Significance of LDL-C Lowering Therapy in Diabetic Patients

Sergio Martinez-Hervas; Rafael Carmena; Juan F Ascaso


Clin Lipidology. 2011;6(4):389-399. 

In This Article


Statins are potent inhibitors of hepatic cholesterol biosynthesis and act by reversibly inhibiting the 3-hydroxy-3-methylglutaril coenzyme A reductase. They lower LDL-C by 20–55% depending on the statin and dose used, in a dose-dependent manner. Statins also induce a mild reduction of TG (7–30%) and a slight rise of HDL-C (5–10%) (Table 2 & Figure 1).[32,33]

Figure 1.

Percentage lowering of LDL-C with different statins. Based on the data published by Law MR et al. 89 who evaluated three meta-analyses to determine how much statins reduce serum concentrations of LDL-C.

Statins have demonstrated efficacy, safety and tolerability across a broad range of patients, both in primary and secondary prevention of CHD in a wealth of prospective, randomized, clinical trials.[34–38] In the Cholesterol Treatment Trialists' Collaborators (CTTC) meta-analysis of 14 statin trials and 90,056 individuals, for each 39 mg/dl (1 mmol/l) reduction in LDL-C there was a reduction in cardiovascular events of 21% and a reduction in coronary events of 23%.[24] Moreover, a more recent meta-analysis, also by the CTTC, demonstrated that further reductions in LDL-C with more intensive therapy safely produced further reductions in the annual rate of major vascular events (incidence of heart attack, revascularisation and ischemic stroke).[23]

In addition, several trials have demonstrated the efficacy of statins to reduce CVD in different populations.[22–24] The first study showing the cardiovascular benefits of statins in diabetics, although in post hoc analysis, was the Scandinavian Simvastatin Survival Study (4S). In the 202 diabetic patients with previous MI or angina pectoris, cholesterol lowering with simvastatin reduced by 55% the risk for a major coronary artery disease event compared with those receiving placebo.[34] Later, using new diagnostic criteria for diabetes (≥7.0 mmol/l) and impaired fasting glucose (6.0–6.9 mmol/l), 483 subjects with diabetes were identified, 251 on simvastatin and 678 with impaired fasting glucose. This larger cohort of individuals confirmed the benefit of cholesterol lowering with simvastatin on CHD events in diabetics.[39] In addition, subjects with impaired fasting glucose levels also presented benefits in CHD events.

Diverse trials with statins that included diabetics with previous CHD reduced cardiovascular events significantly "in a similar way than other subjects". Most of the studies were not specifically designed to evaluate the effect of statins on CVD in subjects with diabetes (Table 3). The Heart Protection Study (HPS) included 20,536 UK adults randomly allocated to 40 mg of simvastatin daily or placebo during a 5-year treatment period.[35] 5963 (1816 women) of these subjects were Type 2 diabetics.[40] There was a 22% reduction in major vascular events (major coronary event, stroke or revascularization) in subjects on simvastatin. These results were independent of age, gender, lipid concentration, duration of Type 2 diabetes, and levels of glycosylated hemoglobin.

The first statin trial designed to evaluate the benefit of LDL-C lowering in patients with diabetes was Collaborative Atorvastatin Diabetes Study (CARDS).[41] This primary prevention study included 2838 Type 2 diabetics randomized to placebo or atorvastatin 10 mg daily. The trial was terminated 2 years earlier than expected because of the benefits of atorvastatin on CVD. Atorvastatin reduced LDL-C by approximately 40%, a benefit similar to that observed in nondiabetic subjects. Atorvastatin lowered the relative risk of a first major cardiovascular event by 37% and that of stroke by 48%. Along the same lines, in the treated arm of the Anglo–Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm study (ASCOT-LLA),[42] 10 mg/day of atorvastatin reduced CVD events by more than 20%. However, there are also trials of statins in diabetes with negative results. In the Atorvastatin Study for Prevention of coronary heart disease Endpoints in Noninsulin-dependent diabetes mellitus (ASPEN) including Type 2 diabetics and the Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack Trial (ALLHAT-LLT) in general population including more than 3500 diabetics, statins did not demonstrate a significant reduction in CVD.[43,44] In the same line, the German Diabetes and Dialysis Study (4D), in subjects with Type 2 diabetes mellitus receiving hemodyalisis, atorvastatin had no significant effect on CVD death.[45] Nevertheless, the results of CARDS, HPS and ASCOTT-LLA provide compelling evidence for the use of statins in diabetic persons free of CVD.

An important issue is related with the dose of statins. Is intensive lipid lowering necessary in all subjects with diabetes? Should the LDL-C goal be <100 mg/dl or <70 mg/dl? Recently, some statin trials including an important number of subjects with diabetes have compared treatments of differing intensity to determine whether there really is incremental benefit from additional LDL-C lowering in patients with prior CHD. The Aggrastat to Zocor (A-to-Z),[46] Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE-IT),[47] Treating to New Targets (TNT),[48] Incremental Decrease in End-points Through Aggressive Lipid lowering (IDEAL),[49] and the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH)[50] trials using high-dose statin achieved LDL-C lowering between 100 and 70 mg/dl, demonstrating a significant reduction in cardiovascular events and vascular death. In the Atorvastatin Versus Revascularization Treatment (AVERT) study[51] 341 patients with stable CHD referred for percutaneous revascularization were randomly assigned to receive medical treatment with atorvastatin 80 mg per day or to undergo the recommended angioplasty. After a follow-up period of 18 months, aggressive lipid-lowering therapy was at least as effective as angioplasty in reducing the incidence of ischemic events. Moreover, studies such as Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL),[52] A Study To Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID),[53] Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin (METEOR),[54] and Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER)[55] have shown that LDL-C levels close to 70 mg/dl are associated with a regression of the carotid atheroma plaque determined by carotid ultrasonography or the coronary plaque evaluated by intravascular ultrasonography (IVUS). However, some of these studies (AVERT, REVERSAL and ARBITER), although positive, showed less benefit in diabetes than in the general population. Nevertheless, according to previous data, there is a strong association between LDL-C and progression or regression of atherosclerosis. Therefore, an LDL <70 mg/dl goal would be suitable for subjects with high cardiovascular risk, such as diabetics. Moreover, if drug-treated patients do not reach lipid targets on maximal tolerated statin therapy, a reduction in LDL-C of about 30–40% from baseline could be an acceptable goal. Safety is an important issue. Trials have demonstrated that high dose of statins (80 mg/day of atorvastatin or 40 mg/day of simvastatin) are safe and unrelated to significant increases in adverse effects. Muscle-related adverse events and increased levels of transaminases are unusual and not more frequent than with standard statin doses.[56,57] Thus, when needed, there is no reason to avoid the use of high doses to achieve the recommended goals.

Another important aspect of discussion is whether the commonly referred to as 'pleiotropic effects' of statins are clinically relevant. Statins have demonstrated effectiveness in primary and secondary prevention of CVD. However, evidence supports the idea that reductions in cardiovascular risk are dependent on mechanisms beyond cholesterol reduction alone. Besides the lipid-lowering effects, statins have also been shown to improve endothelial function, enhance the stability of atherosclerotic plaques, decrease oxidative stress and inflammation, and inhibit the thrombogenic response amongst others.[58–60] The pleiotropic effects could add more relevance to the use of statins for lipid lowering. However, more studies are necessary to assess the possible influence of pleiotropic effects.

On the other hand, different statin trials have reported an association between the use of statins and incident diabetes, raising the question about the safety of long-term use of statins. A meta-analysis of 13 clinical trials including 91,140 participants of whom 4278 developed diabetes during a mean period of 4 years has analyzed the possible influence of statins on glycemic control and incidence of diabetes. Statin therapy was associated with a slightly increased risk of development of diabetes. However, the risk was low both in absolute terms and when compared with the reduction in coronary events. Thus, recommendations about clinical practice should not change in patients with moderate or high cardiovascular risk or existing CVD.[61]

Another important question to address is whether statin therapy should be initiated in all adult subjects at the diagnosis of diabetes. According to the recently published ADA standards of medical care,[27] along with lifestyle modification, statin therapy should be initiated regardless of baseline lipid levels in diabetic persons with established CVD. ADA guidelines also recommend treatment with statins, even if the patient has no history of CVD but is over the age of 40 years and has at least one associated CVD risk factor. For lower risk patients (under the age of 40 years and without CVD) statin therapy should be considered if LDL-C is over 2.6 mmol/l. Similar recommendations are proposed by the American Heart Association.[62] The Canadian guidelines also consider younger patients with shorter duration of disease and without diabetic complications and without other CVD risk factors in a different manner in respect to diabetes.[30] However, although it is recognized that not all diabetics are at the same risk, given that LDL-C lowering with statins has demonstrated a substantial risk reduction of cardiovascular events in a wide spectrum of individuals, including diabetics, irrespective of baseline lipid profile or other characteristics the general recommendation could be that all patients with diabetes should initiate statin therapy to a target goal of less than 100 mg/dl, or less than 70 mg/dl in high cardiovascular risk patients. Even, a greater decline in LDL-C levels is expected to further decrease CVD risk.

In summary, according to current guidelines, all diabetics should follow these recommendations. However, atherogenic dyslipidemia is characteristic of Type 2 diabetes due to insulin resistance. In Type 1 diabetes, this pattern of dyslipidemia only appears when glycemic control is inappropriate. Nevertheless, epidemiological evidence demonstrate that CVD risk is increased 2–20-fold in Type 1 diabetes, especially in those with diabetic nephropathy.[63,64] Moreover it has been observed that CVD risk factors accumulate among children and adolescents with Type 1 diabetes early in life.[65] Most of the trials with statins have been carried out in Type 2 diabetes, lacking information about Type 1 diabetes. In the HPS trial in a subgroup analysis only 615 out of 5963 diabetic subjects were patients with Type 1 diabetes.[40] This study demonstrated a relative risk reduction for major vascular events in subjects with Type 1 diabetes similar to that in subjects with Type 2 diabetes in response to 40 mg of simvastatin. In the CTTC meta-analysis, 1466 individuals with Type 1 diabetes were included. These individuals showed identical relative risk in major vascular events than Type 2 diabetics.[66]

In conclusion, it is well established that statins are the preferred lipid-lowering drugs in the treatment of dyslipidemia to prevent CVD. The type of statin and its dose will depend on the LDL-C lowering needed to achieve the recommended goals. Although some points are yet under discussion, most authors consider that in secondary prevention and in high cardiovascular risk subjects LDL-C should be as low as possible and statins should be prescribed early following a cardiovascular event. More controversies exist identifying the LDL-C target in primary prevention.


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