Comparative evaluation of effects of combined oral anti-diabetic drugs (sulfonylurea plus pioglitazone and sulfonylurea plus metformin) over lipid parameters in type 2 diabetic patients
Keywords:
Type 2 diabetes, Sulfonylureas, Metformin, Pioglitazone, Serum lipid parametersAbstract
Background: Type 2 diabetes is associated with significant cardiovascular morbidity and mortality. Dyslipidemia, which affects almost 50% of patients with type 2 diabetes, is a cardiovascular risk factor characterized by elevated triglyceride levels, low high-density lipoprotein (HDL) cholesterol levels, and a preponderance of small, dense, low-density lipoprotein (LDL) particles. In addition to their glucose-lowering properties, oral anti-diabetic agents may have effects on lipid levels, especially triglycerides (TGs), HDL-C, LDL-C and total cholesterol levels.
Methods: A prospective, open-labeled, randomized, parallel-group study was carried out in sizable number of patients (n=40) of established type 2 diabetes on combined oral anti-diabetic drugs, to investigate the effects of combined oral anti-diabetic on lipid parameters who was not receiving any hypolipidemic agent in addition.
Results: Statistically significant mean reduction of triglycerides (TGs) of 25.1mg/dl (a 15.30% reduction from baseline value) and by 13.5 mg/dl (a 8.94% reduction from baseline value) in the SU (sulfonylurea) plus PIO (pioglitazone) and SU plus MET (metformin) group respectively. Present study also shows improvement in HDL cholesterol with SU plus PIO group by 13.18% which is almost twice that observed in SU plus MET group (8.06%). Present study also shows increase in LDL cholesterol with SU plus PIO group by 2.10%, is just opposite to SU plus MET group (4.92 % decrease). With SU plus PIO group, a statistically significant mean reduction of total cholesterol (TC) of 8.33mg/dl (5.14 % decrease) and by 7.62 mg/dl (4.28% decrease) in the SU plus MET group.
Conclusions: Pioglitazone, a thiazolidinedione, has been shown to improve the lipid profile in patients with type 2 diabetes by increasing HDL-C levels and by decreasing triglyceride and total cholesterol levels in monotherapy or combination regimens with sulfonylurea. Metformin also has been shown to reduce LDL-C, TC, and TG levels and increase HDL-C levels in monotherapy and in combination regimens with sulfonylurea. In contrast, LDL cholesterol levels mild increase with pioglitazone monotherapy or with SU combination therapy. Thus the results of this study have demonstrated that SU plus pioglitazone is an effective combination regimen for patients insufficiently treated with SU monotherapy and may provide possible positive effects on other coronary risk factors/ dyslipidemias associated with the type 2 diabetes.
References
Power AC. Diabetes mellitus. In: Fauci AS, Branunwald E, Kasper DL, eds. Harrison’s principles of internal medicine.17th ed. New York, NY: McGraw-Hill; 2005:2275.
The global burden. Diabetes Atlas update, 2012. Available at http://www.idf.org/diabetesatlas/5e/the-global-burden. Accessed 9 October 2012.
United Kingdom Prospective Diabetes Study: Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex (UKPDS 27). Diabetes Care 1997;20:1683-7.
Adiels M, Olofsson SO, Taskinen MR, Boren J. Diabetic dyslipidaemia. Curr Opin Lipidol 2006;17:238-46.
Ginsberg HN. Diabetic dyslipidemia: basic mechanisms underlying the common hypertriglyceridemia and low HDL cholesterol levels. Diabetes1996;45(Suppl 3):S27-S30.
Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-12.
Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS 23). BMJ 1998;316:823-8.
Farmer JA. Diabetic dyslipidemia and atherosclerosis: evidence from clinical trials. Curr Diab Rep 2008;8:71-7.
DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 2000;133:73-4.
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Moller DE. Role of AMP- activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167-74.
Nobel J, Baerlocher MO, Silverberg J. Management of type 2 diabetes mellitus. Role of thiazolidinediones. Can Fam Physician 2005;51:683-7.
DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 2000;133:73-4.
Reasner CA. Reducing cardiovascular complications of type 2 diabetes by targeting multiple risk factors. J Cardiovasc Pharmacol 2008;52:136-44.
Richmond W. Preparation and properties of cholesterol oxidase from Nocardia sp. and its application to the enzymatic assay of total cholesterol in serum. Clin Chem 1973;19:1350-6.
Foosati P, Prencipe L. Serum triglyceride determined colorimetrically with an enzyme that produce hydrogen peroxide. Clin Chem 1982;28:2077-80.
Warnick GR, Nauck M, Rifai N. Evolution of methods for measurement of HDL-C: from ultracentrifugation to homogenous assays. Clin Chem Sept 2001;47:1579-96.
Rifai N, Warnick GR, eds. Laboratory measurements of lipids, lipoproteins and apolipoproteins. AACC press, Washington DC, USA 1994.
Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.
Kipnes MS, Krosnick A, Rendell MS, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Am J Med 2001;111:10-7.
Hanefeld M, Brunetti P, Guntram H, Schernthaner MD, Matthews DR, Charbonnel BH. On behalf of the QUARTET Study Group: One-year glycaemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 Diabetes. Diabetes Care 2004;27:141-7.
Gervois P, Torra IP, Fruchart JC, Staels B. Regulation of lipid and lipoprotein metabolism by PPAR activators. Clin Chem Lab Med 2000;38:3-11.
Yamasaki Y, Kawamori R, Wasada T, Sato A,Omori Y, Eguchi H, et al. Pioglitazone (AD-4833) ameliorates insulin resistance in patients with NIDDM. AD-4833 Glucose Clamp Study Group. Japan Tohoku J Exp Med 1997;183:173-83.
Hopkins GJ, Barter PJ. Role of triglyceride-rich lipoproteins and hepatic lipase in determining the particle size and composition of HDLs. J Lipid Res 1986;27:1265-77.
Kontush A, Chapman MJ. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev 2006;58:342-74.
Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR Jr, Bangdiwala S, Tyroler HA. High-density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation 1989;79:8-15.
Henry RR. Thiazolidinediones. Endocrinol Metab Clin North Am 1997;26:553-73.
Chait A, Brazg RL, Tribble DL, Krauss RM. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am J Med 1993;94:350-6.
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low –density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-24.
Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM. PPAR promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998;93:241-52.
Wood PA. How Fat Works. Harvard University Press 2006, 249.
Rendella MS, Glazerb NB, Yeb Z. Combination therapy with pioglitazone plus metformin or sulfonylurea in patients with Type 2 diabetes: Influence of prior antidiabetic drug regimen. J Diabetes Complications 2003;17:211-7.
Derosa G, Cicero AF, Gaddi A, Ragonesi PD, Fogari E, Bertone G, Ciccarelli L, Piccinni MN. Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with glimepiride: a twelve-month, multicenter, double-blind, randomized, controlled parallel-group trial. Clin Ther 2004;26:744-54.
Giugliano D, Rosa ND, Maro GD, Marfella R, Acampora R, Buoninconti P, D'Onofrio F. Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care 1993;16:1387-90.
Kelly IE, Han TS, Walsh K, Lean ME. Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care 1999;22:288-93.
