Residual microvascular risk in diabetes: unmet needs and future directions.

The burden of microvascular disease in patients with type 2 diabetes mellitus continues to escalate worldwide. Current standards of care reduce but do not eliminate the risk of diabetic retinopathy, nephropathy or neuropathy in these patients. Correction of atherogenic dyslipidemia, which is characterized by elevated triglyceride levels and low levels of HDL cholesterol, might provide additional benefit. Whereas promising data have been published with respect to fibrate therapy for maculopathy, fenofibrate for diabetic retinopathy, and statin or fibrate therapy for diabetic nephropathy, further studies are warranted to define optimal management strategies for reducing the residual microvascular risk. Such strategies are especially relevant in cases of diabetic peripheral neuropathy, where even optimal care fails to affect disease progression. Identification of those factors that are most relevant to residual diabetes-related microvascular risk is a priority of an ongoing multinational epidemiological study. In this Review, we highlight an urgent need to address the issue of microvascular residual risk in patients with or at risk of type 2 diabetes mellitus.

The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia.

Despite achieving targets for low-density lipoprotein (LDL) cholesterol, blood pressure, and glycemia in accordance with current standards of care, patients with dyslipidemia remain at high residual risk of vascular events. Atherogenic dyslipidemia, characterized by elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, often with elevated apolipoprotein B and non-HDL cholesterol, is common in patients with established cardiovascular disease (CVD), type 2 diabetes mellitus, or metabolic syndrome and contributes to both macrovascular and microvascular residual risk. However, atherogenic dyslipidemia is largely underdiagnosed and undertreated in clinical practice. The Residual Risk Reduction Initiative (R3i) was established to address this highly relevant clinical issue. The aims of this position paper are (1) to highlight evidence that atherogenic dyslipidemia is associated with residual macrovascular and microvascular risk in patients at high risk for CVD, despite current standards of care for dyslipidemia and diabetes; and (2) to recommend therapeutic intervention for reducing this residual vascular risk supported by evidence and expert consensus. Lifestyle modification with nutrition and exercise is an important, effective, and underutilized first step in reducing residual vascular risk. Therapeutic intervention aimed at achievement of all lipid targets is also often required. Combination lipid-modifying therapy, with the addition of niacin, a fibrate, or omega-3 fatty acids to statin therapy, increases the probability of achieving all lipid goals. Outcomes studies are in progress to evaluate whether these combination treatment strategies translate to a clinical benefit greater than that achieved with statins alone. The R3i highlights the need to address with lifestyle and/or pharmacotherapy the high level of residual risk of CVD events and microvascular complications among patients with dyslipidemia receiving therapy for high levels of LDL cholesterol and for diabetes in accordance with current standards of care.

The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient.

Despite current standards of care aimed at achieving targets for low-density lipoprotein (LDL) cholesterol, blood pressure and glycaemia, dyslipidaemic patients remain at high residual risk of vascular events. Atherogenic dyslipidaemia, specifically elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, often with elevated apolipoprotein B and non-HDL cholesterol, is common in patients with established cardiovascular disease, type 2 diabetes, obesity or metabolic syndrome and is associated with macrovascular and microvascular residual risk. The Residual Risk Reduction Initiative (R3I) was established to address this important issue. This position paper aims to highlight evidence that atherogenic dyslipidaemia contributes to residual macrovascular risk and microvascular complications despite current standards of care for dyslipidaemia and diabetes, and to recommend therapeutic intervention for reducing this, supported by evidence and expert consensus. Lifestyle modification is an important first step. Additionally, pharmacotherapy is often required. Adding niacin, a fibrate or omega-3 fatty acids to statin therapy improves achievement of all lipid risk factors. Outcomes studies are evaluating whether these strategies translate to greater clinical benefit than statin therapy alone. In conclusion, the R3I highlights the need to address with lifestyle and/or pharmacotherapy the high level of residual vascular risk among dyslipidaemic patients who are treated in accordance with current standards of care.

PKC inhibition and diabetic microvascular complications.

In patients with diabetes, the hyperglycaemia is known to promote high levels of diacylglycerol which activates protein kinase C (PKC) in the vascular tissues and leads to production of vascular endothelial growth factor (VEGF) in the retina. PKC activation is likely to play a key role in diabetic microvascular complications, particularly changes in vascular permeability and ischaemia in the retina. A new potential therapeutic agent, the PKC-beta inhibitor ruboxistaurin, has been studied in animal and human clinical trials in diabetic microvascular disease, particularly in patients with diabetic retinopathy. The mechanism of action of PKC and the results of these trials are discussed in this review. Ruboxistaurin shows promise as an oral treatment for diabetic retinopathy. The trials have demonstrated a significant reduction in visual loss and need for laser treatment in patients with moderate to severe diabetic retinopathy over a 3-year period. There have been no significant concerns over safety or the side-effects profile in the clinical trials. Ruboxistaurin currently has approvable status pending further randomized trials defined by the US Food and Drug Administration (FDA).

Diabetic retinopathy: treatment and prevention.

Diabetic eye disease is the major cause of blindness and vision loss among working-age people in developed countries. Microangiopathy and capillary occlusion underlie the pathogenesis of disease. While laser treatment is regarded as the standard therapy, intensive medical management of glycaemia and hypertension is also a priority in order to reduce the risk of diabetic retinopathy. Recent data have prompted a re-evaluation of the role of lipid-modifying therapy in reducing diabetic retinopathy. The Fenofibrate Intervention for Event Lowering in Diabetes (FIELD) study demonstrated a significant 30% relative reduction in the need for first retinal laser therapy in patients with (predominantly early-stage) type 2 diabetes treated with fenofibrate 200 mg daily, from 5.2% with placebo to 3.6% with fenofibrate, p=0.0003. The benefit of fenofibrate was evident within the first year of treatment. These promising data justify further evaluation of the mechanism and role of fenofibrate, in addition to standard therapy, in the management of diabetic retinopathy.