Module 8 Lipid Management in Diabetic Patients
Background
Accelerated atherosclerosis is multifactorial and begins years/decades prior to the diagnosis of type 2 diabetes: Risk for atherosclerotic events is two to four-fold greater than in non-diabetic
subject. Responsible for 80% of diabetic mortality. (75% due to coronary heart
disease and 25% due to stroke and peripheral vascular disease). >75% of all hospitalisations for diabetic complications1. In Hong Kong one-third of patients hospitalised for stroke, myocardial
infarction and coronary heart failure have diabetes 2,3. Dyslipidaemia is a major risk factor for diabetes macrovascular complications 4. Typical characteristics of dyslipidaemia in type 2 diabetes include
hypertriglyceridaemia and low HDL-Cholesterol, the LDL-Cholesterollevel is similar to that in non-diabetic 5, but qualitatively more atherogenic(increased glycation, triglyceride enrichment with increased proportion ofsmall dense LDL-Cholesterol), thus leading to accelerated atherosclerosis.
Screening
At least annual screening of lipid profile, and more frequently if needed for treatment modification. Optimal treatment target of various lipid components:
● LDL-Cholesterol (LDC-C): < 2.6 mmol/L<1.8 mmol/L (for patients with pre-existing
cardiovascular diseases)● HDL-Cholesterol (HDL-C): >1.0 mmol/L for male
>1.3 mmol/L for female ● Triglyceride (TG): <1.7 mmol/L
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Module 8 Lipid Management in Diabetic Patients
Management
Lifestyle modification Reduction of dietary fat intake Total fat <30% of total calorie/day Saturated fat <7%, cholesterol <200 mg, trans fat <1% of total calorie intake/day
Drug treatment (Table 1)(1) Statins (HMG - CoA reductase inhibitors) 6,7,8 ↓ LDL-C 25-55%, ↓ TG 15-30%, ↑ HDL-C 5-10% 25-55% risk reduction in cardiovascular diseases (coronary heart disease,
stroke) in primary and secondary prevention studies Practical algorithm of statin usage is illustrated in Figure 1
(2) Fibrates 9 ↓ TG 25-50% + ↑ HDL-C 10-20% 24 % risk reduction in cardiovascular diseases (MI, stroke) in diabetes subgroup
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Module 8 Lipid Management in Diabetic Patients
Figure 1. Practical algorithm of statin usage
Liver disease/ unexplained, persistent elevations of liver enzymes/ pregnant or lactating women
NO
Relative contraindications10
Concomitant use of cyclosporine, gemfibrozil, niacin, macrolide antibiotics, various antifungal agents, and cytochrome P-450 inhibitors
NO
Trade name of statins can be searched inhttps://www.drugoffice.gov.hk/eps/do/en/healthcare_providers/home.htmlStarting doseSimvastatin 10mg nocte / Pravastatin 10mg note / Atorvastatin 10mg daily / Rosuvastatin 5mg daily / Lovastatin 10mg daily / Fluvastatin 20mg daily
LDL not reaching targets
On titration of statins● Rule of Six11: Doubling of dosage of statin will result in 6% LDL reduction but increased
risk of transaminase elevationThe following demonstrates the doubling of dosage of statin: Simvastatin12,13 10mg → 20mg → 40mg Pravastatin14,15,16,17 10mg → 20mg → 40mg Atorvastatin18,19 10mg → 20mg → 40mg → 80mg Rosuvastatin20,21 5mg → 10mg → 20mg Lovastatin22 10mg → 20mg → 40mg Fluvastatin 20mg → 40mg → 80mg See Notes on hepatic side effects of statins
If LDL does not reach targets despite titration of statin or side effects develop on higher doses of statin, consider referral to specialist for combination lipid lowering therapies with statin and other medications.
YES
Consider other treatment modalities
YES#
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Module 8 Lipid Management in Diabetic Patients
Monitoring-Laboratory
ALT/AST10
Before start 12 weeks after start of statin Thereafter repeat if
clinically indicated <3 x ULN → careful monitoring >/=3 x ULN → STOP
Monitoring-Symptoms Headache and Dyspepsia10
Initial 6-8 weeks after therapy Each follow up
Muscle Soreness/Tenderness/Pain10
Blood for CK only if muscle symptoms arise Increase in CK → Rule out common causes like
exercise / strenuous work → Advise Moderation CK> 10x ULN → STOP CK 3-10x ULN + symptoms STOP → Progressive but asymptomatic CK elevation →
Reduction in dose or temporary discontinuation10
Notes on hepatic side effects of statin: Elevated hepatic transaminase generally occurs in 0.5%-2% of cases and
is dose dependent 23,24, with↑relative risk 2 – 4 fold at higher doses ofstatin
Progression to liver failure specifically due to statin is exceedingly rare if everoccurs 25
Reversal of transaminase elevation is frequently noted with a reduction in dose,and elevations do not often recur with either re-challenge or selection of anotherstatin 26,27
# Combination of statin with drugs listed may carry an increase in risk of myositis and liver derangement.
^ (i) LDL lowering efficacy on ezetimibe + lowest-dose statin is comparable to maximum dose of every statin (up to 60% lowering) but there is slightly higher percentage of patients having elevated ALT/AST compared with statin monotherapy (~1%); all were asymptomatic, transient and reverted to baseline with discontinuation of drugs 28-30.(ii) Niaspan can slow down the progression of the atherosclerosis, regression the atherosclerotic plaque volume and decrease the cardiovascular morbidity and mortality (surrogate and hard endpoints) 31-35. The side effect of most concern of Niaspan is flushing.
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Module 8 Lipid Management in Diabetic Patients
Simvastatin dose limitationsWhen used with simvastatin, the following medications can raise the levels of simvastatin in the body and increase the risk of myopathy. Taking no more than the recommended dose of simvastatin with these medications will help keep simvastatin levels in the body at a safer level.
New simvastatin label
Contraindicated with simvastatin:● Itraconazole● Ketoconazole● Posaconazole (New)● Erythromycin● Clarithromycin● Telithromycin● HIV protease inhibitors● Nefazodone● Gemfibrozil● Cyclosporine● Danazol
Do not exceed 10 mg simvastatin daily with:● Verapamil● Diltiazem
Do not exceed 20 mg simvastatin daily with:● Amiodarone● Amlodipine (New)● Ranolazine (New)
Avoid large quantities of grapefruit juice (>1 quart daily)
FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. 15 Dec 2011.http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm
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Module 8 Lipid Management in Diabetic Patients
Table 1. Management of diabetic dyslipidemia (in order of priorities) (Adopted from American Diabetes Association)36
I. LDL-C lowering– HMG-CoA reductase inhibitor (statin)
II. HDL-C raising– Behavioural interventions such as weight loss, increased physical
activity and smoking cessation may be useful– Fibrates (gemfibrozil, fenofibrate) or nicotinic acid
III. Triglyceride lowering– Glycaemic control– Fibrates– Statins moderately effective at high dose in hypertriglyceridaemia
subjects who also have high LDL-C
IV. Combined hyperlipidemia– First choice - Improved glycaemic control plus high dose statin– Second choice - Improved glycaemic control plus statin plus
fibrates* (gemfibrozil, fenofibrate)– Third choice - Improved glycaemic control plus statin plus
nicotinic acid* (glycaemic control must be monitored carefully)
* The combination of statins with gemfibrozil or fenofibrate, or evennicotinic acid may carry an increased risk of myositis.
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Reference:
1. Lewis GF. Diabetic dyslipidemia: a case for aggressive intervention in the absence of clinical trial and cost effectiveness data. Can J Cardiol.1995; 11 Suppl C: 24C-28C.
2. Hu YH, Pan XR, Liu PA, Li GW, Howard BV, Bennett PH. Coronary heartdisease and diabetic retinopathy in newly diagnosed diabetes in Da Qing, China:the Da Qing IGT and Diabetes Study. Acta Diabetol. 1991;28(2):169-73.
3. Chan JC. Heterogeneity of diabetes mellitus in the Hong Kong Chinesepopulation. The Chinese University of Hong Kong–Prince of Wales HospitalDiabetes Research and Care Group. Hong Kong Med J. 2000;6(1):77-84.
4. Turner RC, Millns H, Neil HAW, Stratton IM, Manley SE, Matthews DR, et al.Risk factors for coronary artery disease in non-insulin dependent diabetesmellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ.1998;316(7134):823-28.
5. Janus ED, editor. The Hong Kong Cardiovascular Risk Factor PrevalenceStudy 1995-1996: Hong Kong: Queen Mary Hospital; 1997.
6. The Scandinavian Simvastatin Survival Study Group. Randomised trialof cholesterol lowering in 4444 patients with coronary heart disease: theScandinavian Simvastatin Survival Study (4S). Lancet 1994;344(8934):1383-9.
7. Heart Protection Study Collaborative Group, MRC/BHF Heart ProtectionStudy of cholesterol lowering with simvastatin in 20,536 high-risk individuals:a randomised placebo-controlled trial. Lancet 2002; 360(9326): 7-22.
8. Colhoun HM, Betteridge D, Durrington PN, Hitman GA, Neil HA, LivingstoneSJ, et al. Primary prevention of cardiovascular disease with atorvastatin intype 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS):multicentre randomised placebo-controlled trial. Lancet 2004: 364(9435): 685-96.
9. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al.Gemfibrozil for the secondary prevention of coronary heart disease in menwith low levels of high-density lipoprotein cholesterol. Veterans AffairsHigh-Density Lipoprotein Cholesterol Intervention Trial Study Group. NewEngl J Med. 1999; 341(6):410-8.
10. ACC/AHA/NHLBI Clinical Advisory on the use and safety of statins. JACC2002; 40:567-72.
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Module 8 Lipid Management in Diabetic Patients
11. Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVESInvestigators. Comparative dose efficacy of Atorvastatin versusSimvastatin, Pravastatin, Lovastatin, and Fluvastatin in patients withhypercholesterolemia (The CURVES study). Am J Cardiol 1998;81:582-7.
12. Scandinavian Simvastatin Survival Study Group. Randomised trial ofcholesterol lowering in 4,444 patients with coronary heart disease:Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-9.
13. Heart Protection Study Collaborative Group. MRC/BHF HeartProtection Study of cholesterol lowering with Simvastatin in 20536high-risk individuals: a randomized placebo-controlled trial. Lancet2002; 30(9326):7-22.
14. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heartdisease with Pravastatin in men with hypercholesterolemia. West ofScotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301-7.
15. Sacks FM, Pfeffer MA, Moye LA, for the Cholesterol and RecurrentEvents Trial Investigators. The Effects of Pravastatin on CoronaryEvents after Myocardial Infarction in Patients with Average CholesterolLevels. N Engl J Med 1996; 335:1001-9.
16. The Long-Term Intervention with Pravastatin in Ischaemic Disease(LIPID) Study Group Prevention of Cardiovascular Events and Deathwith Pravastatin in Patients with Coronary Heart Disease and a BroadRange of Initial Cholesterol Levels. N Engl J Med 1998; 339:1349-57.
17. Shepherd J, Blauw GJ, Murphy MB et al. PROSPER study group.Pravastatin in elderly individuals at risk of vascular disease(PROSPER): a randomized control trial. PROspective Study ofPravastatin in the Elderly at Risk. Lancet 2002; 360:1623-30.
18. Sever PS, Dahlof B, Poulter NR, et al. ASCOT investigators. Preventionof coronary and stroke events with Atorvastatin in hypertensive patientswho have average or lower-than-average cholesterol concentrations, inthe Anglo-Scandinavian Cardiac Outcomes Trial- Lipid Lower Arm(ASCOT-LLA): a multicentre randomized controlled trial. Lancet 2003;361:1149-58.
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19. Cannon CP, Braunwald E, McCabe CH et al. Pravastatin or AtorvastatinEvaluation and Infection Therapy - Thrombolysis in Myocardial Infarction22 Investigators. Intensive versus moderate lipid lowering with statins afteracute coronary syndromes. N Engl J Med 2004; 350:1495-1504.
20. Nissen SE, et al. Effect of very high-intensity statin therapy on regression ofcoronary atherosclerosis. JAMA 2006; 295:1556-65.
21. Ridker PM, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359:2195-207.
22. Downs JR, Clearfield M, Weis S. Primary prevention of acute coronaryevents with lovastatin in men and women with average cholesterol level:results of AFCAPS/TexCAPS. JAMA 1998; 279:1615-22.
23. Hsu I, Spinler SA, Johson NE. Comparative evaluation of the safety andefficacy of HMG-CoA reductase inhibitor monotherapy in the treatmentof primary hypercholesterolemia. Ann Pharmacother 1995; 29:743-59.
24. Bradford RH, Shear CL, Chremos AN, et al. expanded ClinicalEvaluation of Lovastatin (EXCEL) study results. I. Efficacy inmodifying plasma lipoproteins and adverse event profile in 8245patients with moderate hypercholesterolemia. Arch Intern Med 1991;11:43-9.
25. Pedersen TR, Tobert JA. Benefits and risks of HMG-CoA reductaseinhibitors in the prevention of coronary heart disease: a reappraisal.Drug Saf 1996; 14:11-24.
26. Cressman MD, hoogwerf BJ, moodie DS, Olin JW, Weinstein CE.HMG-CoA reductase inhibitors. A new approach to the management ofhypercholesterolemia. Cleve Clin J Med 1988; 55:93-100.
27. Hunninghake DB. Drug treatment of dyslipoproteinemia. EndocrinolMetab Clin North Am 1990; 19:345-60.
28. Kastelein JJP, et al. Simvastatin with or without ezetimibe in familialhypercholesterolemia. N Eng J Med 2008; 358:1431-43.
29. Rossebo AB et al. Intensive lipid lowering with Simvastatin andezetimibe on carotid atherosclerosis in type 2 diabetes. J Med 2008;359:1343-56.
30. Fleg JL, et al. Effect of statin alone versus statins plus ezetimibe oncarotid atherosclerosis. JAMA 2006; 295:1556-65.
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31. Brown BG, Albers JJ, Fisher LD. Regression of coronary artery as a resultof intensive lipid lowering therapy in men with high levels ofapolipoprotein B. N Engl J Med 1990; 323:1289-98.
32. Brown BG, et al. Very intensive lipid therapy with lovastatin, niacin,and colestipol for prevention of death and myocardial infarction: a 10year Familial Atherosclerosis Treatment Study (FATS) follow-up.Circulation 1998; 98(Suppl I):1-635.
33. Brown BF, et al. Simvastatin and niacin, antioxidant vitamins, or thecombination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92.
34. Taylor AJ, et al. Arterial Biology for the Investigation of the TreatmentEffects of Reducing Cholesterol (ARBITER) 2: a double-blind,placebo-controlled study of extended-release niacin on atherosclerosisprogression in secondary prevention patients treated with statins.Circulation 2004; 110-3512-7.
35. Taylor AJ, et al. The efficacy of 24 months of combination statin andextended –release niacin on carotid intima-media thickness: ARBITER3. Curr Med Res Opin 2006; 22:2243-50.
36. American Diabetes Association. Standards of Medical Care inDiabetes-2010. Diabetes Care 2010; 33 Suppl. 1: S11-61.
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