Does atorvastatin work more effectively than biguanides in reducing cardiovascular risk factors?

Increased risk of coronary artery disease in diabetic persons is associated with increased level of lipoproteins. Usually, such risks are reverted with glycemic control by antidiabetic medicines in Type I diabetes millitus. However, in Type II diabetes mellitus lipid values can be improved using antidiabetics but still the risk of coronary artery disease remains. The initial approach for reducing lipid contents in diabetic patients should include glycemic control, diet, weight loss, and exercise. But if it fails then lipid-lowering agents like fibrate and HMG CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase) inhibitors should work effectively. In the present study results of atorvastatin compared with biguanides proved atorvastatin as a more effective lipid-lowering agent along with antidiabetic activity so it can effectively help in reducing the risk of cardiovascular disease (CVD).

Obesity and lack of physical activity are the two main causes of Type II diabetes mellitus.[1] Cardiovascular risks are associated with both types of diabetes.[2] Diabetes itself is a major independent risk factor for several forms of cardiovascular diseases including cardiomyopathy, stroke, congestive heart failure, atherosclerotic disease and renal diseases affecting 97% adults in United States.[34] All other factors including smoking, lack of exercise, obesity, high serum cholesterol continue to contribute further in developing cardiovascular disorders (CVDs) in diabetic patients.[5]

Several studies showed that the glucose level of a Type II diabetic patient will be normal during the initial stage due to increased release of insulin in response. However, with age, insulin secretion declines and its resistance fails to maintain plasma glucose level which contributes as CVD risk factor.[6-9]

Alteration in Coagulation factors found in insulin-resistant patients is the leading cause of arterial thrombosis, another risk of CVD.[10]

Elevated lipid low-density lipoprotein (LDL) is found in CVD patients with insulin resistance. Although the role of LDL levels has not yet been satisfactorily explained in hyperglycemic patients.[11] However, an elevated LDL level is found to be a major risk for CVD. Lipoprotein analysis in diabetic dyslipidemia helps in the assessment of risk of CVD. Diabetic dyslipidemia is characterized by abnormal levels of three lipoproteins (i.e. LDL, high-density lipoprotein (HDL) and very low density lipiprotein (VLDL)) and cholesterol.[12]

Continued smoking in diabetic patients will further aggravate the risk of CVD.[13]

According to an epidemiological study it is estimated that globally the number of diabetic patients will rise from 151 to 221 million per year. And the principal cause of morbidity and mortality of a diabetic patient is atherosclerosis.[14] The ideal treatment approach of a diabetic patient would be a drug that can not only control glucose levels but prevent the complication of CVD through lipid deposition. Unfortunately, very limited such drugs that can control both are available.[15]

Role of biguanides and atorvastatin in lowering cardiovascular risks

The role of biguanides and atorvastatin in lowering lipid contents is measured in several studies and it is considered that both these help to reduce the chance of ischemic cardiac disease by reducing serum cholesterol level, although both belong to two different classes. In diabetic patients HBA1C (glycated hemoglobin) level is a fundamental exhibitor to indicate the control of glucose level. Biguanides are very effective in controlling not only the glucose level but decreasing lipid contents in those having cardiovascular risks.[16] The probable mechanism of biguanides is to reduce the LDL contents which are mainly involved in atherosclerosis. Additionally, it is effective in reducing body mass index. It is very important that the cardiac risk should be reduced in a patient with diabetes. Increasing data shows that atorvastatin plays a vital role in lowering lipid contents of diabetic patients which helps to reduce further cardiovascular risks. It is necessary that along with the drug therapy a healthy lifestyle should also be strictly followed to control cardiovascular risks in diabetes.[17-19] As coronary artery disease is the leading cause of death in both Type I and Type II diabetes it is, therefore, necessary to take immediate therapeutic measures which help to prevent and treat the cause of death in diabetes. The atorvastatin family was examined and found effective in controlling cardiovascular risk by lowering the action of enzymes in the liver that play vital role in genesis of cholesterol and lipoproteins. According to a Diabet. Med. 2002 study, the chance of cardiovascular risk can be reduced by atorvastatin, however, some other beneficial steps help to reduce and control the risks are exercise, healthy food, avoiding smoking and drinking habits. In many people atorvastatin is considered powerful enough to control the risk.[18-19]

Materials and Methods

Chemicals

Tablet forms of Biguanides-metformin and HMG-CoA reductase inhibitor-atorvastatin are used. Kits for the biochemical analysis were supplied by Human (Germany).

Animals

Young Albino rabbits, average weight around 1.5 kg, purchased from a local supplier were used in the study. Ethical approval was taken from the Department of Pharmacology, University of Karachi.

Experimental design

The study was conducted on 30 healthy male white rabbits. These were divided into three groups and each group consisted of ten animals. One group served as control and was given normal saline, however, the test groups received biguanides and atorvastatin respectively.

Preparation and administration of drugs

The dose was calculated according to their per kg body weight, given for a period of eight weeks. Drugs were administered in a single dose orally by gavage using a syringe fitted with a suitable size canula daily. The dose of biguanides was 42.85 mg/kg and 1.1 mg/kg of atorvastatin, while control group animals received an equivalent volume of dose for the same period of time.[16]

Biochemical analysis

Blood samples of rabbits were collected in a siliconised glass tube 1 h after the last dose, collection was done through cardiac puncture and their serum was immediately separated by centrifugation at 3000 rpm for 15 minutes to yield platelet poor serum by Humax 14 K (Germany). Lipid profile, glucose and HBA1c were estimated by using autoanalyzer (Microlab 2000). In addition, the changes in body weight were recorded.

Statistical analyses

The results are expressed as mean ± SD. All the data were analyzed by one-way ANOVA of variance. A value of P < 0.05 was considered as statistically significant.[20]

Results

Effect on body weight

Effect on body weight of groups normal, atorvastatin and biguanides was observed during the study time and decrease in body weight was compared with the initial weight (weight when first dose given) and final weight (at the end of last dose – before collection of blood sample). It was found that the control group showed a significant increase (P < 0.05) in weight at the time of sacrifice, while a considerable decrease (P < 0.05) in the weight of the atorvastatin group as well as the biguanides group was observed at the end of the final doses [Table 1]. The effect on weight is explained in Figure 1which clearly shows that the decrease in weight of the atorvastatin group was slightly greater with respect to the biguanides group.

Table 1

Effect on body weight of animals (kg)

Figure 1

Effect on the weight of the test groups and their comparison with control

Effect on serum glucose level and HBA1C

Table 2 shows that the glucose level and HBA1C was increased with respect to control in animals receiving biguanides, which was not significant. However, the group which received atorvastatin showed a significant decrease (P < 0.05) in the level of both the parameters. Figure 2 shows the variation in a graphical way which explains the change in serum glucose and HbA1C.

Table 2

Effect of biguanides and atorvastatin on serum glucose level and HbA1C

Figure 2

Variation in the serum glucose level and HBA1C of the test groups with respect to control

Effect on lipid profile

Table 3 shows that the levels of lipid contents including cholesterol, triglycerides, HDL and LDL were significantly reduced (P < 0.05) with respect to control while the reduction was greater (P < 0.05) in those animals who received atorvastatin. Figure 3 explains the change and variation with respect to control in a bar graph and we can see that the LDL level, which is involved in atherosclerosis plaque development in arteries, reduced to the level which is almost negligible amount present in the blood vessels.

Table 3

Effect of biguanides and atorvastatin on lipid profile

Figure 3

Variation and comparison in lipid contents of drugs

Discussion and Conclusion

Cardiovascular diseases are the leading cause of death in diabetic patients, where insulin resistance or shortage of insulin is the main cause of diabetes. Insulin is mainly required for burning glucose in our body and burning or utilization of glucose provides energy to the body to work.[15-17] The major reason for Type II diabetes is insulin resistance, the condition where insulin is produced but does not work. It has been discovered that diabetic patients are at high risk of atherosclerotic cardiovascular disorder in which plaque blocks the blood flow to the different organs to supply sufficient oxygen. There are various mechanisms involved in the development of plaque, for example high blood sugar irritates the inner vascular lining that prompts the accumulation of plaque. Another mechanism is oxidative stress. As excessive glucose level in the vessels increases the free radicals in the blood vessels which oxidizes lipid contents resulting is the formation of lipid free radicals plaque in the inner lining of arterial wall.[1821] Free radical injury damages the vital organs of the body. In the present study we compared the drugs used to control lipid contents and obesity, as obesity is one of the causes of Type II diabetes and obese people are advised to reduce weight for controlling their sugar level.[1922]

High lipid levels and sugar levels are considered as markers for obesity and are implicated in the genesis of cardiovascular risks in diabetic patients. In the present study which was done on 30 healthy male rabbits we compared the effects of biguanides and atorvastatin in controlling body weight as well as biochemical lipid and glucose levels.[23] For the study 30 healthy male rabbits were divided into three groups, each group consisted of ten animals and one group served as normal or control group. The test groups of animals received atorvastatin and biguanides respectively, orally, for 60 days while the control group was given similar volume of normal saline. The doses of medicines were calculated as per their body weight and given per day at morning.[24]

After 60 days the HBA1C, glucose and lipid profile were checked for all groups along with their body weight. It was found that animals given biguanides showed decrease in their body weight i.e. 1.28± 0.132 kg (mean ± S.D) which was not significant (P > 0.05) with respect to their initial weight at the time of inclusion in the study i.e. 1.41± 0.138 kg. The reduction in weight was significant (P < 0.05) in the group that received atorvastatin for 60 days i.e. 1.18±0.141 kg with respect to their initial weight taken at the time of first dose administered i.e. 1.42± 0.208 kg. However, the control group showed a significant increase (P < 0.05) in their body weight with respect to initial weight. The bar graph [Figure 1] shows the comparative change in weight with respect to initial weight.

The levels of HBA1C and glucose were compared, as shown in Figure 2, a significant reduction (P < 0.05) was found in HBA1C i.e. 3.9 ± 0.299% and glucose level i.e. 92.56 ± 0.235 mg/dl in the group that received atorvastatin with respect to control (HBA1C 4.618 ±0.139 % and glucose 107.3 ± 0.33 Mg/dl).

Lipid profiles including cholesterol, triglycerides, HDL and LDL were also compared. It was observed that cholesterol, triglyceride, HDL and LDL of the group that received biguanides showed a significant decrease (P < 0.05) i.e. 27.21 ± 0.112, 28.14 ± 0.688, 2.66 ± 0.156 and 18.468 ± 0.934 respectively as compared to the control group. However, the group that received atorvastatin showed a more significant decrease (**P < 0.05) in cholesterol, HDL and LDL levels i.e. 10.09 ± 0.162, 1.8 ± 0.22 and 0.562±0.255 respectively and no any significant change was observed in the level of triglycerides i.e. 38.64 ± 0.468 with respect to control 37.25 ± 0.25 [Table 3]. Figure 3 shows the bar graph representing the comparative changes in lipid contents in the three groups.

In conclusion, atorvastatin is more effective than biguanides in lowering body weight, and the level of biochemicals including glucose, HBA1C and lipid contents. It is therefore considered from the above study that atorvastatin is more effective in reducing cardiovascular risk factors in diabetic patients; moreover, it helps to control the glucose level. The dose taken during the above study showed significant efficiency of atorvastatin.[25]