Evolving Therapy for Type 2 Diabetes Complications

August 18, 2009

The past 3 decades have seen a profound paradigmatic shift in the treatments available for type 2 diabetes mellitus. Because the disease is complicated by a variety of macrovascular and microvascular pathologies, interventions must be broad-based (tight glycemic and blood pressure [BP] control, serum lipid and urinary protein reductions). This "multifactorial" approach has proven successful.

The past 3 decades have seen a profound paradigmatic shift in the treatments available for type 2 diabetes mellitus. Because the disease is complicated by a variety of macrovascular and microvascular pathologies, interventions must be broad-based (tight glycemic and blood pressure [BP] control, serum lipid and urinary protein reductions). This "multifactorial" approach has proven successful. A host of newer oral hypoglycemic agents and insulins (such as the long-acting products) has been augmented by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Statins have decreased low-density lipoprotein (LDL) cholesterol levels and added so-called pleiotropic benefits (eg, anti-inflammatory actions). Tight BP control can be achieved through a veritable panoply of new drug classes; now even renin can be suppressed. Unfortunately, despite the success of these interventions, the complications of type 2 diabetes remain far from conquered.

PREVENTION OF CVD IN TYPE 2 DIABETES: BEYOND LDL LOWERING
Although many randomized, controlled, prospective trials have shown that lowering LDL cholesterol with statins decreases cardiac end points in patients with type 2 diabetes,1 these patients still have cardiovascular event rates that are comparable to those of nondiabetic patients receiving placebo in other LDL-lowering studies. Because diabetic dyslipidemias are more than an LDL problem- decreased high-density lipoprotein (HDL), elevated triglycerides, and increased non-HDL cholesterol are also part of the picture-statins alone may not be sufficient.

In a number of studies, fibrates are being added to lipid-lowering therapy for patients with type 2 diabetes. For example, in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study, fenofibrate was compared with placebo in approximately 9800 persons with type 2 diabetes. Even though coronary events were not reduced significantly in the fenofibrate limb, total cardiovascular events were lower among those who took fenofibrate (12.5%) than among those who received placebo (13.9%).2

PREVENTION OF OTHER VASCULAR COMPLICATIONS
Another analysis of the FIELD data looked at a microvascular complication of type 2 diabetes: retinopathy. The need for a first laser treatment for diabetic retinopathy, the progression of retinopathy in patients who already required laser therapy, and the complication of macular edema were all significantly lower in patients with type 2 diabetes who had received fenofibrate.3

Lipid abnormalities are expected to aggravate macrovascular, not microvascular complications. What if, just as the statins do, fenofibrate provides its own pleiotropic benefits (reducing levels of inflammatory markers such as tumor necrosis factor or affecting other mediators such as vascular endothelial growth factor)? It seems that it does.

Recent data from the FIELD Study have added more food for thought. Diabetes mellitus is the leading cause of nontraumatic leg amputations. The standard multifactorial approach (glycemic and BP control, lowering cholesterol) has had little effect on this problem. Of the 9795 patients with type 2 diabetes enrolled in the FIELD Study, 115 had 1 or more lower extremity amputations. Fewer patients in the fenofibrate limb underwent first amputations (45 vs 70) and minor amputations without large-artery disease (18 vs 34).4

It may be that multifactorial therapy targeting the complications of type 2 diabetes will be expanded in the next few years to include fenofibrate. The initial prospect of lowering triglycerides to mitigate the risk of largevessel pathology (atherosclerosis) may be only the "tip of the therapeutic iceberg." Fenofibrate, like the statins before it, may bode well for those with type 2 diabetes because of yet poorly understood pleiotropic effects that protect against both microvascular and macrovascular complications.

References:

REFERENCES:1. Goff DC Jr, Gerstein HC, Ginsberg HN, et al; ACCORD Study Group. Preventionof cardiovascular disease in persons with type 2 diabetes mellitus: currentknowledge and rationale for the Action to Control Cardiovascular Risk inDiabetes (ACCORD) trial. Am J Cardiol. 2007;99(12A):4i-20i.

2. Keech A, Simes RJ, Barter P, et al; FIELD study investigators. Effects of longterm fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial [published corrections appear in Lancet. 2006;368:1415, 1420]. Lancet. 2005;366:1849-1861.

3. Keech AC, Mitchell P, Summanen PA, et al; FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet. 2007;370:1687-1697.

4. Rajamani K, Colman PG, Li LP, et al; FIELD study investigators. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet. 2009;373: 1780-1788.