Excess cardiovascular risk in patients with type 2 diabetes: do we need to look beyond LDL cholesterol?

Authors

  • Alan Rees Consultant Physician in Diabetes, Endocrinology and Clinical Lipidology, University Hospital of Wales, Cardiff, UK

DOI:

https://doi.org/10.15277/bjdvd.2014.003

Abstract

Despite impressive advances in treatment, cardiovascular disease (CVD) remains a significant healthcare burden in the UK and worldwide. The clustering of CVD risk factors in patients with type 2 diabetes underlines the need for a multifactorial treatment approach, yet even when receiving optimal therapy according to best standards of care, there remains a substantial risk of CVD and microvascular disease. Risk prediction tools  traditionally provide an estimate of risk over 10 years, however this approach is dominated by chronological age and gender and has a number of recognised  limitations. A move from 10-year to lifetime risk  calculation has been proposed, and should encourage  intervention at a much earlier stage. This move,  alongside aggressive and broad control of modifiable risk factors, aims to ease the burden of atherosclerosis prior to the manifestations of CVD. This will be of  particular benefit to those with type 2 diabetes, who have been exposed to hyperglycaemia and other risk factors for extended periods of time. The atherogenic dyslipidaemia common in this group also ensures they will benefit most from treatment strategies under  investigation to further reduce macrovascular and  microvascular risk.

References

Scarborough P. Trends in Coronary Heart Disease. Wickramasinghe K. 1961-2011. 2011. British Heart Foundation.

WHO. Cardiovascular disease: Fact sheet 317. 2013.

WHO. Obesity and overweight: Fact sheet 311. 1-4. 2012.

Tsigos C, Hainer V, Basdevant A et al. Management of obesity in adults: European clinical practice guidelines. Obes Facts 2008;1:106-16. http://dx.doi.org/10.1159/000126822

WHO. Diabetes: Fact sheet 312. 1-3. 2012.

Finucane MM, Stevens GA, Cowan MJ et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 2011;377:557-67. http://dx.doi.org/10.1016/S0140-6736(10)62037-5

Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol 2008;28:629-36. http://dx.doi.org/10.1161/ATVBAHA.107.151092

International Diabetes Federation. IDF Diabetes Atlas. 5th Edition. 2013. Brussels, Belgium, International Diabetes Federation.

Pinhas-Hamiel O, Zeitler P. The global spread of type 2 diabetes mellitus in children and adolescents. J Pediatr 2005;146:693-700. http://dx.doi.org/10.1016/j.jpeds.2004.12.042

D'Adamo E, Caprio S. Type 2 diabetes in youth: epidemiology and pathophysiology. Diabetes Care 2011;34(suppl 2):S161-S165. http://dx.doi.org/10.2337/dc11-s212

Pinhas-Hamiel O, Zeitler P. Acute and chronic complications of type 2 diabetes mellitus in children and adolescents. Lancet 2007;369:1823-31. http://dx.doi.org/10.1016/S0140-6736(07)60821-6

Gu K, Cowie CC and Harris MI. Mortality in adults with and without diabetes in a national cohort of the U.S. population, 1971-1993. Diabetes Care 1998;21:1138-45. http://dx.doi.org/10.2337/diacare.21.7.1138

Moss SE, Klein R and Klein BE. Cause-specific mortality in a population-based study of diabetes. Am J Public Health 1991;81:1158-62. http://dx.doi.org/10.2105/AJPH.81.9.1158

Gu K, Cowie CC and Harris MI. Diabetes and decline in heart disease mortality in US adults. JAMA 1999;281:1291-7. http://dx.doi.org/10.1001/jama.281.14.1291

Ford ES and Capewell S. Coronary heart disease mortality among young adults in the U.S. from 1980 through 2002: concealed leveling of mortality rates. J Am Coll Cardiol 2007;50:2128-32. http://dx.doi.org/ 10.1016/j.jacc.2007.05.056

O'Flaherty M, Ford E, Allender S et al. Coronary heart disease trends in England and Wales from 1984 to 2004: concealed levelling of mortality rates among young adults. Heart 2008;94:178-81. http://dx.doi.org/10.1136/hrt.2007.118323

Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998;317:703-13. http://dx.doi.org/10.1136/bmj.317.7160.703

Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-89. http://dx.doi.org/10.1056/NEJMoa0806470

DECODE. Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes Care 2003;26:688-96. http://dx.doi.org/10.2337/diacare.26.3.688

Lawes CM, Parag V, Bennett DA et al. Blood glucose and risk of cardiovascular disease in the Asia Pacific region. Diabetes Care 2004;27:2836-42. http://dx.doi.org/10.2337/diacare.27.12.2836

Khaw KT, Wareham N, Luben R et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ 2001;322:15-18. http://dx.doi.org/10.1136/bmj.322.7277.15

Sarwar N, Gao P, Seshasai SR et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:2215-22. http://dx.doi.org/10.1016/S0140-6736(10)60484-9

Hex N, Bartlett C, Wright D et al. Estimating the current and future costs of Type 1 and Type 2 diabetes in the UK, including direct health costs and indirect societal and productivity costs. Diabet Med 2012;29:855-62. http://dx.doi.org/10.1111/j.1464-5491.2012.03698.x

Bagust A, Hopkinson PK, Maier W et al. An economic model of the long-term health care burden of Type II diabetes. Diabetologia 2001;44:2140-55. http://dx.doi.org/10.1007/s001250100023

Morgan CL, Peters JR, Dixon S et al. Estimated costs of acute hospital care for people with diabetes in the United Kingdom: a routine record linkage study in a large region. Diabet Med 2010;27:1066-73. http://dx.doi.org/10.1111/j.1464-5491.2010.03086.x

Currie CJ, Morgan CL, Dixon S et al. Comparative estimates of the financial burden to the UK health system of hospital care for people with and without diabetes in the year before death. Diabetes Res Clin Pract 2004;65:267-74. http://dx.doi.org/10.1016/j.diabres.2004.01.009

Bagust A, Hopkinson PK, Maslove L et al. The projected health care burden of Type 2 diabetes in the UK from 2000 to 2060. Diabet Med 2002;19 Suppl 4:1-5. http://dx.doi.org/10.1046/j.1464-5491.19.s4.2.x

Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937-52. http://dx.doi.org/10.1016/S0140-6736(04)17018-9

Wingard DL, Barrett-Connor E, Criqui MH et al. Clustering of heart disease risk factors in diabetic compared to nondiabetic adults. Am J Epidemiol 1983;117:19-26.

Stamler J, Vaccaro O, Neaton JD et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434-44. http://dx.doi.org/ 10.2337/diacare.16.2.434

Turner RC, Millns H, Neil HA et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998;316:823-8. http://dx.doi.org/ 10.1136/bmj.316.7134.823

Adler AI, Stevens RJ, Neil A et al. UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes Care 2002;25:894-9. http://dx.doi.org/10.2337/diacare.25.5.894

Pyorala K, Pedersen TR, Kjekshus J et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997;20:614-20. http://dx.doi.org/10.2337/diacare.20.4.614

Ravid M, Lang R, Rachmani R et al. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. A 7-year follow-up study. Arch Intern Med 1996; 156:286-9. http://dx.doi.org/10.1001/archinte.1996.00440030080010

Yusuf S, Sleight P, Pogue J et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-53. http://dx.doi.org/10.1056/NEJM200001203420301

Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012;55:1577-96. http://dx.doi.org/10.1007/s00125-012-2534-0

American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care 2012;35[(suppl 1)]:S11-S63.

NICE. Type 2 Diabetes - newer agents. Clinical Guidelines 87. 1-49. 2009. NICE.

Gaede P, Vedel P, Larsen N et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93. http://dx.doi.org/10.1056/NEJMoa021778

Gaede P, Lund-Andersen H, Parving HH et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358: 580-91. http://dx.doi.org/10.1056/NEJMoa0706245

British Cardiac Society. Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, Stroke Association, and JBS 2. Heart 2005;91(suppl v):v1-v52.

Perk J, De BG, Gohlke H et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2012;33:1635-701. http://dx.doi.org/10.1093/eurheartj/ehs092

Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-421.

Framingham Heart Study. About the Framingham Heart Study. The National Heart, Lung and Blood Institute and Boston University2013. Available at: http://www.framinghamheartstudy.org/about/index.html [Last accessed 24 June 2013]

Anderson KM, Wilson PW, Odell PM et al. An updated coronary risk profile. A statement for health professionals. Circulation 1991;83:356-62. http://dx.doi.org/10.1161/01.CIR.83.1.356

Guzder RN, Gatling W, Mullee MA, Mehta RL, Byrne CD. Prognostic value of the Framingham cardiovascular risk equation and the UKPDS risk engine for coronary heart disease in newly diagnosed type 2 diabetes: results from a United Kingdom study. Diabet Med 2005;22:554-62. http://dx.doi.org/10.1111/j.1464-5491.2005.01494.x

McEwan P, Williams JE, Griffiths JD, Bagust A, Peters JR, Hopkinson P, Currie CJ. Evaluating the performance of the Framingham risk equations in a population with diabetes. Diabet Med 2004;21:318-23. http://dx.doi.org/10.1111/j.1464-5491.2004.01139.x

Coleman RL, Stevens RJ, Retnakaran R, Holman RR. Framingham, SCORE and DECODE do not provide reliable cardiovascular risk estimates in type 2 diabetes. Diabetes Care 2007;30:1292-3. http://dx.doi.org/10.2337/ dc06-1358

Lloyd-Jones DM, Leip EP, Larson MG et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006;113:791-8. http://dx.doi.org/10.1161/CIRCULATIONAHA.105.548206

Cohen JC, Boerwinkle E, Mosley TH, Jr. et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264-72. http://dx.doi.org/10.1056/NEJMoa054013

Ference BA, Yoo W, Alesh I et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 2012;60:2631-9. http://dx.doi.org/10.1016/j.jacc.2012.09.017

Nambi V and Ballantyne CM. "Risky business": ten years is not a lifetime. Circulation 2009;119:362-4. http://dx.doi.org/10.1161/CIRCULATIONAHA.108.830281

Berry JD, Liu K, Folsom AR et al. Prevalence and progression of subclinical atherosclerosis in younger adults with low short-term but high lifetime estimated risk for cardiovascular disease: the coronary artery risk development in young adults study and multi-ethnic study of atherosclerosis. Circulation 2009;119:382-9. http://dx.doi.org/10.1161/CIRCULATIONAHA.108.800235

Marma AK, Berry JD, Ning H et al. Distribution of 10-year and lifetime predicted risks for cardiovascular disease in US adults: findings from the National Health and Nutrition Examination Survey 2003 to 2006. Circ Cardiovasc Qual Outcomes 2010;3:8-14. http://dx.doi.org/10.1161/CIRCOUTCOMES.109.869727

Wilkins JT, Ning H, Berry J, Zhao L, Dyer AR, Lloyd-Jones DM. Lifetime risk and years lived free of total cardiovascular disease. JAMA 2012; 308:1795-801. http://dx.doi.org/10.1001/jama.2012.14312

Fox CS, Pencina MJ, Wilson PW, Paynter NP, Vasan RS, D'Agostino RB Sr. Lifetime risk of cardiovascular disease among Individuals with and without diabetes stratified by obesity status in the Framingham Heart Study. Diabetes Care 2008;31:1582-4. http://dx.doi.org/10.2337/dc08-0025

UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia 1991;34:877-90.

Hypertension in Diabetes Study (HDS): I. Prevalence of hypertension in newly presenting type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic complications. J Hypertens 1993; 11:309-17. http://dx.doi.org/10.1097/00004872-199303000-00012

UK Prospective Diabetes Study 6. Complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Res 1990;13:1-11.

Staessen JA, Thijisq L, Fagard R et al. Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial. J Hypertens 2004;22:847-57. http://dx.doi.org/10.1097/00004872-200404000-00029

Gerstein HC, Miller ME, Byington RP et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59. http://dx.doi.org/10.1056/NEJMoa0802743

Patel A, MacMahon S, Chalmers J et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72. http://dx.doi.org/10.1056/NEJMoa0802987

Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360:129-39. http://dx.doi.org/10.1056/NEJMoa0808431

Mannucci E, Monami M, Lamanna C, Gori F, Marchionni N. Prevention of cardiovascular disease through glycemic control in type 2 diabetes: A meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis 2009;19:604-12. http://dx.doi.org/10.1016/j.numecd.2009.03.021

Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-89. http://dx.doi.org/10.1056/NEJMoa0806470

Lehto S, Ronnemaa T, Haffner SM et al. Dyslipidemia and hyperglycemia predict coronary heart disease events in middle-aged patients with NIDDM. Diabetes 1997;46:1354-9. http://dx.doi.org/10.2337/diab.46.8.1354

Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319-35. http://dx.doi.org/10.3132/dvdr.2008.046

Younis NN, Soran H, Sharma R, et al. Small-dense LDL and LDL glycation in metabolic syndrome and in statin-treated and non-statin-treated type 2 diabetes. Diab Vasc Dis Res 2010;7:289-95. http://dx.doi.org/ 10.1177/1479164110383063

Chait A, Brazg RL, Tribble DL, Krauss RM. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am J Med 1993;94:350-356. http://dx.doi.org/10.1016/0002-9343(93)90144-E

Liu ML, Ylitalo K, Vakkilainen J, et al. Susceptibility of LDL to oxidation in vitro and antioxidant capacity in familial combined hyperlipidemia: comparison of patients with different lipid phenotypes. Ann Med 2002;34:48-54. http://dx.doi.org/10.1080/078538902317338643

Moro E, Alessandrini P, Zambon C, et al. Is glycation of low density lipoproteins in patients with Type 2 diabetes mellitus a LDL pre-oxidative condition? Diabetic Med 1999;16:663-9. http://dx.doi.org/10.1046/j.1464-5491.1999.00136.x

Assmann G, Schulte H, Cullen P et al. Assessing risk of myocardial infarction and stroke: new data from the Prospective Cardiovascular Munster (PROCAM) study. Eur J Clin Invest 2007;37:925-32. http://dx.doi.org/10.1111/j.1365-2362.2007.01888.x

Assmann G, Schulte H and Seedorf U. Cardiovascular risk assessment in the metabolic syndrome: results from the Prospective Cardiovascular Munster (PROCAM) Study. Int J Obes (Lond) 2008;32 Suppl 2:S11-S16. http://dx.doi.org/10.1038/ijo.2008.29

Sarwar N, Danesh J, Eiriksdottir G et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007;115:450-8. http://dx.doi.org/10.1161/CIRCULATIONAHA.106.637793

Jiang R, Schulze MB, Li T et al. Non-HDL cholesterol and apolipoprotein B predict cardiovascular disease events among men with type 2 diabetes. Diabetes Care 2004;27:1991-7. http://dx.doi.org/10.2337/diacare.27.8.1991

Bansal S, Buring JE, Rifai N et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007;298:309-16. http://dx.doi.org/10.1001/jama.298.3.309

Nordestgaard BG, Benn M, Schnohr P et al. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299-308. http://dx.doi.org/10.1001/jama.298.3.299

Boekholdt SM, Arsenault BJ, Mora S, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 2012;307:1302-09. http://dx.doi.org/10.1001/jama.2012.366

Lu W, Resnick HE, Jablonski KA et al. Non-HDL cholesterol as a predictor of cardiovascular disease in type 2 diabetes. Diabetes Care 2003;26:16-23. http://dx.doi.org/10.2337/diacare.26.1.16

Jenkins AJ, Rowley KG, Lyons TJ et al. Lipoproteins and diabetic microvascular complications. Curr Pharm Des 2004;10:3395-418. http://dx.doi.org/10.2174/1381612043383188

Chew EY, Klein ML, Ferris FL, III et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Arch Ophthalmol 1996;114:1079-84. http://dx.doi.org/10.1001/archopht.1996.01100140281004

Ucgun NI, Yildirim Z, Kilic N et al. The importance of serum lipids in exudative diabetic macular edema in type 2 diabetic patients. Ann N Y Acad Sci 2007;1100:213-17. http://dx.doi.org/10.1196/annals. 1395.021

Chowdhury TA, Hopkins D, Dodson PM et al. The role of serum lipids in exudative diabetic maculopathy: is there a place for lipid lowering therapy? Eye (Lond) 2002;16:689-93. http://dx.doi.org/10.1038/sj.eye.6700205

Davis MD, Fisher MR, Gangnon RE et al. Risk factors for high-risk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic Retinopathy Study Report #18. Invest Ophthalmol Vis Sci 1998; 39:233-52.

Lyons TJ, Jenkins AJ, Zheng D et al. Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthalmol Vis Sci 2004;45:910-18. http://dx.doi.org/10.1167/iovs.02-0648

Retnakaran R, Cull CA, Thorne KI et al. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes 2006;55:1832-9. http://dx.doi.org/10.2337/db05-1620

Tesfaye S, Chaturvedi N, Eaton SE et al. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005;352:341-50. http://dx.doi.org/10.1056/NEJMoa032782

Kempler P, Tesfaye S, Chaturvedi N et al. Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study. Diabet Med 2002;19:900-09. http://dx.doi.org/10.1046/j.1464-5491.2002.00821.x

Collins R, Armitage J, Parish S et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-16. http://dx.doi.org/10.1016/S0140-6736(03)13636-7

Colhoun HM, Betteridge DJ, Durrington PN et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685-96. http://dx.doi.org/10.1016/S0140-6736(04)16895-5

Kearney PM, Blackwell L, Collins R et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008;371:117-25. http://dx.doi.org/10.1016/S0140-6736(08)60104-X

Frikke-Schmidt R, Nordestgaard BG, Stene MC et al. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA 2008; 299:2524-32. http://dx.doi.org/10.1001/jama.299.21.2524

Johannsen TH, Kamstrup PR, Andersen RV et al. Hepatic lipase, genetically elevated high-density lipoprotein, and risk of ischemic cardiovascular disease. J Clin Endocrinol Metab 2009;94:1264-73. http://dx.doi.org/10.1210/jc.2008-1342

Haase CL, Tybjaerg-Hansen A, Qayyum AA et al. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals. J Clin Endocrinol Metab 2012; 97:E248-E256. http://dx.doi.org/10.1210/jc.2011-1846

Voight BF, Peloso GM, Orho-Melander M et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012;380:572-80. http://dx.doi.org/10.1016/S0140-6736(12)60312-2

Johansen CT and Hegele RA. Using Mendelian randomization to determine causative factors in cardiovascular disease. J Intern Med 2013; 273:44-7. http://dx.doi.org/10.1111/j.1365-2796.2012.02586.x

Boden WE, Probstfield JL, Anderson T et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67. http://dx.doi.org/10.1056/NEJMoa1107579

HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34:1279-91. http://dx.doi.org/10.1093/eurheartj/eht055

Barter PJ, Caulfield M, Eriksson M et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22. http://dx.doi.org/10.1056/NEJMoa0706628

Schwartz GG, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-99. http://dx.doi.org/10.1056/NEJMoa1206797

Khera AV, Cuchel M, Llera-Moya M et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011;364:127-35. http://dx.doi.org/10.1056/NEJMoa1001689

Cannon CP, Shah S, Dansky HM et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010; 363:2406-15. http://dx.doi.org/10.1056/NEJMoa1009744

Nicholls SJ, Brewer HB, Kastelein JJ et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 2011;306:2099-109. http://dx.doi.org/10.1001/jama.2011.1649

ClinicalTrials.gov. NCT01252953: REVEAL: Randomised evaluation of the effects of anacetrapib through lipid modification. 2012. ClinicalTrials.gov.

ClinicalTrials.gov. NCT01687998: A study of evacetrapib in high-risk vascular disease (ACCELERATE). 2012. ClinicalTrials.gov.

Tenenbaum A, Fisman EZ, Motro M et al. Optimal management of combined dyslipidemia: what have we behind statins monotherapy? Adv Cardiol 2008;45:127-53. http://dx.doi.org/10.1159/000115192

Wilding JP, Gause-Nilsson I and Persson A. Tesaglitazar, as add-on therapy to sulphonylurea, dose-dependently improves glucose and lipid abnormalities in patients with type 2 diabetes. Diab Vasc Dis Res 2007; 4:194-203. http://dx.doi.org/10.3132/dvdr.2007.040

Long GG, Reynolds VL, Lopez-Martinez A et al. Urothelial carcinogenesis in the urinary bladder of rats treated with naveglitazar, a gamma-dominant PPAR alpha/gamma agonist: lack of evidence for urolithiasis as an inciting event. Toxicol Pathol 2008;36:218-31. http://dx.doi.org/10.1177/0192623307311757

Nissen SE, Wolski K and Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005;294:2581-6. http://dx.doi.org/10.1001/jama.294.20.joc50147

Henry RR, Lincoff AM, Mudaliar S et al. Effect of the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 2009; 374:126-35. http://dx.doi.org/10.1016/S0140-6736(09)60870-9

Roche press release: Roche halts investigation of aleglitazar following regular safety review of phase III trial. 2010

Fruchart JC. Selective peroxisome proliferator-activated receptorα modulators (SPPARMα): The next generation of peroxisome proliferator-activated receptor α-agonists. Cardiovasc Diabetol 2013;12:82. http://dx.doi.org/10.1186/1475-2840-12-82

Downloads

Published

2014-04-01

Issue

Section

Reviews