Is there a role for hypolipidaemic drug therapy in the prevention or treatment of microvascular complications of diabetes?

Abstract

A plethora of statin survival trials and meta-analyses have demonstrated a substantial reduction in cardiovascular disease (CVD) morbidity and mortality, mainly related to a low-density lipoprotein cholesterol (LDL-C) reduction [1]. One of them, the prospective, randomised, double-blind, secondary prevention Treating to New Targets (TNT, n = 10,001) trial, randomised patients to either 10 or 80 mg/day of atorvastatin. During a 5-year period the 10 mg/day patients had a rate of major CVD events of 10.9%, while those randomised to 80 mg/day had an 8.7% event rate. This was despite the concurrent and successful treatment of other CVD risk factors, the 22% (p<0.001) CVD risk reduction compared with atorvastatin 10 mg/day, and the achievement of LDL-C levels of 77 mg/dl (well below those suggested by guidelines at that time) [2]. Similar were the data from the prespecified post hoc subgroup analysis of TNT that included patients (n = 1,401) with type 2 diabetes mellitus (T2DM) that had mild to moderate chronic kidney disease (CKD, a microvascular complication of DM) or normal renal function [3]. Compared with 10 mg of atorvastatin, 80 mg of atorvastatin reduced the relative risk (RR) of major CVD events by 35% (absolute event rate 21 vs 14%; hazard ratio (HR) = 0.65; 95% confidence interval (CI) = 0.43-0.98; p = 0.04) in those with CKD and by 10% in patients with T2DM and normal renal function (14.8 vs 14%; HR = 0.90; p = 0.56) [3]. In any case (with or without diabetic nephropathy) a residual CVD risk was present, as in all statin survival trials [1]. In the Steno-2 study, intensive multifactorial intervention in patients with T2DM during a 5-year follow-up, significantly reduced CVD events (HR = 0.47, 95% CI = 0.24-0.73, p = 0.008) and CVD mortality (HR = 0.43, 95% CI = 0.19-0.94, p = 0.04), but failed to prevent the development or the progression of microvascular complications of T2DM in up to 50% of patients [4, 5]. This contributed to a lesser reduction of CVD mortality or morbidity rates, and was recorded despite the effort to control glycaemia, blood pressure, body weight, smoking, physical activity, and LDL-C levels [4,5]. Thus, residual risk is related both to macrovascular complications connected to atherogenic dyslipidaemia [high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C) levels, prevalent in DM] and to microvascular complications of T2DM, which contribute to the excess CVD and all cause morbidity and mortality [6-8]. The gains in CVD prevention and treatment are being challenged by the impact of global epidemics of obesity, metabolic syndrome (MetS) and T2DM [9]. Recent data suggest a possible reversal in CVD mortality rates, especially in younger men and women [10, 11]. These trends have a negative impact on life expectancy (each year 4.3 million CVD deaths are reported in Europe [12]) and quality of life as well as on the cost of managing CVD, estimated in 2008 at about $450 billion per annum in the United States (US) [13] and $300 billion in Europe [12]. DM-related complications, including CVD, CKD, neuropathy, blindness, and lower-extremity amputation, are significant causes of increased morbidity and mortality, and further increase the economic burden on health care systems. In 2050, the number of people in the US with diagnosed DM is estimated to grow to 48.3 million, from 20 million in 2005 [14]. It was thought until recently that current standards of care, such as effective glycaemic control, reduce CVD events (on a very long term basis), and improve microvascular complications of DM [diabetic retinopathy (DR), nephropathy (DNeph) or neuropathy (DNeur) [6]. A recent meta-analysis of 14 clinical trials that randomised 28,614 participants with T2DM (15,269 to intensive and 13,345 to conventional glycaemic control) showed that intensive control did not significantly affect the relative risks of all cause or macrovascular and microvascular disease (as a composite outcome or retinopathy or nephropathy or amputations alone) [15], while compared with conventional glycaemic control it increased the risk of severe hypoglycaemia by 30%. The latter might lead to increased mortality rates [15]. If intensive glycaemic control is dangerous and does not prevent microvascular complications of DM, as we believed until recently, then what can? Is it possible that arterial hypertension or atherogenic dyslipidaemia (both closely related to DM) may contribute to the pathogenesis of microvascular complications of DM [16]? The Action to Control Cardiovascular Risk in Diabetes - Eye (ACCORD-EYE) study showed that there was no significant effect of intensive vs standard blood-pressure control on the progression of macrovascular and at least the 1 microvascular complication (DR) of DM during a 4 year follow-up [17]. On the other hand it seems that there is a link between atherogenic dyslipidaemia and microvascular complications of DM [18, 19]; this is further confirmed by data suggesting that combinations or monotherapies of hypolipidaemic drugs (through hypolipidaemic [20] or off-target effects) improve existing or prevent new microvascular complications of DM [21, 22] thus providing a fresh approach for the treatment of this feature of DM that still has unmet needs [21, 22]. There are some data suggesting that this might be one way to solve this problem [7,16,23].