Moderate-intensity statin therapy seems ineffective in primary cardiovascular prevention in patients with type 2 diabetes complicated by nephropathy. A multicenter prospective 8 years follow up study
CVDs are the primary cause of mortality and morbidity globally and produce immense health and economic burdens [29]. This prospective and multicenter study shows the lack of CV protective effect of statin treatment in primary prevention in a T2DM population at very high CV risk, such as our cohort with clinical diagnosis of diabetic nephropathy (based on the concomitant presence of abnormal albuminuria and severe retinopathy). The CV outcome has never been evaluated for this high-risk population, but the cross-sectional phase of the NID-2 study pointed out that this category of patients showed a 10-year risk of CV events greater than 10 % [30]. In patients with T2DM and nephropathy the interaction between albuminuria and GFR is statistically significant, and it influences the risk for fatal and non-fatal CV events [30]. Moreover, both GFR and albuminuria have a great influence on CVD burden, independently of the classification system used for CKD in T2DM [31]. A recent large retrospective study on about 58,000 T2DM patients based on a UK primary care database confirms that all-cause mortality and the risk of cardiovascular events significantly increase with the decrease of GFR values [32]. Therefore, a careful management of GFR, albuminuria and CV risk factors represents a winning strategy to reduce the risk of fatal and non fatal CV events.
In this particular study we have only considered the population in primary CV prevention according to the above-mentioned inclusion criteria. It is very interesting to note that, according to 2014 ADA guidelines [28], the main aim for statin treatment was to gain the LDL-cholesterol target (100 mg/dl in primary CV prevention, 70 mg/dl in secondary CV prevention), independently on the dose and the drug chosen.
The most recent ADA guidelines [15] recommend lifestyle modification to improve the lipid profile in patients with diabetes, and suggest an addition of high-intensity statin therapy for patients of all ages with diabetes and overt CVD (level A of evidence). Moreover, for primary CVD prevention diabetes patients should be treated with statins if they are aged over 40 years regardless of CV risk factors. In particular, for patients with diabetes aged 40–75 years with additional atherosclerotic cardiovascular disease risk factors (e.g. LDL cholesterol 100 mg/dl, high blood pressure, smoking, albuminuria, and family history of premature CVD), high-intensity statin and lifestyle therapy should be used (level B of evidence). According to the position statement of ADA, a high-intensity statin therapy (e.g. atorvastatin 40–80 mg and rosuvastatin 20–40 mg daily) reduces LDL cholesterol by 50 % [15].
These Guidelines were based on the observation of the effectiveness of specific doses of statins against placebo or other statins, rather than aiming at specific LDL cholesterol levels [33]. Thus, the ADA considers the patients with increased cardiovascular risk similarly to those with known CVD.
Notably, all patients of our cohort (group A) were treated with a moderate-intensity statin.
Because of the high rate of patients at target for LDL-cholesterol in group A, it seems evident that, in this observational study, all physicians followed the old “treat to target” method rather than the recent ADA position statement. Actually, we can state that, independently on the dose and kind of the statin used, physicians appropriately prescribed statins to the group A individuals.
Actually, evidence for the efficacy of statins is dominated by randomized controlled trials mostly focused on general population at high CV risk or on CVD secondary prevention [16–19]. However, there is still some controversy such the use of statins in diabetes patients for primary CVD prevention [20–23] and most of the trials are not specifically designed for selected categories of diabetic patients. All the statin clinical trials on diabetic populations examined patients with unspecific proteinuria. Our study is focused on type 2 diabetes complicated by diabetes nephropathy stricto sensu. A recent review [34], supporting the use of statins in primary CV prevention, showed that statins significantly reduce the risk of myocardial infarction, coronary death, coronary revascularisation and the risk of stroke in patients with documented diabetes at baseline irrespective of a prior history of vascular disease. However, the absolute risk for people with diabetes was probably affected by the entry criteria of the trials, so the observed absolute benefits of statin cannot be directly extended to any categories of people with diabetes but have to be evaluated case by case.
A meta-analysis pooled the data from eight randomized trials that compared statins with placebo in primary prevention in populations at increased CV risk and found that total mortality was not reduced by statins [20]. Similarly, another meta-analysis showed that treatment with lipid lowering drugs in primary prevention lasting 5–7 years reduced coronary heart disease events and mortality by about 30 % but their effect on all-cause mortality was not significant [35]. Moreover, a recent literature-based meta-analysis of 11 randomized controlled trials involving 65,229 participants did not find evidence for the benefit of statin therapy on all-cause mortality in a high-risk primary prevention set-up [36].
The most recently published Cochrane systematic review on statins for the primary prevention of CBD [37], included 18 randomised controlled trials (56,934 patients), dating from 1994 to 2008, that compare statins with usual care or placebo. All-cause mortality and fatal and non-fatal CVD events were reduced with the use of statins as it was the need for revascularisation (coronary artery bypass graft or angioplasty). Of these trials, only 4 included patients with diabetes: ASPEN, CARDS, MRC/BHF Heart Protection Study and CERDIA. The main outcome of CERDIA [38] was to determine the effect of statin therapy on the progression of carotid intima-media thickness, so only the other three have as main outcome the effects of statins in major vascular events.
The MRC/BHF Heart Protection Study is a large randomised placebo-controlled trial [39], conducted between 1994 and 1997, which recruited 2912 patients with diabetes (type 1 and type 2) without any diagnosed coronary or other occlusive arterial disease at study entry, of whom 50 % were allocated to simvastatin 40 mg. It showed a highly significant (nearly 30 %) proportional reduction of the first major vascular event in the group treated with simvastatin compared to the placebo. However, among the diabetic patients in CDV primary prevention, the absolute risk of major vascular events was influenced to a lesser extent by their initial concentrations of LDL-cholesterol as a 1.0 mmol/L reduction in LDL cholesterol would translate into avoidance of major vascular events during 5 years in about 3 % individuals compared to about 9 % in people with diabetes in CVD secondary prevention.
The West of Scotland Coronary Prevention Study (WOSCOPS) was the first trial to demonstrate a significant 31 % reduction in CV events for primary prevention in patients treated with statin therapy for 5 years [40]. The twenty-year follow-up of the WOSCOPS further suggested that treatment with a statin for 5 years might provide a persistent reduction in CVD mortality and hospitalizations, but no impact on stroke [41]. The AFCAPS study compared lovastatin with placebo for primary CV prevention in a population who had average total cholesterol and LDL-C and below-average HDL-C. After a 5 years follow up, treatment with lovastatin resulted in a 37 % reduction in the risk for first fatal or nonfatal acute major coronary events [42]. Compared to our results and those of the other trials on statin treatment in primary prevention, the WOSCOPS and the AFCAPS recruited a relatively younger population (mean age around 55–58 years) and only 1–2 % had a diagnosis of DM. Moreover the WOSCOPS recruited only males and with higher mean LDL cholesterol levels (192 mg/dl) and the AFCAPS excluded those managed with insulin.
Notably, although diabetic patients in our study had a mean BMI of 29.3 kg/m2, they did not experience a significant survival benefit from the prescription of statins before MI, unlike observed in overweight patients with diabetes elsewhere [43].
Statin treatment failed to show a positive effect on primary CV prevention in our cohort of high CV risk patients as shown by 18.9 % MACE, although partially related to the concomitant nephropathy. These findings are similar to those found in the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN). In this study 2400 type 2 diabetic patients, of whom 1905 without prior myocardial infarction, were randomized to atorvastatin or placebo and were followed up for 4 years. Primary composite end point (CV death, nonfatal myocardial infarction, nonfatal stroke, recanalization, coronary artery bypass grafting, resuscitated cardiac arrest, or worsening or unstable angina requiring hospitalization) was not significantly different between the two groups [44]. These results are further supported by other RCTs, such as the CARDS study which enrolled T2DM patients aged 40–75 years with no documented previous history of cardiovascular disease and at least an additional CV risk factor (retinopathy, albuminuria, current smoking or hypertension). After 3.9 years of follow-up, atorvastatin treatment showed a significant reduction of MACE, but didn’t record a significant fall in all-cause mortality [45]. Notably, in these two studies atorvastatin was used at high-intensity doses.
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) over 19,000 hypertensive patients and with at least three additional CV risk factors were randomized to receive amlodipine or atenolol. The lipid-lowering arm (LLA) of the trial randomized a subgroup of patients to additional treatment with atorvastatin or placebo, of whom 2532 were classified as having type 2 diabetes. After 3 years of follow-up there was a significant reduction in MACEs among the patients allocated on atorvastatin, although these reductions were not statistically significant in the DM subgroup [46]. Moreover the 11-year mortality follow-up of the lipid-lowering arm in the UK confirmed any significant reduction of CV deaths [47].
PROSPER was a controlled, randomized study involving around 6000 patients aged over 70 years, with a history of or risk factors for CVD. During the 3 years of follow-up, pravastatin reduced the risk of fatal and non-fatal CVD, but did not affect the risk of stroke and did not demonstrate a reduction in mortality [48]. Moreover the extended follow up over 8.6 years found no evidence that treatment of older high-risk subjects with pravastatin for several years prolonged life expectancy as it failed to show any reduction in stroke or all-cause mortality [49]. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) was a multicenter study conducted in 10,355 hypertensive patients with mean age of 66 years, of whom 14 % had a history of CVD and 25 % had T2DM. After a follow up of 3.3 years, reduction in all-cause mortality or CVD was not significant in the group treated with Pravastatin compared with usual care [50].
Our study shared similar baseline characteristics of the population recruited in the above trials, especially with regard to the glycaemic control (HbA1c 10 %), blood pressure (140/80 mmHg), BMI (30 kg/m2) and LDL (130 mg/dl). We had a higher percentage of smokers (26 %) and females (55 %). Moreover we recruited patients with clinically detected diabetic nephropathy. The CARDS was the only study that mentioned 17 % of their diabetic population had micro- or macroalbuminuria. The ASCOT and ALLHAT included hypertensive patients whereas the PROSPER recruited an older population (mean age 75 years). Compared to our cohort, the Heart Protection Study recruited patients with both type 1 and type 2 diabetes and shorter disease duration (5 years), better glycaemic control (mean HbA1c 7 %) and better renal function (mean baseline creatinine 88 µmol/L).
From these studies appeared that the impact of statins on CV outcomes in diabetic patients is different between primary and secondary prevention. In particular the findings from studies in primary prevention were not obtained by high-intensity statin. Therefore, the recent ADA position statement seems to be not supported by experimental evidence (level B).
More studies are required about unknown actions and overall actions of statins, regarding to potential side effects of statin use for short-term [51] and, particularly, extended periods [52].