DYSLIPIDEMIA Michael Brändle, Stefan Bilz Cardiovascular risk in patients with DM Current guidelines with emphasis on patients with DM Familial Hypercholesterolemia PCSK9-inhibitors
Primary Prevention of CVD in Patients with Diabetes mellitus Consensus among various guidelines that lipid lowering therapy should be based on cardiovascular risk categories High cv risk may result from a a priori condition (e.g. clinical cardiovascular disease, heterozygous familial hypercholesterolemia, diabetes mellitus,...) or the simultanenous presence of multiple risk factors ( risk calculators) Patients with DM are considered high-risk and statins are recommended EAS/ESC (2011): Type 2 DM and type 1 DM with end-organ damage, e.g. microalbuminuria treat to target (LDL-C < 1.8 mmol/l) ADA/AHA (2013): Type 2 and type 1 DM, 40-75 years and LDL-C > 1.8 mmol/l, at younger age only if risk factors are present moderate to high-intensity statin NICE (2014): Type 2 DM if 10-year CVD risk > 10% (QRISK2), type 1 DM if > 40 years, diabetes duration > 10 years, nephropathy, risk factors Atorvastatin 20 mg q.d
Are all patients with type 2 DM at equally increased cardiovascular risk? 20% 15% Absolute Cardiovascular Mortality in Type 2 DM Type 2 DM Controls 19.0% 17.7% 10% 5% 0% 1.1% 2.8% 0.4% 1.3% 6.5% 4.3% < 55 55-64 65-74 >75 Age (years) Swedish National Diabetes Register 1998-2011 Mean Follow-up for Patients and Controls 4.6 and 4.8 years Tancredi M et al., N Engl J Med 2015;373:1720-32.
Are all patients with type 2 DM at equally increased cardiovascular risk? Fold increase in cv mortality 6 4 2 0 Relative Cardiovascular Mortality Risk in Type 2 DM according to Age & HbA1c <55Yr 55-64Yr 65-74Yr >75Yr Ref. <6.9% 7.0-7.8% 7.9-8.7% 8.8-9.6% >9.7% Swedish National Diabetes Register 1998-2011 Mean Follow-up for Patients and Controls 4.6 and 4.8 years Tancredi M et al., N Engl J Med 2015;373:1720-32.
Are all patients with type 1 DM at equally increased cardiovascular risk? Adjusted Hazard Ratio 10 5 0 Relative Increase in cv Mortality in T1DM according to HbA1c 1.0 2.4 2.4 3.1 3.7 Ref. <6.9 7.0-7.8 7.9-8.7 HbA1c (%) 8.8-9.6 8.5 >9.7 30 20 10 0 Relative Increase in cv Mortality in T1DM according to Albuminuria 1.0 2.8 4.9 9.8 Albuminuria category 28.1 Swedish National Diabetes Register 1998-2011 Mean Follow-up for Patients and Controls 8.0 and 8.3 years Lind M. et al., N Engl J Med 2014; 371:1972-82.
Summary & considerations Cardiovascular risk in both type 1 & type 2 DM is as we all know very heterogeneous. This is not reflected in current guidelines, which attribute a very high risk to almost all patients with DM. Although absolute cv risk is low in otherwise healthy, young patients with type 1 & 2 DM, their relative cv risk is already considerably increased. Lifetime risk may be a better surrogate on which primary prevention strategies can be based. This is not supported by scientific evidence and not part of guidelines, but may (should?) be considered individually.
Current Guidelines Based on EAS/ESC/AGLA Several Swiss professional societies (including ours) denied to adopt the new AHA/ADA guidelines Do not read the Swiss Medical Board report either...
Guidelines AGLA/EAS/ESC (2011-14) HIGH RISK CATEGORIES VERY HIGH HIGH Type 2 DM, Type 1 DM + target organ damage Chronic kidney disease (egfr < 60 ml/min) 10 year cardiovascular mortality risk > 10%* Familial dyslipidemias (HeFH, FCHL) Severe hypertension 10 year cardiovascular mortality risk > 5-10%** Corresponding to 30% * and 15-30%** of fatal and non-fatal cardiovascular disease (AGLA-Score)
For everybody else except patients with T1DM (this acutally means you don t need it in the diabetes clinic...) AGLA - Risikorechner Für ein tödliches Koronarereignis oder einen nicht-tödlichen Herzinfarkt in den nächsten 10 Jahren
Guidelines AGLA/EAS/ESC (2011-14) LOW RISK CATEGORIES MODERATE LOW 10 year cardiovasc ular mortality risk 1-5%* 10 year cardiovascu lar mortality risk < 1%** Corresponding to a 3-15%* and <3%** risk of fatal and non-fatal cardiovascular disease (AGLA-Score)
Guidelines AGLA/EAS/ESC RISK CATEGORIES AND LDL-C- GOALS Very high High < 1.8 mmol/l a/o 50% reduction < 2.5 mmol/l Moderate < 3.0 mmol/l LOW < 4.0 mmol/l
Do we need to prescribe statins to all patients with diabetes and is there a universal LDL-C goal of < 1.8 mmol/l? Current guidelines suggest to treat all patients with T2DM (except those with LDL-C < 1.8 mmol/l) with an LDL-C-target < 1.8 mmol/l Some patients with T2DM without any further risk factors may not be at very high risk and a less strict treatment threshold and LDLgoal may applicable (< 2.5 mmol/l) Few data are available for patients with type 1 DM. Statins are recommended in T1DM if micro- and/or macrovascular complications are present with an LDL-C-target < 1.8 mmol/l. In those with Type 1 DM and cardiovascular risk factors statin therapy may be recommended if the LDL-C is > 2.5 mmol/l.
Non-statin lipid lowering drugs Fibrates: little evidence for reduction of cardiovascular mortality. There may be some benefit in patients with moderately increased Tg and low HDL-C (ACCORD-Lipid-post hoc analysis) Fibrates may be considered for the prevention of chylomicronemia if TG concentrations are > 5-10 mmol/l Ezetimibe: small further reduction (RRR 6.4%) in cv risk demonstrated if added to statins to reach very low LDL-C levels (1.4 mmol/l) IMPROVE-IT. CETP-inhibitors: only one left anacetrapib Torcetrapib, dalcetrapib and evacetrapib have been withdrawn due to an increase in cv risk (torcetrapib) or lack of efficacy Niacin: withdrawn due to lack off efficacy (HPS-THRIVE, Aim-High) PCSK9-inhibitors: rising stars see later
Life-style modification: Mediterranian diet successful in lowering cv risk PREDIMED STUDY Estruch R, N Engl J Med 368: 1279, 2013
Familial Hypercholesterolemia (more correct: Autosomal-dominant-Hypercholesterolemia to include Apo B and PCSK9-Mutations) Frequent disorder carrying a very high cardiovascular risk (1:200 1:500, corresponding to 15 000 30 000 people in CH) Less than 10% correctly diagnosed, prevalence up to 50% in those with premature coronary disease Diagnosis should be established using scores (e.g. Dutch-Lipid-Network, Simone- Broome) Primary prevention with statins should be started when the disease has been diagnosed (including children from age 12) Family members should be identified by a cascade-screening strategy Genetic testing, which may be helpful in identifying affected patients, is currently not reimbursed, but may become available (new technologies such as NGS) If you find a patient, you need to treat the family!!!
PCSK9-Inhibitors Proprotein convertase subtilisin/kexin type 9 Inhibitors
Schulz R, Basic Res Cardiol 110: 4, 2015
PCSK9-Antibodies Fully humanized monoclonal antibodies directed against PCSK9, a protease which interferes with LDL-receptor-recycling Lower LDL-C by approximately 50%, regardless of pretreatment additional 25% decrease in Lipoprotein (a) Twice monthly s.c. injection with a disposable device (similar to insulin pen) Currently 2 substances approved by FDA and EMA, Alirocumab (Praluent, Sanofi) and Evolocumab (Repatha, Amgen) FDA:...for use in addition to diet and maximally-tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), or clinical atherosclerotic cardiovascular disease, such as heart attacks or strokes, who require additional lowering of LDL cholesterol... (...those are many!) EMA:... is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet: in combination with a statin or statin with other lipidlowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or,- alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contra-indicated... Current annual costs: USD 14 000, EUR 7 500, CHF?? Swissmedic approval pending, but expected for early 2016
ALIROCUMAB AS ADD-ON TO ATORVASTATIN VERSUS OTHER LIPID TREATMENT STRATEGIES Bays H et al, JCEM epub 2015
PCSK9-INHIBITORS AND CARDIOVASCULAR MORTALITY (METAANALYSIS OF PHASE 2/3 STUDIES, CV OUTCOME STUDIES ONGOING) Navarese EP, et al, Ann Int Med epub 2015