Triple verses glimepiride plus metformin therapy on cardiovascular risk biomarkers and diabetic cardiomyopathy in insulin resistance type 2 diabetes mellitus rats

https://doi.org/10.1016/j.ejps.2009.09.004Get rights and content

Abstract

IRtype2DM patients are often treated with a combination of antidiabetic agents. Drugs with different complementary mechanisms of action frequently used in daily clinical practice but glycemic control with monotherapeutic attempts fail in the long run. To date, biomarkers for cardiovascular risk and insulin sensitivity with combination of triple oral hypoglycemic therapies are not fully revelled in view of additional cardiovascular risk reduction. In the present study, IRtype2DM induced by administering streptozotocin (90 mg/kg, i.p.) in neonatal rat model. IRtype2DM rats were selected by determining FPI [>60 pmol/l]; HOMA-IR & Hyperinsulinemic euglycemic clamp technique at 6 weeks and then treated for 8 weeks with (i) Metformin (120 mg/kg, o.d.) + Glimepiride (1 mg/kg, o.d.), (ii) Metformin (265 mg/kg, o.d.) + Rosiglitazone (1 mg/kg, o.d.) + Glimepiride (0.7 mg/kg, o.d.). At the end cardiovascular risk parameters evaluated by ELISA kits and insulin sensitivity were determined by HOMA-IR. In conclusion, triple oral hypoglycemic therapy improves glycemic control, insulin sensitivity, retards diabetic cardiomyopathy and does not increased body weight; decrease more detrimental inflammatory markers, increase interlukin-10 and adiponectin in neonatal streptozotocin-induced IRtype2DM Wistar Albino Rats. Triple therapy showed a synergistic effect and was promising in insulin resistance, better in additional cardiovascular risk reduction and those nonresponders to metformin add on glimepiride therapy.

Introduction

Type 2 diabetic patients are often treated with a combination of antidiabetic agents. The need to use drugs with different and complementary mechanisms of action frequently arises in daily clinical practice. There are several reasons to do this; namely, the disease itself is progressive, with deterioration of glycemic control over time, and monotherapeutic attempts to achieve and maintain glycemic control often fail in the long run (Turner et al., 1999, Matthews et al., 1998).

Some patients do not accept insulin treatment because of the fear of needles and injections, the fear that the complications of diabetes are caused by insulin, and other false beliefs, and are willing to take as many antidiabetic pills the doctor is prepared to prescribe.

The combination of a sulfonylurea with metformin is commonly used in clinical practice. But when this potent combination is no longer able to provide acceptable glycemic control, the addition of an antidiabetic drug with a different mode of action may lead to improved metabolic control.

The peroxisome proliferator activated receptor-γ (PPAR-γ) agonist rosiglitazone has been shown to produce significant improvement in glycemic control when administered to patients who were inadequately controlled on the combination of glibenclamide and metformin (Jones et al., 2001). Similar findings were obtained in a trial with troglitazone, the first member of the thiazolidinedione class of antidiabetic agents. In a double-blind placebo-controlled trial, the addition of troglitazone in a therapeutic regimen of sulfonylurea and metformin in inadequately controlled type 2 diabetic patients led to significant improvement in glycemic control (Yale et al., 2001, Putheti and Patil, 2009). The trial was completed before troglitazone was taken off the market because of hepatotoxicity.

Rosiglitazone treatment has rarely been associated with severe liver reactions (Al-Salman et al., 2000, Forman et al., 2000, Gouda et al., 2001). No symptoms or signs of liver disease were observed, and no change in liver function tests was noted in the patients in our treatment groups for the 20-week period of follow-up. The findings are in accordance with those of other investigators who found that in inadequately controlled type 2 diabetic patients, on treatment with a sulfonylurea and metformin, the addition of rosiglitazone produces significant improvement in glycemic control and is safe and well tolerated (Kiayias et al., 2002).

Examination of the efficacy of rosiglitazone when added to a therapeutic regimen of glimepiride and metformin in type 2 diabetic patients was done. The treatment with rosiglitazone was well tolerated. Hypoglycemia was the most frequent side effect in both patient groups (18.6% at 4 mg/day and 28% at 8 mg/day). The dose of glimepiride and/or metformin was reduced in patients with hypoglycemic episodes, and the reduction proved to be effective in avoiding hypoglycemic reactions. Mean body weight increased in both rosiglitazone groups (4.2 kg at 4 mg/day and 4.6 kg at 8 mg/day) (Kiayias et al., 2002).

Given the analogous results obtained with troglitazone, it is very possible that this is a class effect of thiazolidinediones and not a specific action of pioglitazone. However, a major issue is whether hepatotoxicity is a class characteristic of all thiazolidinediones related at least partly to the activation of PPAR-γ receptors, or whether it is unique to troglitazone and thus spares newer glitazones, such as rosiglitazone and pioglitazone (Kiayias et al., 2002).

However the glycemic control of rosiglitazone in combination with glimepiride plus metformin done as described above. To date, biomarkers for cardiovascular risk and insulin sensitivity with triple oral hypoglycemic therapy are not fully reveled in view of additional cardiovascular risk reduction. PPAR-γ activation results in an array of effects on traditional and non-traditional cardiovascular risk factors that are independent of their effects on glycemic control. In the present study, retardation of diabetic cardiomyopathy and cardiovascular risk factors such as PAI-1; vWF; MMP-9; TNF-α; CRP; Hcy; IL-10 and Adiponectin were evaluated for triple therapy of rosiglitazone in combination with glimepiride plus metformin verses glimepiride add on metformin to access relative beneficiary effect of on cardiovascular complications in IRtype2DM rats. Insulin sensitivity was determined by Fasting Plasma Insulin [>60 pmol/l], Homeostasis Model Assessment of Insulin Resistance (Matthews et al., 1985) & Hyperinsulinemic euglycemic clamp technique (DeFronzo et al., 1979).

Section snippets

Animals

The experimental protocol was approved by Institutional Animal Ethical Committee (Protocol number: DIPSAR/IACE/14/2006).

Wister Albino Rats of either sex weighing 150–250 g were procured from animal house, DIPSAR, Pushpvihar, Sector-III, New Delhi, India. The animals were housed under standard laboratory conditions of 21 ± 2 °C temperature, relative humidity of 55% and 12:12 h light:dark cycles were maintained during the study. The animals were given standard rat pellet and tap water ad libitum.

Streptozotocin-induced neonatal rat model (Bonner-Weir et al., 1981)

Glycemic control

Glycemic control improved in both treatment groups during the study; a similar proportion of animals in each treatment group achieved a decrease in Fasting Blood Glucose (FBG) (Rosiglitazone + Glimepiride + Metformin (162.667 ± 15.871 to 76.667 ± 4.302 mg/dl [−54.2289%], P < 0.001), Metformin + Glimepiride (184.333 ± 14.645 to 79.833 ± 6.559 mg/dl [−52.3383%], P < 0.001) as compared to DiabeticIR group [Fig. 2, Fig. 3].

Insulin resistance

Rosiglitazone + Glimepiride + Metformin treatment was associated with a significant decrease Fasting

Discussion

In the last few years, there has been increasing focus on the impact of interventions on cardiovascular outcomes in patients with type 2 diabetes. Insulin resistance and hyperglycemia often co-exist with a cluster of risk factors for coronary artery disease and cardiomyopathy but the underlying mechanisms leading to the development of such vascular complications are complex. The over-production of free radicals in patients suffering from diabetes results in a state of oxidative stress, which

Conflicts of interest

There are no conflicts of interests.

Acknowledgements

Authors are thankful to AICTE, New Delhi, India; Panecea Biotec Ltd., India & Torrent Pharmaceuticals Ltd., India for providing the gift samples of the drugs.

Institutional approval: The experimental protocol was approved by Institutional Animal Ethical Committee (Protocol number: DIPSAR/IACE/14/2006).

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