Age and the Residual Risk of Cardiovascular Disease following Low Density Lipoprotein-Cholesterol Exposure
Abstract
:1. Introduction
2. Review of the Lipid Hypothesis
3. Calculation of Residual Risk
4. Association between Age and Absolute Risk
5. Association between Age and Residual Risk Seen in RCTs Using LDL-C Reducing Agents—Trials Included in the CTT Collaboration Stratified by Age
6. Review of Atherogenesis and Cumulative LDL-C Exposure
7. Possible Reasons That the Rate Ratio of 0.78 Seen in the CTT Collaboration Is Preserved in the Subgroups
8. Review of Additional Non-Traditional Risk Factors That May Contribute to Residual Risk
- a.
- Potential Inflammatory Risk
- b.
- Potential Thrombotic Risk
- c.
- Potential Metabolic Risk
- d.
- Potential Risk Associated with Endothelial Dysfunction
9. Discussion
10. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Cardiovascular Diseases (CVDs)—World Health Organisation 11th June 2021. Available online: www.who.int/health-topics/cardiovascular-diseases#tab=tab_1 (accessed on 14 May 2023).
- Timmis, A.; Kazakiewicz, D.; Torbica, A.; Townsend, N.; Huculeci, R.; Aboyans, V.; Vardas, P. Cardiovascular disease care and outcomes in West and South European countries. Lancet Reg. Health Eur. 2023, 33, 100718. [Google Scholar] [CrossRef] [PubMed]
- Tsao, C.W.; Ramachandran, V.S. Cohort Profile: The Framingham Heart Study (FHS): Overview of milestones in cardiovascular epidemiology. Int. J. Epidemiol. 2015, 44, 1800–1813. [Google Scholar] [CrossRef] [PubMed]
- Anderson, K.M.; Wilson, P.W.; Odell, P.M.; Kannel, W.B. An updated coronary risk profile. A statement for health professionals. Circulation 1991, 83, 356–362. [Google Scholar] [CrossRef] [PubMed]
- Assmann, G.; Cullen, P.; Schulte, H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Münster (PROCAM) study. Circulation 2002, 105, 310–315. [Google Scholar] [CrossRef] [PubMed]
- SCORE2 working group and ESC Cardiovascular risk collaboration. SCORE2 risk prediction algorithms: New models to estimate 10-year risk of cardiovascular disease in Europe. Eur. Heart J. 2021, 42, 2439–2454. [Google Scholar] [CrossRef] [PubMed]
- SCORE2-OP working group and ESC Cardiovascular risk collaboration. SCORE2-OP risk prediction algorithms: Estimating incident cardiovascular event risk in older persons in four geographical risk regions. Eur. Heart J. 2021, 42, 2455–2467. [Google Scholar] [CrossRef] [PubMed]
- Hippisley-Cox, J.; Coupland, C.; Vinogradova, Y.; Robson, J.; May, M.; Brindle, P. Derivation and validation of QRISK, a new cardiovascular disease risk score for the United Kingdom: Prospective open cohort study. BMJ 2007, 335, 136. [Google Scholar] [CrossRef]
- Ramachandran, S.; Bhartia, M.; König, C.S. The lipid hypothesis: From resins to Proprotein Convertase Subtilisin/Kexin Type-9 inhibitors. Front. Cardiovasc. Drug Discov. 2020, 5, 48–81. [Google Scholar]
- Toft-Nielsen, F.; Emanuelsson, F.; Benn, M. Familial Hypercholesterolemia Prevalence Among Ethnicities-Systematic Review and Meta-Analysis. Front. Genet. 2022, 13, 840797. [Google Scholar] [CrossRef]
- Sharifi, M.; Rakhit, R.D.; Humphries, S.E.; Nair, D. Cardiovascular risk stratification in familial hypercholesterolaemia. Heart 2016, 102, 1003–1008. [Google Scholar] [CrossRef]
- Board, J. Joint British Societies’ consensus recommendations for the prevention of cardiovascular disease (JBS3). Heart 2014, 100 (Suppl. S2), ii1–ii67. [Google Scholar]
- The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984, 251, 351–364.
- Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010, 376, 1670–1681. [Google Scholar] [CrossRef] [PubMed]
- Baigent, C.; Landray, M.J.; Reith, C.; Emberson, J.; Wheeler, D.C.; Tomson, C.; Wanner, C.; Krane, V.; Cass, A.; Craig, J.; et al. SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): A randomised placebo-controlled trial. Lancet 2011, 377, 2181–2192. [Google Scholar] [CrossRef] [PubMed]
- Cannon, C.P.; Blazing, M.A.; Giugliano, R.P.; McCagg, A.; White, J.A.; Théroux, P.; Darius, H.; Lewis, B.S.; Ophuis, T.O.; Jukema, J.W.; et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N. Engl. J. Med. 2015, 372, 2387–2397. [Google Scholar] [CrossRef] [PubMed]
- Sabatine, M.S.; Giugliano, R.P.; Keech, A.C.; Honarpour, N.; Wiviott, S.D.; Murphy, S.A.; Kuder, J.F.; Wang, H.; Liu, T.; Wasserman, S.M.; et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 2017, 376, 1713–1722. [Google Scholar] [CrossRef] [PubMed]
- Schwartz, G.G.; Steg, P.G.; Szarek, M.; Bhatt, D.L.; Bittner, V.A.; Diaz, R.; Edelberg, J.M.; Goodman, S.G.; Hanotin, C.; Harrington, R.A.; et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N. Engl. J. Med. 2018, 379, 2097–2107. [Google Scholar] [CrossRef]
- Ramachandran, S.; French, J.M.; Vanderpump, M.P.; Croft, P.; Neary, R.H. Using the Framingham model to predict heart disease in the United Kingdom: Retrospective study. BMJ 2000, 320, 676–677. [Google Scholar] [CrossRef]
- Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994, 344, 1383–1389. [Google Scholar]
- Ference, B.A.; Graham, I.; Tokgozoglu, L.; Catapano, A.L. Impact of Lipids on Cardiovascular Health: JACC Health Promotion Series. J. Am. Coll Cardiol. 2018, 72, 1141–1156. [Google Scholar] [CrossRef]
- Ridker, P.M.; Danielson, E.; Fonseca, F.A.; Genest, J.; Gotto, A.M., Jr.; Kastelein, J.J.; Koenig, W.; Libby, P.; Lorenzatti, A.J.; MacFadyen, J.G.; et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med. 2008, 359, 2195–2207. [Google Scholar] [CrossRef] [PubMed]
- Cannon, C.P.; Braunwald, E.; McCabe, C.H.; Rader, D.J.; Rouleau, J.L.; Belder, R.; Joyal, S.V.; Hill, K.A.; Pfeffer, M.A.; Skene, A.M. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med. 2004, 350, 1495–1504. [Google Scholar] [CrossRef] [PubMed]
- Ridker, P.M.; Everett, B.M.; Thuren, T.; MacFadyen, J.G.; Chang, W.H.; Ballantyne, C.; Fonseca, F.; Nicolau, J.; Koenig, W.; Anker, S.D.; et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 2017, 377, 1119–1131. [Google Scholar] [CrossRef] [PubMed]
- Antithrombotic Trialists’ (ATT) Collaboration; Baigent, C.; Blackwell, L.; Collins, R.; Emberson, J.; Godwin, J.; Peto, R.; Buring, J.; Hennekens, C.; Kearney, P.; et al. Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009, 373, 1849–1860. [Google Scholar]
- Bonaca, M.P.; Bhatt, D.L.; Cohen, M.; Steg, P.G.; Storey, R.F.; Jensen, E.C.; Magnani, G.; Bansilal, S.; Fish, M.P.; Im, K.; et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N. Engl. J. Med. 2015, 372, 1791–1800. [Google Scholar] [CrossRef] [PubMed]
- Steg, P.G.; Bhatt, D.L.; Simon, T.; Fox, K.; Mehta, S.R.; Harrington, R.A.; Held, C.; Andersson, M.; Himmelmann, A.; Ridderstråle, W.; et al. Ticagrelor in Patients with Stable Coronary Disease and Diabetes. N. Engl. J. Med. 2019, 381, 1309–1320. [Google Scholar] [CrossRef] [PubMed]
- Mega, J.L.; Braunwald, E.; Wiviott, S.D.; Bassand, J.P.; Bhatt, D.L.; Bode, C.; Burton, P.; Cohen, M.; Cook-Bruns, N.; Fox, K.A.; et al. Rivaroxaban in patients with a recent acute coronary syndrome. N. Engl. J. Med. 2012, 366, 9–19. [Google Scholar] [CrossRef]
- Eikelboom, J.W.; Connolly, S.J.; Bosch, J.; Dagenais, G.R.; Hart, R.G.; Shestakovska, O.; Diaz, R.; Alings, M.; Lonn, E.M.; Anand, S.S.; et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N. Engl. J. Med. 2017, 377, 1319–1330. [Google Scholar] [CrossRef]
- Paré, G.; Çaku, A.; McQueen, M.; Anand, S.S.; Enas, E.; Clarke, R.; Boffa, M.B.; Koschinsky, M.; Wang, X.; INTERHEART Investigators; et al. Lipoprotein(a) Levels and the Risk of Myocardial Infarction Among 7 Ethnic Groups. Circulation 2019, 139, 1472–1482. [Google Scholar] [CrossRef]
- Bhatt, D.L.; Steg, P.G.; Miller, M.; Brinton, E.A.; Jacobson, T.A.; Ketchum, S.B.; Doyle RTJr Juliano, R.A.; Jiao, L.; Granowitz, C.; Tardif, J.C.; et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N. Engl. J. Med. 2019, 380, 11–22. [Google Scholar] [CrossRef]
- Rohatgi, A.; Khera, A.; Berry, J.D.; Givens, E.G.; Ayers, C.R.; Wedin, K.E.; Neeland, I.J.; Yuhanna, I.S.; Rader, D.R.; de Lemos, J.A.; et al. HDL cholesterol efflux capacity and incident cardiovascular events. N. Engl. J. Med. 2014, 371, 2383–2393. [Google Scholar] [CrossRef] [PubMed]
- AIM-HIGH Investigators; Boden, W.E.; Probstfield, J.L.; Anderson, T.; Chaitman, B.R.; Desvignes-Nickens, P.; Koprowicz, K.; McBride, R.; Teo, K.; Weintraub, W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 2011, 365, 2255–2267.32. [Google Scholar] [CrossRef]
- Barter, P.J.; Caulfield, M.; Eriksson, M.; Grundy, S.M.; Kastelein, J.J.P.; Komajda, M.; Lopez-Sendon, J.; Mosca, L.; Tardif, J.-C.; Waters, D.D.; et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 2007, 357, 2109–2122. [Google Scholar] [CrossRef] [PubMed]
- Frick, M.H.; Elo, O.; Haapa, K.; Heinonen, O.P.; Heinsalmi, P.; Helo, P.; Huttunen, J.K.; Kaitaniemi, P.; Koskinen, P.; Manninen, V.; et al. Helsinki Heart Study: Primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N. Engl. J. Med. 1987, 317, 1237–1245. [Google Scholar] [CrossRef] [PubMed]
- Rubins, H.B.; Robins, S.J.; Collins, D.; Fye, C.L.; Anderson, J.W.; Elam, M.B.; Faas, F.H.; Linares, E.; Schaefer, E.J.; Schectman, G.; et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N. Engl. J. Med. 1999, 341, 410–418. [Google Scholar] [CrossRef]
- BIP STUDY GROUP. Bezafibrate Infarction Prevention (BIP) study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation 2000, 102, 21–27. [Google Scholar] [CrossRef]
- Keech, A.C.; Simes, R.J.; Barter, P.J.; Best, J.D.; Scott, R.A.P.; Taskinen, M.R.; Forder, P.M.; Pillai, A.; Davis, T.M.; Glasziou, P.; et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet 2005, 366, 1849–1861. [Google Scholar] [CrossRef]
- ACCORD Study Group; Ginsberg, H.N.; Elam, M.B. Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med. 2010, 362, 1563–1574. [Google Scholar] [CrossRef]
- Bruckert, E.; Labreuche, J.; Deplanque, D.; Touboul, P.J.; Amarenco, P. Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenicdyslipidemia profile: A systematic review and meta-analysis. J. Cardiovasc. Pharmacol. 2011, 57, 267–272. [Google Scholar] [CrossRef]
- Zinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; Woerle, H.J.; et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med. 2015, 373, 2117–2128. [Google Scholar] [CrossRef]
- Yusuf, S.; Sleight, P.; Pogue, J.F.; Bosch, J.; Davies, R.; Dagenais, G. Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N. Engl. J. Med. 2000, 342, 145–153. [Google Scholar] [PubMed]
- Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Lancet 2000, 355, 253–259. [Google Scholar] [CrossRef]
- Hansson, L.; Lindholm, L.H.; Niskanen, L.; Lanke, J.; Hedner, T.; Niklason, A.; Luomanmäki, K.; Dahlöf, B.; de Faire, U.; Mörlin, C.; et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999, 353, 611–616. [Google Scholar] [CrossRef] [PubMed]
- Estacio, R.O.; Jeffers, B.W.; Hiatt, W.R.; Biggerstaff, S.L.; Gifford, N.; Schrier, R.W. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N. Engl. J. Med. 1998, 338, 645–652. [Google Scholar] [CrossRef] [PubMed]
- König, C.S.; Atherton, M.; Cavazzuti, M.; Gomm, C.; Ramachandran, S. The association of peak systolic velocity in the carotid artery with coronary heart disease: A study based on portable ultrasound. Proc. Inst. Mech. Eng. H. 2021, 235, 663–675. [Google Scholar] [CrossRef] [PubMed]
- Dhindsa, D.S.; Sandesara, P.B.; Shapiro, M.D.; Wong, N.D. The Evolving Understanding and Approach to Residual Cardiovascular Risk Management. Front. Cardiovasc. Med. 2020, 7, 88. [Google Scholar] [CrossRef] [PubMed]
- Shipman, K.E.; Strange, R.C.; Ramachandran, S. Use of fibrates in the metabolic syndrome: A review. World J. Diabetes 2016, 7, 74–88. [Google Scholar] [CrossRef]
- Jun, M.; Foote, C.; Lv, J.; Neal, B.; Patel, A.; Nicholls, S.J.; E Grobbee, D.; Cass, A.; Chalmers, J.; Perkovic, V. Effects of fibrates on cardiovascular outcomes: A systematic review and meta-analysis. Lancet 2010, 375, 1875–1884. [Google Scholar] [CrossRef]
- Perkovic, V.; Jardine, M.J.; Neal, B.; Bompoint, S.; Heerspink, H.J.L.; Charytan, D.M.; Edwards, R.; Agarwal, R.; Bakris, G.; Bull, S.; et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N. Engl. J. Med. 2019, 380, 2295–2306. [Google Scholar] [CrossRef]
- Wiviott, S.D.; Raz, I.; Bonaca, M.P.; Mosenzon, O.; Kato, E.T.; Cahn, A.; Silverman, M.G.; Zelniker, T.A.; Kuder, J.F.; Murphy, S.A.; et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2019, 380, 347–357. [Google Scholar] [CrossRef]
- Marso, S.P.; Daniels, G.H.; Brown-Frandsen, K.; Kristensen, P.; Mann, J.F.; Nauck, M.A.; Nissen, S.E.; Pocock, S.; Poulter, N.R.; Ravn, L.S.; et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2016, 375, 311–322. [Google Scholar] [CrossRef] [PubMed]
- Marso, S.P.; Bain, S.C.; Consoli, A.; Eliaschewitz, F.G.; Jódar, E.; Leiter, L.A.; Lingvay, I.; Rosenstock, J.; Seufert, J.; Warren, M.L.; et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N. Engl. J. Med. 2016, 375, 1834–1844. [Google Scholar] [CrossRef] [PubMed]
- Hernandez, A.F.; Green, J.B.; Janmohamed, S.; D’Agostino RBSr Granger, C.B.; Jones, N.P.; Leiter, L.A.; Rosenberg, A.E.; Sigmon, K.N.; Somerville, M.C.; Thorpe, K.M.; et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): A double-blind, randomised placebo-controlled trial. Lancet 2018, 392, 1519–1529. [Google Scholar] [CrossRef] [PubMed]
- Chhabra, N. Endothelial dysfunction—A predictor of atherosclerosis. Internet J. Med. Update 2009, 4, 33–41. [Google Scholar] [CrossRef]
- Peiffer, V.; Sherwin, S.J.; Weinberg, P.D. Does low and oscillatory wall shear stress correlate spatially with early atherosclerosis? A systematic review. Cardiovasc. Res. 2013, 99, 242–250. [Google Scholar] [CrossRef] [PubMed]
- Zhou, J.; Li, Y.S.; Chien, S. Shear stress-initiated signaling and its regulation of endothelial function. Arterioscler. Thromb. Vasc. Biol. 2014, 34, 2191–2198. [Google Scholar] [CrossRef] [PubMed]
- Srikanth, S.; Deedwania, P. Management of Dyslipidemia in Patients with Hypertension, Diabetes, and Metabolic Syndrome. Curr. Hypertens Rep. 2016, 18, 76. [Google Scholar] [CrossRef]
- Anderson, S.G.; Hutchings, D.C.; Woodward, M.; Rahimi, K.; Rutter, M.K.; Kirby, M.; Hackett, G.; Trafford, A.W.; Heald, A.H. Phosphodiesterase type-5 inhibitor use in type 2 diabetes is associated with a reduction in all-cause mortality. Heart 2016, 102, 1750–1756. [Google Scholar] [CrossRef]
- Andersson, D.P.; Lagerros, Y.T.; Grotta, A.; Bellocco, R.; Lehtihet, M.; Holzmann, M.J. Association between treatment for erectile dysfunction and death or cardiovascular outcomes after myocardial infarction. Heart 2017, 103, 1264–1270. [Google Scholar] [CrossRef]
- Hackett, G.; Heald, A.H.; Sinclair, A.; Jones, P.W.; Strange, R.C.; Ramachandran, S. Serum testosterone, testosterone replacement therapy and all-cause mortality in men with type 2 diabetes: Retrospective consideration of the impact of PDE5Inhibitors and statins. Int. J. Clin. Pract. 2016, 70, 244–253. [Google Scholar] [CrossRef]
- Mach, F.; Baigent, C.; Catapano, A.L.; Koskinas, K.C.; Casula, M.; Badimon, L.; Chapman, M.J.; De Backer, G.G.; Delgado, V.; Ference, B.A.; et al. ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Eur. Heart J. 2020, 41, 111–188. [Google Scholar] [CrossRef] [PubMed]
- Contois, J.H.; Langlois, M.R.; Cobbaert, C.; Sniderman, A.D. Standardization of Apolipoprotein B, LDL-Cholesterol, and Non-HDL-Cholesterol. J. Am. Heart Assoc. 2023, 12, e030405. [Google Scholar] [CrossRef] [PubMed]
- Ramachandran, S.; König, C.S.; Hackett, G.; Livingston, M.; Strange, R.C. Managing clinical heterogeneity: An argument for benefit based action limits. J. Med. Diagn. Ther. 2018, 1, 034701. [Google Scholar] [CrossRef]
- Missen, F.; Nicholls, S.; Sipahi, I. ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: The ASTEROID trial. JAMA 2006, 295, 1556–1565. [Google Scholar]
- Nicholls, S.J.; Borgman, M.; Nissen, S.E.; Raichlen, J.S.; Ballantyne, C.; Barter, P.; Chapman, M.J.; Erbel, R.; Libby, P. Impact of statins on progression of atherosclerosis: Rationale and design of SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin versus AtorvastatiN). Curr. Med. Res. Opin. 2011, 27, 1119–1129. [Google Scholar] [CrossRef]
- Dawson, L.P.; Lum, M.; Nerleker, N.; Nicholls, S.J.; Layland, J. Coronary Atherosclerotic Plaque Regression: JACC State-of-the-Art Review. J. Am. Coll Cardiol. 2022, 79, 66–82. [Google Scholar] [CrossRef]
Evidence | Main Finding | Reference | |
---|---|---|---|
LDL-C reduction | Review of RCTs by Ramachandran et al. | Validity of the LDL-C (lipid) hypothesis | [9] |
CTT Collaboration (review of 26 RCTs using statins) | Establishing a relative CVD risk reduction of 22% per mmol/L decrease in LDL-C | [14] | |
RCTs using Ezetimibe | CVD decrease in line with the CTT Collaboration | [15,16] | |
RCTs using Proprotein Convertase Subtilisin/Kexin Type-9 inhibitors | [17,18] | ||
Residual Risk | Rate ratio of 0.78 from the CTT Collaboration | Calculation of RRR, ARR and ResR | [14] |
Age | Framingham Heart Study | Age is a significant risk factor in CVD predictive algorithms | [3,4] |
PROCAM Study | [5] | ||
SCORE Project | [6,7] | ||
QRISK | [8] | ||
Whickham Study | [19] | ||
LDL-C exposure | Analysis of trials by Ference et al. | Cumulative LDL-C exposure is related to CVD | [21] |
Inflammatory Risk | JUPITER RCT | Decrease in high sensitivity C-reactive protein was associated with lower CVD | [22] |
PROVE-IT TIMI 22 RCT | [23] | ||
CANTOS RCT | Moderate dose (not lower or higher) of canakinumab was associated with lower CVD | [24] | |
Thrombotic Risk | Antithrombotic Trialists’ Collaboration RCT | Aspirin reduced CVD | [25] |
PEGASUS-TIMI 54 RCT | Combination of spirin and ticagrelor therapy reduced CVD | [26] | |
THEMIS-PCT RCT | [27] | ||
ATLAS ACS 2-TIMI 51 RCT | Combination of rivaroxaban and antiplatelet therapy reduced CVD | [28] | |
COMPASS RCT | [29] | ||
Metabolic Risk | INTERHEART Study | High lipoprotein (a) levels associated with increased CVD | [30] |
REDUCE-IT RCT | Eicosapentanoic acid associated with lowering of CVD | [31] | |
Dallas Heart Study | HDL-C levels were not associated with CVD | [32] | |
AIM-HIGH RCT | HDL-C increase following niacin treatment was not associated with CVD decrease | [33] | |
ILLUMINATE RCT | HDL-C increase following torcetrapib treatment was not associated with CVD decrease | [34] | |
Helsinki Heart Study | Gemfibrozil treatment was associated with lower CVD | [35] | |
Veterans Affairs High-Density Cholesterol Intervention Trial | [36] | ||
Bezafibrate Infarction Prevention study | Bezafibrate treatment was not associated with lower CVD | [37] | |
Fenofibrate Intervention and Event Lowering in Diabetes | Fenofibrate treatment was not associated with lower CVD | [38] | |
Action to Control Cardiovascular Risk in Diabetes—LIPID | [39] | ||
Analysis by Bruckert et al. of fibrate RCTs | CVD was significantly lower in patients with high triglycerides and low HDL-C | [40] | |
EMPA-REG OUTCOME RCT | Empagliflozin treatment reduced CVD | [41] | |
Endothelial Dysfunction | HOPE RCT | Antihypertensives reduced CVD | [42,43] |
CAPP RCT | [44] | ||
ABCD RCT | [45] | ||
König et al. case-control study | Lower peak systolic velocity was associated with CHD | [46] |
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König, C.S.; Mann, A.; McFarlane, R.; Marriott, J.; Price, M.; Ramachandran, S. Age and the Residual Risk of Cardiovascular Disease following Low Density Lipoprotein-Cholesterol Exposure. Biomedicines 2023, 11, 3208. https://doi.org/10.3390/biomedicines11123208
König CS, Mann A, McFarlane R, Marriott J, Price M, Ramachandran S. Age and the Residual Risk of Cardiovascular Disease following Low Density Lipoprotein-Cholesterol Exposure. Biomedicines. 2023; 11(12):3208. https://doi.org/10.3390/biomedicines11123208
Chicago/Turabian StyleKönig, Carola S., Amar Mann, Rob McFarlane, John Marriott, Malcolm Price, and Sudarshan Ramachandran. 2023. "Age and the Residual Risk of Cardiovascular Disease following Low Density Lipoprotein-Cholesterol Exposure" Biomedicines 11, no. 12: 3208. https://doi.org/10.3390/biomedicines11123208