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Management of Diabetic Dyslipidemia: Controversies generated by new guidelines and the physicians’ dilemma.

26 Jun, 14 | by sghosal

Introduction:

  • An individual patient may have multiple cardiovascular risk factors. Apart from addressing them individually reducing the overall CV (cardiovascular) burden is essential.
  • Elevated LDL (low density lipoprotein) cholesterol and low HDL (high density lipoprotein) cholesterol are the classical CV risk biomarkers.
  • However with time it has become clear that targeting LDL-C is beneficial and not HDL-C.
  • As a result statins have become the backbone of reducing overall CV risk.

Traditional Approach:

  • It was the NCEP/ATP III (National Cholesterol Education Panel’s Adult Treatment Program-3) in 2002[1], which set the stage for the management of dyslipidemia. LDL-C remained the primary target with TG (triglyceride) the secondary target. Elevation of TG above 500mg% warranted treatment with a fibrate and values between 200-499mg% being further evaluated with non-HDL-C and additional drugs considered if it was 30mg% above the LDL-C target [1]. However this was not supported by adequate evidence.
  • In the 2011 AHA (American Heart Association) reviewed the whole issues surrounding TG & CV risk [2]. They concluded that TG was not an independent risk factor for CV events and hence should not be included in the therapeutic agenda for CV risk reduction.
  • This was reflected in the subsequent ESC/EAS (European Society of Cardiology/European Atherosclerosis Society) 2011 [3] & AACE (American Association of Clinical Endocrinologists) 2012 [4] guidelines. According to the former, LDL-C was the solo target for lipid disorder therapy. Triglyceride did not feature as a therapeutic option in any of these guidelines.

The beginning of a controversy…

  • This year we came across the ACC/AHA guidelines based on the available evidence on lipid lowering therapy and reduction of atherosclerotic burden [5].
  • None of the important studies done till date with a statin was conducted in a treat-to-target fashion chasing LDL-C to lower targets. We did not have any evidence that LDL-C in a lower quintile was associated with lower CV events.
  • As a matter of fact the landmark HPS (Heart Protection Study) concluded that we can achieve a 34% relative risk reduction for CV events VS placebo by using a fixed dose of simvastatin (40mg/day) “irrespective of the end-of-study” LDL-C level, a finding replicated in the CARDS trial [6,7].
  • ACC/AHA recommendations as a result did away with LDL-C targets and stressed on using moderate intensity statin therapy as primary prevention and high-intensity statin for all secondary prevention scenarios except heart failure (NYHA II-IV) & CKD (chronic kidney disease) patients on dialysis.
  • This strategy is supported by the NHS 2010 lipid lowering guideline where a “treat and forget strategy” is advocated especially for primary prevention [8].
  • However in the same month we came across a couple of dissenting position papers from the NLA (National Lipid Association) & EAS [9]. They did not advocate this lipid management strategy citing several grounds. The usage of a different CV risk scoring chart with questionable utility for the European or other ethnicity; doing away with lipid therapeutic targets when others existed for BP (blood pressure) & glucose; exclusion of some important RCTs; lack of recommendations for those above 75 years of age; no mention of strategies in those with statin intolerance were some of the criticisms.

Statin use in patients with CKD

  • We are all aware about the several fold increased CV risk in patients with CKD.
  • The CV risk is high even amongst those with early nephropathy with large number of patients dying before developing advanced stages of CKD [10].
  • Most of the meta-analyses found utility of adding or continuing with statins in CKD except for those on dialysis [11].
  • The very recent IAS recommendations as well as the 2013 KDIGO guidelines recommends statins for CKD except for those on dialysis in line with the above-mentioned meta-analyses [12,13]. However they did stop short of recommending in favor of withdrawing a statin when a CKD patient progresses to dialysis.
  • In tune with the ACC/AHA recommendations the KDIGO does not support testing for LDL-C routinely prior to initiating a statin or after it is started. Follow up lipid measurements are only indicated once there is an issue with treatment adherence; change in renal replacement therapy; suspicion of a new secondary cause of dyslipidemia or a high CV-risk estimate in individuals below 50 years of age not on statin therapy.

Statins in the elderly

  • Most of the randomized controlled trials excluded the elderly age group most probably due to increased anticipatory co-morbidities, drop-out rates, poly-pharmacy & and risk of drug interaction.
  • This has erroneously resulted in a conclusion that the elderly do not require cholesterol-lowering treatments.
  • Epidemiological data on the other hand points towards an increased CVD risk in the elderly [14].
  • The PROSPER (Prospective Study of Pravastatin in the Elderly at Risk), SAGE (subjects – the Study Assessing Goals in the Elderly) & GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation) studies pointed at CVD benefits of statins in the elderly age groups [15,16,17]. PROSPER & SAGE confirmed that statins do have a role in reducing the high baseline CV risk in the elderly. GREACE on the other hand demonstrated an increased CV risk in older patients on usual care, which was significantly reduced with structured statin-based care.
  • The ACC/AHA/NHLBI & ESC/EAS guidelines acknowledges the need to treat the elderly with a statin especially in the backdrop of CVD or more than one CV risk factor (apart from age) [18].
  • The use of a statin in the elderly as a primary preventive strategy remains a grey area pending well-conducted trials. The recommending authorities leave this decision on the discretion of the physician considering the individual risk profile of the patients.

The Physicians Dilemma

  • So where do we stand on this issue?
  • We have clear-cut recommendations based on well-conducted evidences on certain areas and have a vast clinical field left uncovered.
  • One thing is for certain that statins remain as one of the most important tools for reducing the overall CVD burden both as a primary as well as a secondary strategy.
  • The clinician is then left to decide whether to follow the treat-to-target policy or the CV risk-based strategy.
Treat-to-target Risk-based
Primary Prevention LDL-C<100mg% Moderate-intensity statin
Secondary Prevention LDL-C<70mg% High-intensity statin

 

  • There are no recommendations from most of the major bodies for using any other lipid-lowering agent for the reduction of the residual CV risk.
  • The ADA 2014 recommendations however gives us the option of considering a fibrate faced with statin intolerance in a patient with HDL-C <40mg% & LDL-C 100-129mg% [19].
  • There is definitive indication to use a statin even in the elderly especially in the backdrop of high CV risk (secondary prophylaxis).
  • Statins should be used to reduce the CVD burden in patients with CKD (not on dialysis). There is no evidence in favor of a treat-to-target approach in this area. We can continue with the statin if the patient is already on one while progressing to advanced stage of CKD necessitating dialysis.

Research Recommendations:

  • The issue of estimating CV risk with the help of a risk score especially in the Asians (ethnicity issue).
  • A dedicated trial designed in the treat-to-target fashion looking into the different quintiles of LDL-C and CV risk reduction.
  • Statin and CV risk reduction in the elderly as a primary preventive strategy.
  • Doing away with the indirect means of assessing atherogenic dyslipidemia (non-HDL-C; apoB) and introducing direct lipoprotein sub fraction analysis methods e.g. electrophoretic method. This will help us in answering whether the residual CV risk is from the other lipid sub fractions (excluding LDL-C) or related to the dysfunctional LDL-C per se.
  • Recommendations faced with statin intolerance.
  • Utility of a combined anti-dyslipidemic therapy (statin & fibrate) on CV outcomes especially in the backdrop of a low HDL-C & a high TG.
  • Impact of lipid lowering strategy in patients with CKD on dialysis.

References:

[1]. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). (2002). [Online] Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf

[Accessed on: 5th March 2014]

[2]. Miller M, Stone MJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, et al. Triglycerides and Cardiovascular Disease: A Scientific Statement From the American Heart Association. 2011; 123(20): 2292-2333.

[3]. ESC/EAS Guidelines for the management of dyslipidaemias. European Heart Journal 2011; 32:1769–1818.

[4]. American Association of Clinical Endocrinologists’ Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. Endocrine Practice 2012; 18(Suppl 1): S1-S78.

[5]. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. (2013). [Online] Available at: https://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.full.pdf

[Accessed on: 5th March 2014].

[6]. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomized placebo controlled trial. Lancet 2002; 360: 7–22.

[7]. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HAW, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative

Atorvastatin Diabetes Study (CARDS): multicenter randomised placebo-controlled trial. Lancet 2004; 364: 685–96.

[8]. NHS. FORTH VALLEY LIPID LOWERING GUIDELINES (2010). [Online] Available at: http://nhsforthvalley.com/wp-content/uploads/2014/02/Clinical-guidelines-for-lipid-lowering.pdf

[Accessed on: 5th March 2014]

[9]. NLA Statement on the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic

Cardiovascular Risk in Adults. (2013). [Online] https://www.lipid.org/nla/2013-accaha-guideline-treatment-blood-cholesterol-reduce-atherosclerotic-cardiovascular-risk

[Accessed on: 5th March 2014]

 

[10]. Olechnowicz-Tietz S, Gluba A, Paradowska A, Banach M, RyszJ . The risk of atherosclerosis in patients with chronic

kidney disease. Int Urol Nephrol 2013; 45(6):1605–1612.

[11]. Nikolic D, Nikfar S, Salari P, Rizzo M, Ray KK, Pencina MJ.

Lipid and Blood Pressure Meta-Analysis Collaboration Group. Effects of statins on lipid profile in chronic kidney

disease patients: a meta-analysis of randomized controlled trials.

Curr Med Res Opin 2013;29(5):435–451.

[12]. An International Atherosclerosis Society Position Paper:

Global Recommendations for the Management of Dyslipidemia. (2013). [Online] Available at: http://www.athero.org/download/IASPPGuidelines_FullReport_2.pdf

[Accessed on: 5th March 2014].

[13]. KDIGO clinical practice guideline for lipid management in chronic kidney disease. 2013; Kidney Int Suppl 3:259–305.

[14]. Szadkowska I, Stanczyk A, Aronow WS, et al. Statin therapy in the elderly: a review. Arch Gerontol Geriatr 2010; 50: 114-8.

[15]. Shepherd J, Blauw GJ, Murphy MB. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360: 1623-30.

[16]. Deedwania P, Stone PH, Bairey Merz CN. Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE). Circulation 2007; 115: 700-7.

[17]. Athyros VG, Katsiki N, Tziomalos K. Statins and cardiovascular outcomes in elderly and younger patients with coronary artery disease: a post hoc analysis of the GREACE study. Arch Med Sci 2013; 9: 418-26.

[18]. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Circulation 2002; 106: 1024-8.

[19]. Standards of Medical Care in Diabetes-2014. American Diabetes Association. Diabetes Care 2014; 37(Suppl 1): S14-S80.

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