Sulfonylureas vs thiazolidinediones for the prevention of diabetic nephropathy

DailyUpdates 30th March: According to WHO, there are some 130 million diagnosed diabetics in the world and the long term consequences of diabetes such as diabetic nephropathy are becoming increasingly frequent and unmet components of diabetes care.  Intensive glycemic control prevents or retards microalbuminuria, an early sign of nephropathy in patients with type 2 diabetes and in a recent study Japanese researchers compare two different classes of oral antidiabetic drugs with respect to their effects on microalbuminuria.  According to WHO, there are some 130 million diagnosed diabetics in the world, a figure that is predicted to increase to 300 million by 2025. The market for diabetes therapeutics is also rising with global sales reportedly topping $8.1 billion for the 12 months to September 2000, a 19% increase over the previous 12 months (for a full analysis of diabetes therapeutics and market opportunities click here). Further increases are inevitable and the market for diabetes medications could exceed $20 billion by 2006. Oral antidiabetic drugs, the leading class of drugs used to treat the disease, accounted for almost 63% of sales.

Oral antidiabetic drugs have traditionally focussed on metformin and sulphonylurea. Until 1995, the sulfonylurea class of drugs which act by increasing insulin secretion was the only choice in the United States other than insulin for treating type 2 diabetes. The explosion of drugs available for controlling blood glucose began when Glucophage (metformin) became available in 1995, quickly followed by the approval of the insulinotropic agent Repaglinide in 1997 and the thiazolidinedione insulin sensitizers such as Avandia and Actos, which were both launched in 1999.

In addition to day to day control of hyperglycemia the endocrinologist is faced with the challenge of long-term, complications of diabetes.  The diabetic microvascular complication, nephropathy, is a condition with high unmet therapeutic needs. It is linked with significant increases in morbidity and mortality risk, and is the most common cause of end-stage renal disease in the US and Europe (for a full analysis of diabetic nephropathy click here).

The prevalence of nephropathy (encompassing microalbuminuria, proteinuria and end-stage renal disease) is 48% in seven countries representing 18.6m type 2 patients. The main focus of therapy in diabetic nephropathy is on tight control of blood pressure and either ACE or ARB therapy is recommended as a first line renoprotective anti-hypertensive therapy. Existing anti-hypertensive therapies can however only delay the progression of diabetic nephropathy. Research elucidating the etiology and pathways of diabetic microvascular disease has revealed new targets for drug design. Within the next 10 years the most promising compounds will come from the ARI, PKC-beta and AGE inhibitor classes.

Intensive glycemic control prevents or retards microalbuminuria, an early sign of nephropathy, in patients with type 2 diabetes, and as well as developing drugs that specifically target diabetic nephropathy it is important to determine whether any of the existing antiglycemics offer a particular advantage with respect to the prevention of microalbuminuria.  This issue was addressed in a recent study by Japanese researchers.

In their March Metabolism journal article, Yanagawa et al compare the effect of the sulfonylurea gliclazide (Diamicron) and pioglitazone (Actos) on microalbuminuria in patients with type 2 diabetes. Each patient received the designated drug for 12 weeks. The 2 groups of patients were well matched for age, duration of diabetes, retinal status, blood pressure, body mass index and the use of antihypertensive drugs.

After treatment, no significant differences were seen in drug efficacy between the 2 groups. Gliclazide and pioglitazone significantly reduced fasting plasma glucose, glycated hemoglobin and total cholesterol levels. Decrements in these metabolic parameters were comparable between the groups. Gliclazide and pioglitazone significantly reduced urinary albumin to creatinine ratio with a comparable decrement in both groups.

These results suggest that 12 weeks of treatment with gliclazide or pioglitazone are equally effective in reducing microalbuminuria with similar improvements in blood glucose and cholesterol levels, independent of their mechanisms of actions. On the basis of these data, there does not therefore appear to be a particular advantage in treatment with gliclazide or pioglitazone with respect to the long-term prevention of diabetic nephropathy.  Further studies comparing the effects of other examples of sulfonylureas and thiazolidinediones, as well as longer term treatment and investigating combined treatment on microalbuminuria may lead to improvements in our approach to the unmet problem of diabetic nephropathy.

(source DailyUpdates 30th March; for a full abstract of the original papers see   Metabolism. 2004 Mar;53(3):353-7; for further information on diabetic nephropathy see Diabetic Nephropathy: Prevalence, Progression, Prevention and Potential)

In this edition of DailyUpdates, LeadDiscovery also highlights the synthesis and biological activity of selective TACE inhibitors...non-peptide alpha(v)beta(3) antagonists...highly potent and long-acting inhibitors of influenza virus neuraminidase...discovery and in vitro evaluation of potent TrkA kinase inhibitors...and much more.