INTRODUCTION:

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia caused by several factors, including reduced insulin secretion, decreased glucose utilization, and increased glucose production. DM can cause chronic complications in several organ systems, including microvascular, macrovascular, and neuropathy disorders that cause disease burden in individual patients and the health system in general^1,2.

The International Diabetes Federation (IDF) predicts an increase in the number of people with diabetes in Indonesia from 10.7 million in 2019 to 13.7 million in 2030³. Type 2 diabetes mellitus (DM) patients have an increased prevalence of fatty abnormalities that contribute to a high risk of atherosclerotic cardiovascular disease (ASCVD) incidence⁴. Dyslipidemia, found in 60-70% of patients with type 2 DM, is one of the causes that contribute to the inflammatory condition in patients^5,6. Diabetes dyslipidemia is characterized by high triglyceride concentrations, low HDL concentrations, and an increase in small-dense LDL concentrations⁷. In patients with one or more of these risk factors, statin therapy is recommended (level of evidence A) with a therapeutic target of LDL <100mg/dL, TG <150mg/dL, and HDL> 40mg/dL^4,8.

Statin works by inhibiting the HMG-CoA reductase enzyme needed to catalyze HMG-CoA conversion to mevalonate, the first step in cholesterol biosynthesis^9,10. By this mechanism, statins also inhibit the formation of isoprenoids such as FPP and GGPP and further inhibit the translocation of Rho and Rac proteins which have a role in the signal delivery process in cells^11,12. The downstream effects arising from this inhibition vary, including, among other things, increased endothelial function, anti-inflammatory and antioxidant effects, reduction of the coagulation cascade, and plaque stabilization. The effects that arise outside of the reduction of cholesterol are referred to as the pleiotropic effects of statins^13,14.

IL-6 is a pro-inflammatory cytokine that can describe inflammatory conditions in DM and their complications¹⁵. IL-6 in circulation correlates with inflammatory activity in the body. IL-6 acts directly as an intermediate cytokine and primary stimulator for C reactive protein (CRP), an inflammatory marker that has been used clinically to assess the risk of cardiovascular disease^15,16. This study aims to determine the effect of atorvastatin on changes in lipid profile (LDL, TG, total cholesterol, HDL) and inflammatory marker IL-6 in diabetics dyslipidemia patients, as well as the correlation between changes between variables before and after atorvastatin therapy for 30 days.

MATERIALS AND METHODS:

The study population was type-2 diabetes with dyslipidemia patients who received treatment in Internal Medicine Polyclinic at General Hajj Hospital, Surabaya. Study inclusion criteria were men and women diagnosed with type-2 diabetes, age >21-75 years old, with LDL > 100mg/dL and/or TG >150mg/dL at initiation therapy. Patients who met the inclusion criteria then signed the informed consent. Ethical eligibility submitted to the Ethics Committee of Surabaya Hajj General Hospital, Surabaya, Indonesia.

The subject of this study received atorvastatin 20mg for 30 days. Blood samples were collected after 12 hours of fasting before and after 30 days of therapy. Lipid profiles (LDL, HDL, TG, Total Cholesterol) were measured at the Laboratory of Surabaya Hajj General Hospital, Surabaya. IL-6 levels were measured by ELISA kit (Biolegend®) at the Laboratory of Infectious Disease Research Center, Campus C Airlangga University, Surabaya. All statistical analysis was performed using SPPS (IBM®) version 21.

RESULT:

Patient characteristic

Table 1. Patient characteristics

Patient characteristic		Total patient (N=19)		*± SD (range)*
Patient characteristic		Sum	%	*± SD (range)*
Gender	Male	6	31.58	-
Gender	Female	13	68.42	-
Age range (years)	26-43	1	5.26	57.316 ± 7.7327
	46-59	11	57.89
	60-74	7	36.84
*BMI (kg/m²)**	18.5-24.9	11	57.89	25.625 ± 3.549
	25-29.9	6	31.57
	30-34.4	2	10.53
Concomitant disease	Hypertension	10	52.63	-
Concomitant disease	Uric acid	7	36.84	-

*BMI = body mass index

Patient demography showed in table 1. Nineteen patients enrolled in this study, 68.42% were female, and 31,58% were male. The largest group of patients was in the middle age range (46-59 years old) and the 18.5-24.9 kg/m² BMI group. The most common concomitant disease is hypertension (52.63%).

Effect of atorvastatin on lipid profile, IL-6, and its correlation:

Figure 1 shows the mean level of LDL, TG, total cholesterol, and HDL before and after therapy. The difference and significance were shown in table 2. There was a significant decrease in the value of the lipid profile of LDL, TG, and total cholesterol, each 40.55%, 15.34%, and 30.70% (p<0.05). HDL value increased by 6.06% after therapy but was not statistically significant (p>0.05).

Figure 1. Effect of atorvastatin 20 mg for 30 days on lipid profiles in diabetic patients with dyslipidemia

Table 2. Percentage of lipid value change and significance

Parameter	% of change	p value
LDL (mg/dL)	40.55	0.00^a
TG (mg/dL)	15.34	0.029^a
HDL (mg/dL)	6.06	0.25^a
Total cholesterol (mg/dL)	30.70	0.00^b

^aPaired t-test

^bWilcoxon test

Table 3 shows the distribution of LDL, TG, total cholesterol, and HDL profiles based on the NCEP ATP III classification, before and after therapy of all study samples. Before therapy, the baseline of LDL, TG, and total cholesterol values mostly distributed in the borderline high group (LDL = 130-159mg/dL; TG = 150-199mg/dL; total cholesterol = 200-239mg/dL). After atorvastatin 20mg therapy for 30 days, the LDL value of 57.89% of samples was distributed to the optimal group (<100mg/dL). For TG value, 73.68% samples shifts to the normal group (<150mg/dL). For total cholesterol value in the post-therapy evaluation, 97.74% of samples were classified into the desirable group (<200mg/dL). Meanwhile, for HDL values, the initial distribution data 21,05% samples were in HDL values <40mg/dL group, and after therapy, it reduced to 5.27%.

Table 3. Changes in lipid profile distribution based on NCEP ATP III classification before and after statin therapy

Parameter	Category	Before	%	After	%
LDL	Optimal (<100 mg/dL)	-	-	11	57.89
	Near optimal (100-129 mg/dL)	-	-	8	42.10
	Borderline High (130-159 mg/dL)	10	52.63	-	-
	High (160-189 mg/dL)	7	36.84	-	-
	Very high (≥190 mg/dL)	2	10.53	-	-
TG	Normal (<150 mg/dL)	7	36.84	14	73.68
	Borderline High (150-199 mg/dL)	9	47.37	3	15.79
	High (200-499 mg/dL)	3	15.79	2	10.53
	Very High (≥500 mg/dL)	-	-	-	-
Total Cholesterol	Desirable (<200 mg/dL)	3	15.79	18	94.74
	Borderline high (200-239 mg/dL)	10	52.63	-	-
	High (≥240 mg/dL)	6	31.58	1	5.26
HDL	Low < 40 mg/dL	4	21.05	1	5.27
HDL	High ≥ 60 mg/dL	4	21.05	4	21.05

Table 4. The Effect of atorvastatin on IL-6 levels before and after atorvastatin therapy

Stat.	IL-6 level (pg/dL)
	Pre	Post
Mean ± SD	4.304 ± 3.45	4.061 ± 3.76
% of change	5.76%
p value	0.736

Table 5. Correlation test between lipid profile and IL-6

Parameter		Correlation coefficient (r)	p value
IL-6	LDL	0.073	0.767
	TG	0.014	0.953
	HDL	-0.063	0.799
	Total cholesterol	-0.231	0.341

After atorvastatin therapy for 30 days, there was a 5.76% decrease in IL-6. The results of the significance test with paired t-test showed no significant difference in IL-6 level before and after therapy (p>0.05) (Table 4). The correlation test between LDL, TG, total cholesterol, and HDL showed no significant correlation between those parameters (p>0.05) (Table 5).

DISCUSSION:

This study has received ethical eligibility approval from the Ethics Committee of Health Research, Surabaya Hajj General Hospital (Ethical Clearance Certificate No. 073/45/KOM.ETIK/2017). Based on gender, there are more female patient than male. The result is the same as several other studies^17,18, but some studies also show that more male patients suffer from DM^19–22. Most patient are in the range of age group between 46 to 59 years old, in resemblance with a study by Geetha et al²³. In Indonesia, according to National Health Research of Indonesia in 2013, the proportion of diabetes patient is more common in women than men, and it increases with age²⁴, with the highest age range of 45-55 years by 2.9%²⁵. Hypertension is found in more than half of patients, and in several other studies, it is one of the most common concomitant disease found in diabetes patient^26–28. Hypertension is twice as common in diabetic patients compared to non-diabetics. In the EUROASPIRE IV survey, only 54% of diabetic patients achieved BP levels of less than 140/90mmHg²⁹. After BMI calculation, 57.89% of patients are within the 18.5-24.9kg/m² group. The effect of obesity on diabetes is not only based on BMI but also on the location of fat accumulation. Enhancement upper body fat that can be seen from the belly circumference or waist-hip ratio also associated with metabolic syndrome, type 2 DM and cardiovascular disease³⁰. Diabetes, hyperlipidemia, age and blood pressure (systolic and diastolic) are some factors that influence the risk of coronary heart disease (CHD)³¹.

The most widely used statins in Indonesia are simvastatin and atorvastatin. Atorvastatin is a statin group that is more effective in reducing LDL-C compared to simvastatin¹⁰. Atorvastatin has a longer half-life of up to 14 hours. Its metabolite compounds have the same ability as the parent compound to inhibit HMG CoA reductase. With the metabolite half-life reaches 20-30 hours, atorvastatin provides a greater and longer reduction in cholesterol synthesis compared to simvastatin^32,33. Atorvastatin 20 mg belongs to the moderate statin group with an average reduction of LDL 30 to <50%³⁰. The effect of TG reduction by statins ranges from 20-40%¹⁰, and HDL value increases by 5% -15% depending on the type and dose of statin used^10,34.

The maximum effect of cholesterol and TG reduction is seen within 2-4 weeks of therapy and the recommendations for statin dose adjustments are made after 4 weeks of therapy^33,35. After 30 days of atorvastatin therapy, patients had improved lipid profile based on the LDL, TG, TC value and lipid profile distribution based on NCEP ATP III classification. This study adds to the knowledge of the effect of atorvastatin on lipid profiles, particularly in the Indonesian population. Another study that also assessed the effect of atorvastatin on the lipid profile of dyslipidemic diabetic patients but with longer statin administration and observation time also showed a significant reduction in the lipid profile^36,37.

From several other studies, it was shown that the regimen of atorvastatin administration with the lowest dose of 10 mg/day and the fastest observation time of 2 weeks showed an improvement in the patient's lipid value. One study showed that atorvastatin can significantly reduce cholesterol levels in the second and fourth weeks after administration in dyslipidemic patients³⁸. The ATGOAL study showed 84.2% of patients achieved the target LDL and did not require dose titration at the 4th week of therapy³⁹. In another study, administering atorvastatin at a dose of 10 mg/day for 4 weeks reduced cholesterol concentrations in all LDL subfractions in hypercholesterolemic, diabetic patients⁴⁰, improving lipoprotein values in hypertriglyceridemic patients⁴¹, and significantly reduced LDL and total cholesterol⁴².

Inflammation is the underlying cause of several comorbid diseases in diabetes⁵. Hyperglycemia conditions will cause an imbalance between NO and ROS which triggers endothelial damage⁶. The inflammatory reaction occurs due to the activation of NF-κB which then induces inflammation, cytokine production and release, and increases the expression of adhesion molecules. NF-κB also plays a role in promoting the synthesis and release of pro-inflammatory cytokines, one of them is IL-6^15,43.

Aside from its efficacy on lipid profile improvement, we also analyze pleiotropic effect of statin on inflammatory marker using IL-6. This pleiotropic effects of statins is associated with a reduction of inflammatory biomarkers such as CRP and cytokines (IL-1, IL-6, IL-12, TNF-α, IFN-γ)¹¹. The mechanism of the anti-inflammatory effect of statins is the inhibition of transcription factor activating protein-1 (AP-1) and NF-κB in endothelial cells which is involved in the regulation of proinflammatory genes and the inflammatory process in general. This inhibitory effect is mediated by specific proteins, namely Rho and Ras. Further studies have shown that statins suppress activation of NF-κB through induction of expression of the transcription factor kruppel-like factor-2 (KLF2) regulator, which can be eliminated by GGPP and involves the Rho pathway^11,44.

The mean value of IL-6 before and after therapy showed in table 2. The mean value of IL-6 before therapy was 4.304±3.45 pg/dL. Compared with other studies, the mean value before therapy obtained in this study is close to the value obtained in other study, 4.2±1.9. pg/dL⁴⁵. Nazari et al., (2017) found a significant increase in IL-6 values in diabetic patients compared to normal values with mean values 4.94±0.94 pg/dL⁴⁶. After atorvastatin administration for 30 days, the IL-6 value was decreased although it was not statistically significant. The statistical test also concluded that there is no correlation between atorvastatin effect on lipid profile and IL-6 value found in this study (table 5).

Previous studies have shown varying results from the effects of atorvastatin on IL-6 level. Generally, things that can affect the normal value of cytokines in the blood include body conditions such as stress, fasting conditions, medication, the body's daily rhythm, and physical activity⁴⁷. In this particular study, several variables that can be influence IL-6 values in patients including age, sex, BMI, co-morbidity, blood glucose values, and other drug consumed by patients. Others variables that also affect IL-6 levels including adipose tissue that produces 10-35% of IL-6⁴⁸, and weight loss gives a significant reduction of CRP⁴⁹. A combination between atorvastatin and antihypertension drug also reduces IL-6 significantly⁵⁰, simvastatin 40mg also showed significant reduction of IL-6 in older people⁵¹. Meanwhile, Mayridis et al., (2008) found that there is a correlation between blood glucose control with IL-6 levels⁵².

From this research study, it can be concluded that administration of atorvastatin 20mg for 30 days can significantly reduce LDL, TG, and total cholesterol levels and increase HDL. Atorvastatin also decrease IL-6 level but not significantly and there is no correlation between changes in lipid profile levels with its pleiotropic effect on IL-6 levels. Patient characteristic that may influence IL-6 level including age, sex, BMI, and hypertension.

ACKNOWLEDGEMENT:

The authors would like to thank the Director of the Surabaya Hajj General Hospital and Head of the Internal Medicine Departement who has facilitated data collection in this study. Highest appreciation for all participants and their caretakers who fully support this study. Part of the result of this study published under the same of corresponding author⁴².

REFERENCES:

1. Powers AC. Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology. In: Kasper DL, Hauser SL, Jameson JL, Fauci AS, Longo DL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 19th ed. New York: McGraw Hill Education; 2015.

2. Dipiro JT, Talbert GC., Yee GR., Matzke BG., Wells LMP. Pharmacotherapy: A Pathophysiology Approach, 10th Edition. In: DiPiro JT, Talbert RI, Yee GC, Matzke GR, Wells BG, Posey IM, editors. Mc-Graw Hill Medical. 10th ed. The McGraw-Hill Companies; 2017. p. 6007–48.

3. International Diabetes Federation. Diabetes Atlas [Internet]. 7th ed. Cavan, David; Fernandez, Joao da Rocha; Makaroff, Lydia; Ogurtsova, Katherine; Webber S, editor. Vol. 102, Diabetes Research and Clinical Practice. Brussel; 2015. Available from: www.diabetesatlas.org

4. American Diabetes Association. Standards of medical care in diabetes-2017. Cefalu WT, editor. Vol. 40, Diabetes Care. 2017. 1–142 p.

5. de Souza Bastos A, Graves DT, de Melo Loureiro AP, Júnior CR, Corbi SCT, Frizzera F, et al. Diabetes and increased lipid peroxidation are associated with systemic inflammation even in well-controlled patients. J Dia Comp. 2016;30(8):1593–9.

6. Wang CCL, Hess CN, Hiatt WR, Goldfine AB. Clinical update: Cardiovascular disease in diabetes mellitus. Circulation. 2016;133(24):2459–502.

7. Chehade JM, Gladysz M, Mooradian AD. Dyslipidemia in type 2 diabetes: Prevalence, pathophysiology, and management. Drugs. 2013;73(4):327–39.

8. PERKENI. Konsensus Pengelolaan dan Pencegahan Diabetes Mellitus Tipe 2 di Indonesia 2015. Pb Perkeni. 2015. 1–93 p.

9. Brunton LL, Chabner BA, Knollman BC, editors. Drug Therapy for Hypercholesterolemia and Dyslipidemia. In: Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 12th ed. California: The McGraw-Hill Companies; 2010.

10. Rosenson RS. Statins: Actions, side effects, and administration [Internet]. Wolter Kluwers. 2016 [cited 2006 Jun 20]. p. 1–26. Available from: www.uptodate.com

11. Zhao J, Zhang X, Dong L, Wen Y, Cui L. The Many Roles of Statins in Ischemic Stroke. Curr Neuropharmacol. 2014;12(6):564–74.

12. Oesterle A, Laufs U, Liao JK. Pleiotropic Effects of Statins on the Cardiovascular System. Circ Res. 2017;120(1):229–43.

13. Ray KK, Cannon CP. The potential relevance of the multiple lipid-independent (Pleiotropic) effects of statins in the management of acute coronary syndromes. J Am Coll Cardiol. 2005;46(8):1425–33.

14. Mihos CG, Pineda AM, Santana O. Cardiovascular effects of statins, beyond lipid-lowering properties. Pharmacol Res. 2014;88:12–9.

15. Tousoulis D, Papageorgiou N, Androulakis E, Siasos G, Latsios G, Tentolouris K, et al. Diabetes mellitus-associated vascular impairment: Novel circulating biomarkers and therapeutic approaches. J Am Coll Cardiol. 2013;62(8):667–76.

16. Ridker PM. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream to Identify Novel Targets for Atheroprotection. Circ Res. 2016;118(1):145–56.

17. Haidari F, Mansoori E, Zakerkish M, Haghighizadeh M. The relationship between metabolic factors and quality of life aspects in type 2 diabetes patients. Res J Pharm Technol. 2017;10(5):1491–6.

18. Jeeva S, Babu M. Knowledge of Diabetic Clients Regarding Self-care Practices in Management of type II Diabetes Mellitus at selected Rural Community of Bangalore, Karnataka. Asian J Nurs Educ Res. 2017;7(1):86.

19. Mohsen H, Shaden H, Faiza AQ, Taghrid H. Correlation of serum leptin levels with insulin resistance in Syrian obese patients with type 2 diabetes mellitus. Res J Pharm Technol. 2013;6(10):1149–51.

20. Panari H, Vegunarani M. Study on Complications of Diabetes Mellitus among the Diabetic Patients. Asian J Nurs Educ Res. 2016;6(2):171.

21. Raphael M, Vijayanarayana K, Thunga G, Karthik Rao N, Sreedharan N. Utilization pattern of anti-diabetic drugs in type 2 diabetes mellitus in tertiary care hospital. Res J Pharm Technol. 2017;10(7):2063–8.

22. Sangeeta M, Raghavendra NS. A Study to assess the effectiveness of Planned Teaching Programme on knowledge regarding self care behaviour among people suffering from Diabetes Mellitus in selected urban health centres of Belgavi. Int J Nurs Educ Res. 2019;7(3):399.

23. Geetha V, Sahu SK, Susila C. Assess Quality of Life (QOL) and Glycemic Level among Type 2 Diabetic Patients in Global Hospital and Research Centre and its Units, Sirohi, Rajasthan. Asian J Nurs Educ Res. 2017;7(4):577.

24. Kementrian Kesehatan. Situasi dan Analisis Diabetes [Internet]. 2014 [cited 2006 Jul 20]. Available from: www.depkes.go.id/resources/download/pusdatin/infodatin/infodatin-diabetes.pdf

25. Mihardja L, Soetrisno U, Soegondo S. Prevalence and clinical profile of diabetes mellitus in productive aged urban Indonesians. J Diabetes Invest. 2014;5(5):507–12.

26. Acharya LD, Rau NR, Udupa N, Surulivel RM, Vijayanarayana K. Trends in prescribing antihypertensive medications and lipid lowering therapy in type-2 diabetic patients in south Indian tertiary care hospital. Res J Pharm Technol. 2016;9(7):857–63.

27. Ranadheer Chowdary P, Praveen D, Vijey Aanandhi M. A prospective study on incidence of dyslipidemia in diabetes mellitus. Res J Pharm Technol. 2017;10(2):431–3.

28. Mounika V, Sarumathy S, Anisha Ebens J, Shanmugarajan TS. A prospective study on incidence of anaemia in type 2 diabetes mellitus patients. Res J Pharm Technol. 2017;10(1):11–4.

29. Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, Schwartz MW, et al. Obesity and type 2 diabetes: What Can be unified and what needs to be individualized? Diabetes Care. 2011;34(6):1424–30.

30. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 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. Circulation. 2013;129(25 SUPPL. 1). Available from: https://www.ahajournals.org/doi/suppl/10.1161/01.cir.0000437738.63853.7a

31. Parsa P, Ahmadinia-Tabesh R, Mohammadi Y. Assessment of the risk of Coronary Heart Disease in Diabetes Patients Type-II. Asian J Nurs Educ Res. 2019;9(2):267.

32. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: An update. Fundam Clin Pharmacol. 2005;19(1):117–25.

33. Lacy C, Armstrong L, Goldman M, Lance L. Drug Information Handbook. 24th ed. New York: Lexicomp; 2016.

34. Anderson N, Tobin JN, Zazula T. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel. NIH. 2002.

35. AHFS. AHFS Drug Information Essentials. McEvoy GK, editor. Maryland: American Society of Health-System Pharmacists; 2011.

36. Mukti AW, Suprapti B, Wibisono S. Effect of atorvastatin treatment on vascular aterogenic factors (LipiD profiles and VCAM-1) in patient diabetes with dyslipidemia. Indones J Pharm. 2019;30(2):128–32.

37. Dorotea D, Ayumuyas NP, Suprapti B, Wibisono S. The Comparison of Simvastatin and Atorvastatin Efficacy in Lowering Lipid Profile and Apolipoprotein-B of Diabetic Dyslipidemia Patient. FMI. 2013;49(3):139–45.

38. Deerochanawong C, Buranakitjaroen P, Nitiyanant W, Suwantamee J, Piamsomboon C, Vongthavaravat V, et al. The atorvastatin goal achievement across risk levels: (ATGOAL) study in Thailand. J Med Assoc Thail. 2007;90(1):72–81.

39. McKenney JM, Davidson MH, Saponaro J, Thompson PD, Bays HE. Use of a treatment algorithm to achieve NCEP ATP III goals with atorvastatin. J Cardiovasc Pharmacol. 2005;46(5):594–9.

40. Geiss HC, Otto C, Schwandt P, Parhofer KG. Effect of atorvastatin on low-density lipoprotein subtypes in patients with different forms of hyperlipoproteinemia and control subjects. Metabolism. 2001;50(8):983–8.

41. Parhofer KG, Laubach E, Barrett PHR. Effect of atorvastatin on postprandial lipoprotein metabolism in hypertriglyceridemic patients. J Lipid Res. 2003;44(6):1192–8.

42. Rosales A, Alvear M, Cuevas A, Saavedra N, Zambrano T, Salazar LA. Identification of pharmacogenetic predictors of lipid-lowering response to atorvastatin in Chilean subjects with hypercholesterolemia. Clin Chim Acta. 2012;413(3–4):495–501.

43. Koh KK, Han SH, Quon MJ. Inflammatory markers and the metabolic syndrome: Insights from therapeutic interventions. J Am Coll Cardiol. 2005;46(11):1978–85.

44. Biasucci LM, Biasillo G, Stefanelli A. Inflammatory markers, cholesterol and statins: Pathophysiological role and clinical importance. Clin Chem Lab Med. 2010;48(12):1685–91.

45. Kanat M, Özcan Y, Tunçkale A, Ceyhan BÖ, Karagoz Y, Altuntas Y, et al. Intensive Lipid Reduction and Proinflammatory Markers in the MODEST Study. Turk Jem. 2010;14:31–4.

46. Nazari A, Sardoo AM, Fard ET. Is IL-6 Increased in Type 2 Diabetes Mellitus Patients Independent of Nephropathic Complication ? J Endocrinol Diabetes Obes. 2017;5:10–2.

47. Aziz N, Detels R, Quint JJ, Li Q, Gjertson D, Butch AW, et al. Stability of cytokines, chemokines and soluble activation markers in unprocessed blood stored under different conditions. Cytokine. 2016;84:17–24.

48. Maggio M, Guralnik JM, Longo DL, Ferrucci L. Interleukin-6 in Aging and Chronic Disease: A Magnificent Pathway. J Gerontol A Biol Sci Med Sci. 2006;61(6):575–84.

49. Belalcazar LM, Haffner SM, Lang W, Hoogeveen RC, Rushing J, Schwenke DC, et al. Lifestyle intervention and/or statins for the reduction of C-reactive protein in type 2 diabetes: From the look AHEAD study. Obesity. 2013;21(5):944–50.

50. Bochar O, Sklyarov E, Bochar V. Leptin and interleukin-6 level in patients with hypertension and obesity combined with non-alcoholic steatohepatitis during treatment with Sartans and Statins. Curr Issues Pharm Med Sci. 2017;30(2):57–60.

51. Kyrsiak R, Gdula-Dymek A, Marek B, Okopien B. The effect of hypolipidaemic treatment on monocyte release of proinflammatory cytokines in different age groups of patients with type 2 diabetes and atherogenic dyslipidaemia. Endokrynol Pol [Internet]. 2013;62(2):190–6. Available from: age; simvastatin; fenofibrate; atherogenic dyslipidaemia; monocytes; cytokines

52. Mavridis G, Souliou E, Diza E, Symeonidis G, Pastore F, Vassiliou AM, et al. Inflammatory cytokines in insulin-treated patients with type 2 diabetes. Nut Metab Cardiovas. 2008;18(7):471–6.

Received on 20.10.2021 Modified on 25.02.2022

Research J. Pharm. and Tech 2022; 15(9):4105-4110.

DOI: 10.52711/0974-360X.2022.00689