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Statin untuk Pencegahan Primer Komplikasi Kardiovaskular pada Pasien DM tipe 2 dengan Profil Lipid yang baik: Laporan Berbasis Bukti Alvin Nursalim,* Pradana Soewondo,** Indah S. Widyahening*** *Fakultas Kedokteran Universitas Indonesia, Jakarta **Departemen Ilmu Penyakit Dalam Rumah Sakit Cipto Mangunkusuno, Jakarta ***Departmen Ilmu Kedokteran Komunitas Fakultas Kedokteran Universitas Indonesia, Jakarta
Abstrak: Penyakit jantung diabetik merupakan penyebab mortalitas tertinggi pada penyandang DM. Faktor risiko yang turut berperan dalam terjadinya komplikasi kardiovaskular pada penyandang DM adalah dislipidemia. Banyak studi menunjukkan efektivitas statin dalam memperbaiki profil lipid penyandang DM tipe 2 dengan dislipidemia yang pada akhirnya menyebabkan penurunan komplikasi kardiovaskular. Laporan ini dibuat untuk mengetahui apakah statin efektif sebagai pencegahan komplikasi kardiovaskular pada penyandang DM dengan profil lipid yang normal. Pencarian terstruktur dilakukan dengan menggunakan Pubmed, Medline dan Google. Setelah dilakukan penapisan judul dan abstrak dengan kriteria inklusi dan eksklusi, sebelas studi ditemukan, tetapi hanya tiga studi yang digunakan penulis. Ketiga studi ditelaah dengan menggunakan kriteria yang mencakup validity, importance, dan applicability untuk menentukan derajat kegunaan dalam studi ini. Ketiga studi tersebut menunjukkan penurunan komplikasi dan mortalitas kardiovaskular pada kelompok terapi statin. Hal ini terlihat dari relative risk reduction yang berkisar antara 18-37,5%. Absolute risk reduction berkisar antara 1,9-3% dan number needed to treat yang berkisar antara 33-53. Selain penurunan angka komplikasi kardiovaskular, ketiga studi itu juga melaporkan terdapatnya penurunan komplikasi serebrovaskular pada pasien yang diberikan terapi statin. Pemberian statin merupakan terapi yang efektif dalam menurunkan komplikasi kardiovaskular pada pasien DM tipe 2 dengan profil lipid normal. J Indon Med Assoc. 2011;61:363-7. Kata Kunci: Diabetes mellitus tipe 2, dislipidemia, statin, profil lipid normal, kardiovaskular
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Statin untuk Pencegahan Primer Komplikasi Kardiovaskular pada Pasien DM tipe 2
Statin Administration for Primary Prevention of Cardiovascular Complication Among Type 2 Diabetic Patients with Good Lipid Profile: Evidence Based Report Alvin Nursalim*, Pradana Soewondo**, Indah S. Widyahening*** *Faculty of Medicine Universitas Indonesia, Jakarta **Department of Internal Medicine Faculty of Medicine Universitas Indonesia Cipto Mangunkusumo Hospital, Jakarta ***Department of Community Medicine, Faculty of Medicine Universitas Indonesia, Jakarta
Abstract: One of the most fatal complications in diabetic patients is diabetic heart disease. Dyslipidemia becomes one of many risk factors that contribute to the occurrence of cardiovascular complication among diabetic patients. Some studies showed the effectiveness of statin in improving lipid profile among type 2 diabetic patients with dyslipidemia, which finally reduce the occurrence of cardiovascular complication. This report aims to identify whether statin is effective in preventing cardiovascular complication among diabetic patients with normal lipid profile. A search was conducted on PubMed and Google. After the selection of title and abstract was done using inclusion and exclusion criteria. Eleven original articles were found, but only three studies were used. All selected studies were critically appraised for its validity, importance and applicability.All three studies showed the reduction in cardiovascular complication and mortality related to cardiovascular. The relative risk reduction ranged from 18-37,5%. The absolute risk reduction ranged from 1,9%-3% and number needed to treat ranged from 33-53. Beside the reduction in cardiovascular complication, statin therapy was also proven to decrease the occurrence of cerebrovascular complication among type 2 diabetic patients. The administration of statin is effective in reducing the risk of cardiovascular complication among type 2 diabetic patients with normal lipid profile. J Indon Med Assoc. 2011;61:363-7. Keywords: Type 2 Diabetes mellitus, dyslipidemia, statin, normal lipid profile, cardiovascular disease.
Introduction Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia. Diabetes mellitus causes a wide variety of chronic complications on so many organs such as: eyes, kidney and blood vessels in long term. DM is commonly accompanied by others metabolic disorders. 1 The prevalence of DM increased in the last two decades. The number of DM cases increased from 30 millions cases in 1985 to 177 millions cases in 2000.2 According to International Diabetes Federation, there will be 380 millions patients with DM in 2025. The prevalence of Type 2 DM in Indonesia is 5,7%.3 As the number of DM patients increased worldwide, the number of DM patients with complication would increase eventually. Diabetic heart disease is the number one cause of mortality among DM patients. It is due to the premature atherosclerosis process.4 Diabetic heart disease refers to heart disease that happens among diabetic patients due to metabolic factors interaction. Compared with people who do not have diabetes, diabetic patients have twice to four times the risk of developing coronary heart disease. Diabetic patients de-
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velop coronary heart disease at younger age compared to those who do not have diabetes.1,5 Many studies show the effectiveness of statin in improving lipid profile among type 2 diabetic patients with dyslipidemia.1,6 A normal lipid profile will reduce the occurrence of cardiovascular complication eventually. This report is made to identify whether statin administration is effective as primary prevention of cardiovascular complication among type 2 diabetic patients with normal lipid profile. Clinical Question Is statin administration effective as primary prevention for cardiovascular complication among type 2 diabetic patients with normal lipid profile? Method The search was conducted on PubMed,® and Google, ® on April 2nd and 4th 2011, using the keywords “adult,” “statin,” “diabetes” and “cardiovascular” along with its synonyms and related terms (Table 1). J Indon Med Assoc, Volum: 61, Nomor: 9, September 2011
Statin untuk Pencegahan Primer Komplikasi Kardiovaskular pada Pasien DM tipe 2 Table 1. Search Strategy Used in PubMed, Medline and Google (Conducted on April 2nd and 4th 2011) Database
Search terms
Pubmed (adult) AND diabetes) AND statin) AND (2 April 2011) (cardiovascular OR vascular event) Google Adult statin diabetesCardiovascular (4 April 2011)
Results
able. These three articles were appraised and considered to have a good validity and relevance. Three articles, obtained after searching, selection and filtration method, reported the use of statin for good to borderline lipid profile.
55 4
Search strategy, results and the inclusion and exclusion criteria are shown in a flowchart (Figure 1).
Search date: April 4, 2011
Figure 1. Flow Chart of Search Strategy
After the selection, critical appraisal was done using several aspects based on Center of Evidence-based Medicine, University of Oxford for therapy study (Table 2).10 Result From the selection and filtration, eleven articles were obtained, out of which only three full-text articles were availJ Indon Med Assoc, Volum: 61, Nomor: 9, September 2011
Discussion Colhoun HM et al7 conducted a study to evaluate whether the administration of 10 mg of atorvastatin is significantly useful in reducing the occurence of primary cardiovascular complication among diabetic patients with good lipid profile. The result of this study is that the administration of 10 mg of atorvastatin everyday reduce the risk of cardiovascular complication as much as 37% with the Control Event Rate (CER) was 5.5%, Experimental Event Rate (EER) was 3.6%, Relative Risk Reduction (RRR) was 34.5%, Absolute Risk Reduction (ARR) was 1.9% and Number Needed to Treat (NNT) was 53 (p=0.001). Collins R. et al8 also found a significant reduction in the occurence of cardiovascular complication. This study involved 20 536 patients, aged between 40-80 years old with good to borderline lipid profile. In the simvastatin group there were 357 patients (3.5%) who finally got cardiovascular complication compared with 574 patients (5.6%) in the placebo group. RRR was 37.5%, ARR was 2.1% and NNT was 47. Goldberg et al9 conducted a study about the administration of pravastatin in 586 diabetic patients. The patients involved in this study have good-borderline lipid profile. The result of this study was the administration of pravastatin reduced mortality rate due to coronary heart disease. The RRR was 18%, ARR was 3%, and NNT was 33. Colhoun et al7, Collins et al8 and Golgberg B et al9 showed similar result that the administration of statin in diabetic patients with good clinical profile will eventually lead to reduction of cardiovascular complication. Colhoun et al7, Collins et al8 and Goldberg B et al9 showed that statin administration significantly reduce the occurence of cardiovascular risk as much as 37%, 37,5% and 46% respectively. Beside the reduction of cardiovascular complication, Colhoun et al7 also showed a 48% reduction in the occurence of stroke. According to this study, statin administration is proven to be effective and safe. The ARRs in these three studies ranged from 1,9 -3% and the NNT ranged from 33-55. The NNT from these three journals can still be considered beneficial since preventive meassure that produced small effects in large numbers of patients will have high NNT. Statin administration is considered safe due to the minimal side effect occured during this study. Out of 2838 patients participated in this study only a small proportion of patients were diagnosed to have rhabdomyolisis (61 patients in statin group and 72 patients in placebo group). Beside cardiovascular complication, Collins et al8 and Goldber B et al9 also provided the comparison of mortality rate among the two groups. The mortality rate reduction in 365
Statin untuk Pencegahan Primer Komplikasi Kardiovaskular pada Pasien DM tipe 2 Table 2. Critical Appraisal of the 3 usefull articles based on criterias by Centre of Evidence Medicine University of Oxford 10 Validity
Relevance Comparable treatment
Intention to treat
Domain
Determinant
Meassurement of outcome
+ + +
Blinding
2838 20536 586
Result
Similarity treatment and control
+ + +
Randomization
Number of patients
Colhoun HM et al7 Collins R. et al8 Goldberg RB et al9
Study design
Articles
+ + +
+ + +
+ + +
? + ?
+ + +
+ + +
+ + +
A B C
Levels of evidence*
1B 1B 1B
Legend: + stated clearly in the article - not being done ? not stated clearly * Levels of evidence based on The Oxford Centre of Evidence-based Medicine A: The result of this study is that the administration of 10 mg atorvastatin everyday reduce the occurence of cardiovascular complication as much as 37% on those patients without previous history of cardiovascular complication (p=0.001) B: There are 357 (3.5%) patients had myocardial infarction in the simvastatin group, compared to 574 (5.6%) in the placebo group. C. The administration of Parastatin on DM patients is related with cardiovascular complication risk reduction (Relative Risk: 25%, p: 0.05)
the statin group is mainly due to the reduction of cardiovascular complication. As stated above, cardiovascular complication is the leading cause of mortality among diabetic patients. Statin is a widely known drug and well distributed acrossed Indonesia. Some statins are affordable and can be purchased with prescription in any pharmacy. According to statin characteristics and its efficacy, statin can be used as a preventive measure of cardiovascular complication among diabetic patients. Conclusion All three studies gave the same recommendation that the administration of statin is a safe and effective way to reduce cardiovascular complication among type 2 diabetic patients with good lipid profile. Beside the reduction of cardiovascular complication, these studies also concluded that statin therapy reduce the mortality rate and the occurence of cerebrovascular complication. Unfortunately, there was no definite lipid profile range as to begin statin therapy, so risk factors stratification could be put into consideration when presented with a diabetic patient with good lipid profile. It is also crucial to encourage a healthy lifestyle modification to all diabetic patients before implementing any medication. Although the side effects observed in these study is minimal, follow-up is recommended for all patients receiving statin therapy. Rhabdyomyolisis, the most common side effect of statin therapy, can be identified by creatine-kinase examination. Recommendation for Clinical Use These report can be translated into clinical practise with the following example. A 46 years old man was diagnosed 366
with type 2 diabetes mellitus. This patient had been smoking for more than 20 years and rarely had excercise. According to physical examination, the patient was in a good condition and there was no diabetic complication observed. The laboratory findings were all within normal range, including lipid profile (total cholesterol, tryglyceride, LDL and HDL). There were no abnormality found on the X-ray and electrocardiography examination. Beside the regular prescriptions of oral diabetic medication, the doctor also prescribed atorvastatin 10 mg to be consumed once daily. The statin prescription for this patient is an effective preventive meassure for cardiovascular complications. References 1.
2. 3. 4.
5. 6. 7.
8.
Powers AC. Diabetes Mellitus. In: Kasper DL, Braunwald E, Hauser S, Longo D, Jameson JL, Fauci AS, editors. Harrison’s Principles of Internal Medicine. 17th edition. New York: McGraw-Hill Co. 2008. p. 2166-8. International Diabetes Federation. Diabetes Atlas. 3 rd edition. Belgia. 2003. Departemen Kesehatan Republik Indonesia. Laporan riset kesehatan dasar Indonesia tahun 2007. Jakarta; 2008 Ligaray KPL, Isley W L. Diabetes Mellitus, type 2. Emedicine [cited 2011 April 4]. Available from: URL:HYPERLINK http:// emedicine.medscape.com/article/117853-overview Meng HT. Diabetes and coronary heart disease. Diabetes spectrum. 1999;12(2):80-3. PERKENI. Konsensus pengelolaan dan pencegahan diabetes mellitus tipe 2 di Indonesia. Jakarta. 2006. 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): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685-96. Collins R, Armitage J, Parish S, Sleight P, Peto R.. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk
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conditions. Lancet. 2004;363:757-67. Goldberg RB, Mellies MJ, Sacks FM, Moye LA, Howard BV, Howard WJ, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels subgroup analyses in the Cholesterol and Recurrent Events (CARE) Trial. Circulation. 1998;98;2513-19.
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10. Centre for Evidence Based Medicine. Oxford Centre for Evidence-based Medicine- Level of Evidence. CEBM. [cited 2011 April 4]. Available from: URL:HYPERLYNK http://www.cebm. net/index.aspx?o=5513 FS
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