People with diabetes need aggressive lipid-lowering—with statins
Diabetes is a coronary heart disease risk equivalent and is associated with high risk of cardiovascular events.41–46 Overall, the risk for these adverse events is two to four times greater in people with diabetes than without. Atherosclerosis-related events account for approximately 65% to 75% of all deaths in people with diabetes, and 75% of these events are coronary. Lipid abnormalities are strongly correlated with the risk of cardiovascular disease in people with diabetes, and aggressive treatment of risk factors, particularly lipid abnormalities, has been shown to reduce this risk.47–49 And data from multiple clinical trials support the use of statins to lower LDL-C as the first-line therapy for dyslipidemia in people with diabetes, just as it is in the general population.3–7,9,13,23,50–61
Analyses of diabetic subgroups encompassing 18,000 to 20,000 patients in the large statin trials have clearly demonstrated the benefits of statin therapy. A recent metaanalysis of 10 placebo-controlled trials that included approximately 16,000 patients with diabetes and 54,000 without diabetes demonstrated a 30% reduction in coronary heart disease, a 19% reduction in strokes, and a 12% reduction in mortality.54 Furthermore, in another meta-analysis of 14 trials, a similar 22% reduction in coronary heart disease was noted in people with diabetes whether or not they had a history of cardiovascular disease.55
Therefore, aggressive treatment of lipid abnormalities with statins as primary treatment has generally been adopted as a standard of care in diabetic patients, particularly those with clinical cardiovascular disease or one or more risk factors. The Adult Treatment Panel III guidelines recommend a minimum LDL-C goal of less than 100 mg/dL and a goal of less than 70 mg/dL as an option for patients with diabetes (Table 1).41,62 Similar recommendations have been issued by the American Diabetes Association together with the American College of Cardiology (Table 2),30 the American Diabetes Association by itself,63 and the American Academy of Pediatrics.6
Is new-onset diabetes as dangerous as established diabetes?
In studies to date, there did not appear to be more events in those who developed new-onset diabetes.
Waters et al,24 evaluating three trials of high-dose atorvastatin therapy, found that major cardiovascular events occurred in 11.3% of those with new-onset diabetes, 10.8% of those without new-onset diabetes (HR 1.02, 95% CI 0.77–1.35), and 17.5% of those who had diabetes at baseline.
Therefore, it may not be appropriate to extrapolate the glucose changes seen on statin therapy to an equivalent increase in adverse cardiovascular events as seen in other diabetic patients. The beneficial reduction in cardiovascular events does not appear to be diminished in those developing diabetes. It is not clear that the increase in glucose on statins has the same implications of a new diagnosis of diabetes. Does this elevation in glucose represent true diabetes or some downstream effect? For example, thiazide diuretics have been known to increase blood glucose levels, but the levels drop when these drugs are discontinued, even after many years of treatment.
On the other hand, it is possible that follow-up of 5 years or less in clinical trials has not allowed sufficient time to examine the influence of the increase in new-onset diabetes on future cardiovascular events. In addition, because of the widespread use of statins across a broad range of cardiovascular risk, even if the effect is small in absolute terms, the potential adverse effects are magnified, particularly in a low-risk population in which the cardiovascular benefits are smaller.
The association is real, but questions remain
In view of the evidence, it is difficult to refute that an association exits between statin use and new-onset diabetes, at least in some subgroups. The dose response noted in some studies further reinforces the conclusion that the association is real. However, many questions remain unanswered regarding mechanism of effect, whether there are differences depending on the particular statin or dose used, or differential effects in the populations treated (such as patients with metabolic syndrome or the elderly).
Until the contradictory observations can be resolved and plausible mechanisms of action elucidated, causality cannot be established. From a clinical standpoint there is no current evidence suggesting that the elevations in blood glucose seen while on lipid-lowering or blood-pressure-lowering therapy are associated with an increased risk of cardiovascular events or that they attenuate the beneficial effects of the therapy.
Statins should continue to be used in patients at high risk
Until further studies are done, statins should continue to be used, after assessing the risks and the benefits.
Primary prevention patients at moderate to high risk and secondary prevention patients stand to gain from statin therapy, and it should not be denied or doses reduced on the basis of concerns about the development of new-onset diabetes. The recognized modest risk of developing diabetes does not appear to blunt the cardioprotective effects of statin therapy in these moderate-to high-risk groups.
Rather than stop statins in patients at risk of diabetes such as the elderly or those with prediabetes, insulin resistance, or metabolic syndrome who are on therapy for appropriate reasons, it is reasonable to continue these drugs, monitoring glucose more closely and emphasizing the importance of weight reduction, diet, and aerobic exercise for preventing diabetes. The Diabetes Prevention Program Research Group, for example, reduced the incidence of diabetes by 58% over 2.8 years of follow-up with intensive lifestyle interventions (a low-calorie, low-fat diet plus moderate physical activity 150 minutes per week) vs usual care in at-risk populations.65
Should statins be used more cautiously in patients at lower risk?
The most recent Cholesterol Treatment Trialists meta-analysis of 27 randomized clinical trials (22 placebo-controlled, 134,537 people; 5 high-dose vs low-dose, 39,612 people) reported that reducing LDL-C with statins lowered cardiovascular risk even in low-risk patients.66 Overall, there were 21% fewer major cardiovascular events (coronary heart disease, stroke, or coronary revascularization) for every 1-mmol/L reduction in LDL-C.
The proportional reduction in events was at least as large in the two lowest-risk groups (estimated 5-year risk of < 5% and 5% to < 10%, 53,152 people) as in the higher-risk groups. This was reflected mainly in fewer nonfatal myocardial infarctions and coronary revascularizations. In these groups, the absolute reduction in risk for each 1-mmol/L reduction in LDL-C was 11 per 1,000 patients over 5 years. Even in this low-risk population, the reduction in cardiovascular risk seems to compare favorably with the small estimated increase risk of diabetes.
However, even in the lowest-risk group studied, the average baseline LDL-C level was greater than 130 mg/dL.
Therefore, in groups in which the benefits of statins on cardiovascular risk reduction are less robust (eg, low-risk primary prevention groups without significant elevations in LDLC, particularly the elderly), it would not be difficult to justify the case for more cautious use of statin therapy. If statins are used in these low-risk groups, restricting their use to those with at least moderate LDL-C elevation, using less aggressive LDL-C-lowering targets, and regular monitoring of fasting glucose seem reasonable until further information is available.