Diabetes and cardiovascular disease: when it comes to lipids, statins are all you need.

THE PREVALENCE OF DIABETES AND CARDIOVASCULAR DISEASE MORTALITY

The prevalence of obesity and diabetes continues to increase rapidly in the U.S. and all over the world (1–3). Obesity and diabetes are major risk factors for cardiovascular diseases (CVDs), but despite the increase in their prevalence, there seems to be a continuous steady decline in death rates from coronary heart disease (CHD) and stroke (4). Moreover, cause-specific excess death associated with obesity has been declining despite the increase in obesity rates (5).

The reason behind this apparent paradox is probably a better control of other risk factors for CVD, such as cholesterol levels, hypertension, and smoking. Several trials demonstrated that more than half the decline in deaths from CHD in the last decades may be attributable to reductions in major risk factors (6). Of all risk factors, treating high cholesterol levels had the highest impact on the decline in CHD mortality (7). This is hardly surprising because the LDL cholesterol level is the strongest determinant of CHD risk, even in diabetic patients (8).

Prevention of CHD in diabetic patients and the question of residual risk

Statins are the most effective agents in reducing the risk of CHD in diabetic patients, reducing the relative risk by about one-third (9,10). An analysis based on the UK Prospective Diabetes Study (UKPDS) risk engine demonstrated that even in the Steno-2 study, in which multifactorial intervention was used for the treatment of diabetes with an impressive reduction of both cardiovascular morbidity and mortality, lipid-lowering therapy accounted for more than 70% of CVD risk reduction (11). Actually, many more patients in the intensive therapy group achieved their cholesterol goal compared with the conventional therapy group (70 vs. 20%), while there was no difference between the groups in the attainment of their triglyceride goal (11). The main difference between the intensive and conventional treatment groups was in the use of statins (12). Eighty-five percent of the patients assigned to intensive therapy were given statins, compared with 22% of the patients assigned to conventional therapy. The result was a mean LDL cholesterol level of 83 mg/dL in the patients assigned to intensive therapy compared with 126 mg/dL in the patients assigned to conventional therapy (12).

However, in all studies, the risk in the group assigned to intensive therapy remained high. The remaining large residual risk is often cited as a proof for statins not being efficient enough in reducing cardiovascular risk, and therefore for the need to combine statins with other lipid-modifying agents (13). A closer look at the data may offer a different explanation.

The intensity of statin treatment

Current guidelines recommend a goal for LDL cholesterol of below 100 mg/dL, with a level of below 70 mg/dL as an optional goal, especially in individuals with diabetes and overt CVD (14). In real life, the mean LDL cholesterol level in patients with diabetes is often higher than 100 mg/dL (15). Even in the controlled setting of statin trials, the mean LDL cholesterol level achieved in patients with diabetes is about 90 mg/dL (16).

But even current goals may not be optimal for high-risk patients. The association between LDL cholesterol levels and CHD risk seemingly remains log linear at very low LDL cholesterol levels (17). In studies like PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) and JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin), high-risk patients achieving LDL cholesterol levels below 40–50 mg/dL had a lower risk for cardiovascular events than patients failing to achieve such low levels (18,19). This may mean that use of high doses of potent statins in high-risk patients, such as those with diabetes, attaining LDL cholesterol levels below 40–50 mg/dL, may further reduce cardiovascular risk. It should be noted that although statins are relatively safe even when given in high doses, high doses of statins may cause muscle cramps in some patients.

The timing of statin treatment

Current guidelines do not consider prediabetic patients to be at high risk of CVD in terms of recommended LDL cholesterol goals. However, prediabetic subjects have an atherogenic pattern of risk factors that may be present for many years and may contribute to the risk of CVD as much as the duration of clinical diabetes itself (20).

In the Nurses’ Health Study, a significantly elevated risk of CVD was found before clinical diagnosis of type 2 diabetes (21). Among women who developed type 2 diabetes during follow-up, the age-adjusted relative risks of myocardial infarction were 3.75 (95% CI 3.10–4.53) for the period before the diagnosis and 4.57 (3.87–5.39) for the period after the diagnosis, compared with women who remained free of diabetes. In the DECODE (Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe) study, patients with impaired glucose tolerance had lower survival rates than those with normal glucose tolerance. Participants with impaired fasting glucose had cumulative mortality curves similar to but worse than those for normoglycemic individuals (22). In the AusDiab (Australian Diabetes, Obesity and Lifestyle) study, compared with those with normal glucose tolerance, the risk of death was increased in those with impaired fasting glucose (hazard ratio 1.6 [95% CI 1.0–2.4]) and impaired glucose tolerance (1.5 [1.1–2.0]) (23).

Long-term follow-up of patients participating in statin trials have demonstrated that the benefit of early statin therapy in high-risk patients that accrued during the double-blind trial period persisted during follow-up, despite a high rate of statin use in both groups after the trial. It seems that the full benefit cannot be achieved by starting treatment 5 years later (24,25).

In the JUPITER study, none of the patients had diabetes, but many of the patients had the metabolic syndrome or other prediabetic states (19,26). These patients, treated with a high-dose potent statin, had a remarkable 45% decrease in the risk for cardiovascular events (19).

However, even in JUPITER there was a 55% residual risk for CVD. This might be because patients in JUPITER were relatively old (mean age 66 years), as in most statin trials (19). There are no studies of statin therapy in young people, but there is a good example of naturally occurring low LDL cholesterol levels from a very young age. In the ARIC (Atherosclerosis Risk in Communities) trial, naturally occurring low LDL cholesterol levels from birth because of mutations and sequence variants in the gene for PCSK9 were associated with an up to 88% reduction in the risk for cardiovascular events (27). Therefore, it seems logical to start statin therapy in prediabetic patients. Such early therapy may reduce risk even further.

Drug treatment of other components of dyslipidemia and the risk for CVD

There have been many attempts to find drugs that would improve triglyceride and HDL cholesterol levels and confer additional benefit when given on top of statins. So far, all have failed. Although fibrates have been shown to reduce cardiovascular risk in some studies such as VA-HIT (Veterans Affairs High-Density Lipoprotein Intervention Trial) (28), their value, when added to statins, have never been proved. Fenofibrate did not reduce morbidity and mortality in diabetic patients in the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) and ACCORD (Action to Control Cardiovascular Risk in Diabetes) trials (29,30). Torcetrapib increased the risks of mortality and morbidity despite increasing HDL cholesterol levels (31). Omega-3 fatty acids were never tested for their ability to decrease morbidity and mortality when used as antilipidemic agents. Niacin decreased morbidity and mortality when used alone in post-myocardial infarction patients (32), but the results of studies testing its effect when given on top of statins are still pending. Moreover, because niacin reduces LDL cholesterol levels as well as increases HDL cholesterol and decreases triglyceride levels, any potential beneficial effects of this drug may be because of its LDL cholesterol–lowering effect. Many other drugs have either failed to reduce cardiovascular morbidity and mortality despite improving HDL cholesterol levels (e.g., roziglitazone, hormone replacement therapy) or even caused harm (e.g., rimonabant, muraglitazar).

In fact, a recent systematic review looking at the association between treatment-induced change in HDL cholesterol and cardiovascular morbidity and mortality change in HDL cholesterol explained almost no variability in any of the outcomes. Reduction in LDL cholesterol levels, on the other hand, was associated with reduction in morbidity and mortality (33).

CONCLUSIONS

LDL cholesterol is the major risk factor for cardiovascular complications in diabetic patients. Statins significantly reduce cardiovascular risk in diabetic patients. Starting statin therapy before diabetes develops and treating to lower LDL cholesterol targets than is currently recommended may reduce risk even further. There is no evidence that other antilipidemic agents improve clinical outcomes.