Prediction of basal glycaemia dynamics during treatment with 6-month lipid-lowering therapy in patients at high risk of cardiovascular disease

Background. A major meta-analysis has confirmed the ability of statins to exert both diabetogenic and hyperglycaemic effects. To date, practical recommendations for predicting glucose dynamics during lipid-lowering therapy have not been developed.

Aims. Identify the combination of factors that can predict changes in basal glycaemia during 6-month lipid-lowering therapy in patients at high risk of cardiovascular disease.

Methods. This study reports on 50 patients with diabetes or impaired glucose tolerance, and 18 patients with coronary artery disease without disorders of carbohydrate metabolism. Of note, 29 of the 50 diabetic or glucose intolerant patients had documented ischaemic heart disease (stable angina). Patients were randomised into three groups: Gr.1 (n=33, atorvastatin therapy), Gr.2 (n=17, atorvastatin in combination with ezetimibe) and Gr.3 (n=18, rosuvastatin therapy). After treatment for 24 weeks, we assessed lipid profile dynamics, metabolism of glucose/insulin and the HOMA-IR index. Multivariate analysis was then performed to identify factors that predicted increases in basal glycaemia.

Results. All of the included patients completed 24 weeks of treatment (N=68). Lipid-lowering effect was significant in all three groups, and overall, target LDL cholesterol level was achieved in 50% of patients (n=34). In Gr.2, basal glucose level increased from 5.5(5.3–6.6) to 6.3(5.6–7.8) mmol/l (p=0.0014), which was accompanied by an increase in HOMA-IR (p=0.024). No significant change in basal glycaemia was observed in Grs.1 and 3. Moreover, an increase in the basal glycaemia was observed in 48.5% of patients in Gr.1, 70.6% in Gr.2 and 44.4% in Gr.3. Multivariate discriminant analysis across all patient groups revealed a canonical linear discriminant function that included the following factors: baseline basal glucose levels, total cholesterol levels, triglycerides and ratio of LDL/HDL cholesterol. Sensitivity and specificity of the model accounted for 75%; 51 out of the 68 cases were correctly classified when predicting the dynamics of basal glucose during lipid-lowering therapy.

Conclusions. Our data demonstrate the ability to predict the dynamics of the basal glycaemia during lipid-lowering therapy. This may allow for a new way to identify patients at high risk of statin-related increases in glycaemia.

lipid-lowering therapy, statins, ezetimibe, basal glycemia, coronary artery disease, diabetes mellitus

1. Catalano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2016;37(39):2999-3058. doi: 10.1093/eurheartj/ehw272

2. Аронов Д.М., Арабидзе Г.Г., Ахмеджанов Н.М., и др. Диагностика и коррекция нарушений липидного обмена с целью профилактики и лечения атеросклероза. Российские рекомендации, V пересмотр // Российский кардиологический журнал. – 2012. – Т.96. – №5 – С. 1–32. [Aronov DM, Arabidze GG, Akhmedzhanov NM, et al. Diagnosis and correction of lipid disorders for the prevention and treatment of atherosclerosis. Russian recommendations. V revision. Russian Cardiology Journal. 2012;96(5):1-32. (In Russ.)]

3. Sattar N, Preiss D, Murray HM, et al. Statin and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet. 2010;375(9716): 735-742. doi: 10.1016/S0140-6736(09)61965-6

4. Chen CW, Chen TC, Huang KY, et al. Differential impact of statin on new-onset diabetes in different age groups: a population-based case-control study in women from an Asian country. PLoS One. 2013;8(8):e71817. doi:10.1371/journal.pone.0071817

5. Mora S, Glynn RJ, Hsia J, et al. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation. 2010;121(9): 1069–1077. doi: 10.1161/circulationaha.109.906479

6. Shen L, Shah BR, Reyes EM, et al. Role of diuretics, β blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study. BMJ. 2013;347:f6745. doi:10.1136/bmj.f6745

7. Ballantyne CM, Houri J, Notarbartolo A et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003;107(19):2409–2415. doi: 10.1161/01.cir.0000068312.21969.c8

8. Moutzouri E, Liberopoulos E, Mikhailidis DP, et al. Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance. Int Clin Pract. 2011;65(11):1141-1148. doi: 10.1016/s1567-5688(11)70080-0

9. Takeshita Y, Takamura T, Honda M, et al. The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia. 2014;57(5):878–890. doi: 10.1007/s00125-013-3149-9

10. Her AY, Kim JY, Kang SM, et al. Effects of atorvastatin 20 mg, rosuvastatin 10 mg, and atorvastatin/ezetimibe 5 mg/5 mg on lipoproteins and glucose metabolism. J Cardiovasc Pharmacol Ther. 2010;15(2):167-174. doi: 10.1177/1074248409357922

11. Wang KL, Liu CJ, Chao TF, et al. Statins, risk of diabetes, and implications on outcomes in general population. J Am Coll Cardiol. 2012;60(14):1231–1238. doi: 10.1016/j.jacc.2012.05.019

12. Кухарчук В.В., Сусеков А.В., Зубарева М.Ю., и др. Диагностика и коррекция нарушений липидного обмена с целью профилактики и лечения атеросклероза. Российские рекомендации. IV пересмотр // Кардиоваскулярная терапия и профилактика. – 2009. – Т. 8. – №6. – С. 3-58. [Kukharchuk VV, Susekov AV, Zubareva M, et al. Diagnosis and correction of lipid disorders for the prevention and treatment of atherosclerosis. Russian recommendations. IV revision. Cardiovascular Therapy and Prevention. 2009;8(6):3-58. (In Russ.)]

13. U.S. Food and Drug Administration [Internet]. FDA Drug Safety Communication. Important safety label changes to cholesterol lowering statin drugs. 2012 [cited 2017 Mar 18]. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm.

14. Maki KC, Ridker PM, Brown WV, et al. An assessment by the Statin Diabetes Safety Task Force: 2014 update. J Clin Lipidol. 2014;8(S3):17-29. doi: 10.1016/j.jacl.2014.02.012

15. Кошельская О.А., Винницкая И.В., Конько Т.Ю., и др. Сравнительное рандомизированное исследование по оценке влияния длительной терапии розувастатином в сочетании с комбинацией аторвастатина и эзетимиба на показатели углеводного обмена и уровень адипокинов у больных ишемической болезнью сердца и сахарным диабетом // Кардиология. – 2015. – Т. 55. – № 3. – С. 67-74. [Koshelskaya OA, Vinnitskaya IV, Konko TYu, et al. Comparative Randomized Study of the Effects of Long-Term Therapy With Rosuvastatin and With Combination of Atorvastatin and Ezetimibe on Carbohydrate Metabolism and Adipokynes Levels in Patients With Coronary Artery Disease and Diabetes Mellitus. Kardiologiia. 2015;55(3):67–74. (In Russ.)] doi: 10.18565/cardio.2015.3.67-74

16. Кошельская О.А., Сушкова А.С., Суслова Т.Е., и др. Длительная терапия аторвастатином у больных ишемической болезнью сердца и сахарным диабетом: влияние на гликемию и локальную сосудистую жесткость // Сердце: журнал для практикующих врачей. – 2013. – Т. 12. – № 4. – С. 223-229. [Koshel’skaya O.A., Sushkova A.S., Suslova T.E., et al. Long-term atorvastatin therapy in patients with ischemic heart disease: effect on glycemia and local vascular stiffness. Russian Heart Journal. 2013;12(4):223-229. (In Russ.)] doi: 10.18087/rhj.2013.4.1820

17. Карпельев В.А., Филиппов Ю.И., Тарасов Ю.В., и др. Математическое моделирование системы регуляции гликемии у пациентов с сахарным диабетом // Вестник Российской Академии Медицинских Наук. – 2015. – Т. 70. – №5. – С. 549-560. [Karpel’ev VA, Filippov YuI, Tarasov YuV, et al. Mathematical Modeling of the Blood Glucose Regulation System in Diabetes Mellitus Patients. Annals of the Russian Academy of Medical Sciences. 2015;70(5):549–560. (In Russ.)] doi: 10.15690/vramn.v70.i5.1441.

18. Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. 2015;385(9965):351-361. doi: 10.1016/S0140-6736(14)61183-1

19. Zaharan NL, Swerdlow DI, Bennet K. Statins and risk of treated incident diabetes in a primary care population. Br J Clin Pharmacol. 2013;75(4):1118–1124. doi: 10.1111/j.1365-2125.2012.04403.x

20. Waters DD, Ho JE, Boekholdt SM, et al. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes. J Am Coll Cardiol. 2013;61(2):148–152. doi: 10.1016/j.jacc.2012.09.042

21. Waters DD, Ho JE, DeMicco DA, et al. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol. 2011;57(14):1535–1545. doi: 10.1016/j.jacc.2010.10.047.

22. Besseling J, Kastelein JJ, Defesche JC, et al. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA. 2015;313(10):1029-1036. doi: 10.1001/jama.2015.1206

23. White J, Swerdlow DI, Preiss D, et al. Association of lipid fractions with risks for coronary artery disease and diabetes. JAMA Cardiol. 2016;1(6):692-699. doi: 10.1001/jamacardio.2016.1884

24. Thompson G. Limitations of cholesterol lowering with PCSK9 inhibitors. Lancet Diabetes Endocrinol. 2017;5(4):241-243. doi: 10.1016/s2213-8587(17)30060-8