A comparative evaluation of safety and efficacy of rosuvastatin , simvastatin , and atorvastatin in patients of type 2 diabetes mellitus with dyslipidemia

AIM: To evaluate and compare the safety and efÞ cacy of rosuvastatin, simvastatin, and atorvastatin in patients of type 2 diabetes mellitus with dyslipidemia. MATERIALS AND METHODS: This open-label, randomized, parallel group, comparative, prospective study of 12-weeks duration included 60 patients of type-2 diabetes with dyslipidemia having good glycemic control with Þ xed dose combination of tablet glimepiride + metformin and divided into three groups of twenty each. Group-1 patients have received tablet rosuvastatin 10 mg once daily, group-2 received tablet atorvastatin 10 mg once daily, and group-3 received tablet simvastatin 10 mg once daily for 12 weeks each. The levels of serum cholesterol, serum triglyceride, LDL, VLDL, and HDL were assessed at baseline and at the end of 12 weeks. RESULTS: The mean serum cholesterol, serum triglyceride, LDLc, and VLDLc levels were signiÞ cantly reduced on therapy (P<0.001). Simultaneously, the mean levels of HDL were highly signiÞ cantly increased (P<0.001) after therapy for 12 weeks with rosuvastatin, atorvastatin, and simvastatin. Reduction of LDL levels in rosuvastatin group was statistically signiÞ cant when compared with those of simvastatin group (P< 0.05) but was statistically nonsigniÞ cant when compared with atorvastatin group (P> 0.05). Conclusion: 10 mg of rosuvastatin was comparable to 10 mg of atorvastatin and more efÞ cacious than 10 mg simvastatin in reducing LDL levels after 12 weeks of therapy in patients of type 2 diabetes mellitus with dyslipidemia.


Introduction
Diabetes mellitus is a very commonly occurring metabolic disorder characterized by hyperglycemia and altered metabolism of lipids, proteins, and carbohydrates which is due to absolute or relative deÞ ciency of insulin or insulin resistance. [1]abetes mellitus is associated with increased oxidative stress due to hyperglycemia.The oxidative damage plays a role in development of micro and macro vascular complications, leading to a signiÞ cant impact on quality of life.Long-term complications involve almost all vital organs such as heart, eyes, kidney, blood vessels, and nervous system.These complications lead to the development of obesity, hypertension, dyslipidemia, and insulin resistance. [2]ere is a close association between complications of diabetes and diabetic dyslipidemia.Diabetic dyslipidemia accounts for around 80 percent diabetic deaths due to cardiovascular complications.There is a growing body of evidence to show that hyperglycemia and dyslipidemia are associated with excess of cardiovascular risk. [3]eatment of type 2 diabetes requires the agents that act beyond their blood glucose eff ect.Drug therapy that not only has an eff ect on blood glucose level but also has a beneÞ cial eff ect on dyslipidemia, hypertension, obesity, hyperinsulinemia, and insulin resistance is likely to be the most useful therapy in treating type-2 diabetes. [4]abetic patients tend to have a higher concentration of small dense LDL particles, which are associated with higher CHD risk.Lowering LDL levels is the Þ rst priority in treating diabetic dyslipidemia.Statins are the Þ rst drug of choice, followed by resins or ezetimibe, then fenoÞ brate, or niacin.Current evidence and guidelines mandate that diabetic dyslipidemia should be treated aggressively, and lipid goals can be achieved in most patients with diabetes when all available products are considered and, if necessary, used in combination. [5]fferent statins require different dosing to reach the same LDL level.The lowering of LDL levels with statins varies from 20 to 60%.Therefore, the greatest eff ects are seen with the most potent statins such as simvastatin, atorvastatin, and rosuvastatin in the higher doses.Besides, majority of diabetic patients are at risk of coronary heart disease and deserve LDL cholesterol lowering to the currently recommended targets. [6]e diabetes atorvastatin lipid intervention (DALI) study concluded that either 10 or 80 mg of atorvastatin is equally eff ective in the treatment of diabetic dyslipidemia. [7]ntensive lowering of LDL-C with high dose atorvastatin does not result in a signiÞ cant reduction in the primary outcome of major coronary events, but reduces the risk of other composite secondary end points and nonfatal acute MI. [8] Atorvastatin is more eff ective than simvastatin-based therapies in achieving treatment targets in patients with familial hypercholesterolemia. [9] Rosuvastatin 10 and 20 mg tablet improves the overall lipid proÞ le of hypercholesterolemic patients better than does milligram equivalent doses of atorvastatin. [10]nsidering the above-mentioned facts, it seems that prevention of cardiovascular complications of diabetes must be considered as a national public health goal in the light of the increasing prevalence of the disease and the high frequency and seriousness of its complications.
The present study was thus planned to primarily evaluate and then to compare the effi cacy and safety of newer emerging and promising statin rosuvastatin vs existing commonly used statins such as simvastatin and atorvastatin in patients with type-2 diabetes mellitus with dyslipidemia, so as to guide the present treatment strategies in the management of diabetes with dyslipidemia in Indian population.

Materials and Methods
This study was open-label, randomized, parallel group, comparative, prospective study in patients with type 2 diabetes mellitus with dyslipidemia.Sixty patients of type-2 diabetes with dyslipidemia having good glycemic control with Þ xed dose combination of tablet glimepiride + metformin were included in the study aft er taking writt en informed consent.The exclusion criteria for patients were clinically signiÞ cant deviation from normal in physical examination, laboratory parameters, ECG, or chest X-ray.Clinically signiÞ cant cardiovascular disease, including a history of congestive heart failure, angina pectoris within 1 year and history of myocardial infarction within 1 year, convulsive disorder, clinically signiÞ cant gastrointestinal disease, including active peptic ulcers within the preceding 5 years, renal disease, hepatic disease, hematologic disease and insulindependent diabetes mellitus, and known infection with human immunodeÞ ciency virus, were excluded.Subjects with the presence of any acute illness, h/o sensitivity to statins, history of any musculo-skeletal disorder, history of alcohol, barbiturate, marĳ uana, or multidrug abuse, participation in other investigational drug studies within 30 days before the start of the study, subjects who are unlikely to be compliant with the protocol requirements, pregnant or lactating females, patients with history of use of any of the statins for at least 6 months prior to the commencement of the study and smokers were also excluded.
Approval of the ethical committee of Government Medical College and Hospital, Aurangabad was taken prior to the start of the study.Sixty patients were enrolled in the study aft er satisfying the inclusion and exclusion criteria.Included patients were explained in detail about the study protocol and related hazards.Informed writt en consent was obtained from all the patients.Those included underwent all baseline investigations such as liver function tests, kidney function tests, blood sugar level, fundoscopy, and baseline lipid proÞ le, which was repeated at the end of the study.Enrolled patients were divided into three groups of twenty each by computer generated randomization chart (calculated from True Epistat, Standard version 1999).Group-1 patients received rosuvastatin10 mg tablet once in a day, group-2 received atorvastatin tablet 10mg once in a day, and group-3 received simvastatin tablet 10 mg once daily for a period of 12 weeks.Each patient in the respective group was provided with the drug supplies for Þ ft een days and was asked to visit the diabetic clinic for follow up and for collection of drugs.At each follow-up visit, patients were assessed for glycemic control, and history pertaining to adverse drug eff ects was asked.All patients were given advice about diet and exercise.
The primary objectives for the study were: 1.To evaluate the eff ect of rosuvastatin, atorvastatin, and simvastatin on the lipid proÞ le of patients with type 2 diabetes mellitus with dyslipidemia.2. To evaluate the eff ect of atorvastatin on the lipid proÞ le of patients with type 2 diabetes mellitus with dyslipidemia.
The secondary objective for the study was to compare the safety and effi cacy of rosuvastatin with simvastatin and atorvastatin in patients with type 2 diabetes mellitus with dyslipidemia.

Results
Rosuvastatin, atorvastatin, and simvastatin were very eff ective in reducing the levels of serum cholesterol, serum triglyceride, LDL, and VLDL aft er treatment for 12 weeks in patients with type 2 diabetes mellitus with dyslipidemia.The reductions in these lipid parameters were highly significant.All the three statins also increased the levels of HDL signiÞ cantly (P < 0.001) aft er treatment for 12 weeks [Table 1].LDL levels by 25.17%.Rosuvastatin showed 30.83% reduction in cholesterol levels while atorvastatin and simvastatin reduced cholesterol levels by 25.75 and 18.17% respectively.The HDL levels were increased by 18.31, 7.11, and 4.56% in the rosuvastatin, atorvastatin, and simvastatin groups respectively [Table 5].
No adverse events were observed in any of the study groups.Rosuvastatin, atorvastatin, and simvastatin group did not deviate signiÞ cantly from their baseline biochemical proÞ le aft er 12 weeks of therapy.

Discussion
Type 2 diabetes is emerging as a major public health problem and seems to occur decade earlier in our country compared to the west.Diabetic care Asian-India study found 40% obesity in urban Indian type 2 diabetes mellitus.They also found inadequate glycemic control and late diabetic complications at the mean duration of one year in over 55 percent of patients. [11]e evidence that lipid lowering drug treatment (especially statins) signiÞ cantly reduces cardiovascular risk in diabetic and nondiabetic patients is strong and suggests that diabetic patients beneÞ t more in both primary and secondary prevention. [12] the present study, the patients studied were type 2 diabetic patients with dyslipidemia, but having good glycemic control with Þ xed dose combination of tablet glimepiride + metformin.The criteria for evaluation were lipid proÞ le parameters, namely, serum cholesterol, serum triglyceride, LDL, VLDL, and HDL.
Rosuvastatin decreased the levels of serum cholesterol, serum triglyceride, LDL, VLDL and increased the levels of HDL aft er therapy for 12 weeks.The diff erence in the studied lipid parameters aft er therapy was highly statistically signiÞ cant (P < 0.001).These results are  in accordance with the pilot study with rosuvastatin conducted by Gleuck et al, at The Cholesterol Centre, Jewish Hospital, Cincinnati, USA. [13]orvastatin and simvastatin also decreased the levels of serum cholesterol, serum triglyceride, LDL, VLDL and increased the levels of HDL aft er therapy for 12 weeks.The diff erence in the studied lipid parameters after therapy in both the drug groups was highly statistically signiÞ cant (P < 0.001).These results are in accordance with the studies conducted by Goudevenos et al [14] and Lewin et al, [15] for the effi cacy of atorvastatin and simvastatin in dyslipidemia, respectively.
When the LDL level reduction in rosuvastatin group with that of atorvastatin and simvastatin group was compared, it was observed that the reduction in LDL levels in rosuvastatin group were statistically signiÞ cant when compared with those of simvastatin group, but were statistically nonsigniÞ cant when compared with atorvastatin group.These results are in contrast to a study conducted by Bullano et al, which concluded that rosuvastatin was more eff ective than both atorvastatin and simvastatin in reducing LDL levels signiÞ cantly. [16]e comparison of reduction in LDL levels between atorvastatin group and simvastatin group were statistically signiÞ cant.This result is in accordance to a study conducted by Wu et al, which showed that patients treated with atorvastatin had a signiÞ cantly greater reduction in low-density lipoprotein cholesterol as compared to simvastatin. [17]e rise in HDL levels in rosuvastatin group after therapy was statistically signiÞ cant when compared with atorvastatin group and was highly statistically signiÞ cant when compared with simvastatin group.In contrast to this, the use of rosuvastatin vs atorvastatin in type 2 diabetes mellitus (URANUS) study group found that both rosuvastatin and atorvastatin increased HDL-C and decreased TG from baseline to 4 weeks, but there were no statistically signiÞ cant diff erences between the groups. [18]The COMETS study (a comparative study with rosuvastatin in subjects with metabolic syndrome) concluded that rosuvastatin increased highdensity lipoprotein cholesterol signiÞ cantly more than atorvastatin. [19]However, the comparison of increase in HDL levels between atorvastatin group and simvastatin group were statistically nonsigniÞ cant.This result is in contrast to the study conducted by Hunninghake et al, which concluded that simvastatin produced larger increases in HDL-C. [20]e comparison of the serum cholesterol reduction in rosuvastatin group with that of atorvastatin and simvastatin group revealed that the reduction in serum cholesterol levels in rosuvastatin group were statistically signiÞ cant when compared with those of simvastatin group but were statistically nonsignificant when compared with atorvastatin group.The comparison of reduction in serum cholesterol levels between atorvastatin group and simvastatin group were statistically nonsigniÞ cant.
The intergroup comparison of reduction of serum triglycerides and VLDL after therapy among the rosuvastatin, atorvastatin, and simvastatin groups was statistically nonsigniÞ cant (P> 0.05).

Conclusion
In summary, 10 mg of rosuvastatin tablet was comparable to 10 mg of atorvastatin tablet and more effi cacious than 10 mg tablet simvastatin in reducing LDL levels aft er 12 weeks of therapy in patients of type 2 diabetes mellitus with dyslipidemia.Also, 10 mg of rosuvastatin was more effi cacious than 10 mg of both atorvastatin and simvastatin in increasing HDL levels aft er 12 weeks of therapy in patients of type 2 diabetes mellitus with dyslipidemia.No adverse events were noted with any of the three statins used.However, further studies are necessary to conclusively prove the efficacy of rosuvastatin over the existing statins.