV outcomes in addition to enhancing lipid lowering effects

  35. Lipid-Lowering Drug Therapies, Starting Dosages, and Dosage RangesPCSK9 Inhibitors • Metabolic Effects: • ↓LDL-C 48%-71%, ↓ non-HDL-C 49%-58%, ↓TC 36%-42%, ↓Apo B 42%-55% by inhibiting PCSK9 binding with LDLRs, increasing the number of LDLRs available to clear LDL, and lowering LDL-C levels • Main Considerations: • Require subcutaneous self-injection; refrigeration generally needed • Overall levels of adverse reactions and discontinuation very low • Adverse reactions with significantly different rates between drug and placebo were: local injection site reactions and influenza • The most common adverse reactions with similar rates for drug vs. placebo were: • Alirocumab: nasopharyngitis, influenza, urinary tract infections, diarrhea, bronchitis, and myalgia • Evolocumab: nasopharyngitis, back pain, and upper respiratory tract infection Abbreviations:apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; SQ, subcutaneous injection; TC, total cholesterol. Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):479-497; Praluent (alirocumab) [PI] 2015; Repatha (evolocumab) [PI]; 2016.

  36. FOURIER

  37. February 2013 through June 2015 Patients: Age ≥ 40 and ≤ 85, ASCVD, CVD risk, LDL-C ≥ 70 mg/dL or Non–HDL cholesterol ≥ 100 mg/dL 27,564 1 : 1 Randomization  Atorvastatin 20 mg + Placebo Atorvastatin 20 mg + Evolocumab 13,784 13,780 140mg every 2 weeks 420mg every month CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization follow-up: 26 months

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