Evidence Mounts for Even Lower LDL
We all know that a lower cholesterol level is better, especially if you have diabetes. The most recent American Diabetes Association (ADA) guidelines recommend that people with diabetes maintain a low-density lipoprotein (LDL, or “bad”) cholesterol level below 100 mg/dl. There’s new evidence, though, that even lower levels offer even more protection.
Three recent studies indicate that intensive treatment of high LDL cholesterol with “statin” drugs lowers the risk of cardiovascular events (such as heart attacks and strokes) significantly. The subjects in the three clinical trials were given statins sufficient to lower their LDL levels as low as 54 mg/dl. LDL cholesterol is a key contributor to atherosclerosis, the “hardening of the arteries” that leads to heart disease, stroke, and peripheral vascular disease.
The latest word
The study known as the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) trial compared a regimen of 40 milligrams (mg) of pravastatin daily (the standard therapy) with a more intensive regimen of atorvastatin at 80 mg a day. The participants in the study had already been diagnosed with an acute coronary syndrome (such as a heart attack), so this was a secondary prevention trial.
Those participants who reached LDL levels of 70 mg/dl or lower had significantly lower rates of second cardiac events. Among elderly participants, there was an 8% absolute lower risk of events and a 40% lower risk relative to those who did not achieve the target LDL levels. In younger people, the corresponding values were 2.3% and 26%.
The Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial was similar in design, comparing a standard 20-mg-per-day dose of simvastatin to 80 mg per day of atorvastatin. The people in this secondary prevention trial had experienced a previous heart attack.
Participants on the more intensive atorvastatin therapy had an 11% reduction in relative risk of coronary death, heart attack, or cardiac arrest with resuscitation. This was not considered statistically significant, but there was a statistically significant reduction of 17% in nonfatal heart attacks.
The largest of the recent trials was the Treating to New Targets (TNT) study, which enrolled 10,000 people in 14 countries who had previously had a heart attack, had previous or current angina (chest pain associated with insufficient oxygen reaching the heart muscle), or had previously had a coronary bypass or angioplasty procedure. The participants were given either a moderate, 10-mg-per-day dose of atorvastatin or an 80-mg-per-day dose.
At the end of the five-year study, participants on the higher dose of atorvastatin had a reduction of 22% in cardiovascular death, heart attack, and stroke.
The diabetes connection
These studies were all focused on secondary prevention—that is, preventing more events in people who had already had a heart attack or other problem. So why are they relevant to people with diabetes who have not had a cardiac event?
Atherosclerosis is much more prevalent in people with diabetes, especially Type 2 diabetes, who have a characteristic profile of blood fats, or “lipids,” that puts them at higher risk. They tend to have low levels of high-density lipoprotein (HDL) cholesterol, often referred to as “good” cholesterol, because it appears to protect against atherosclerosis, and high levels of triglycerides (another form of blood fat).
There is a third very important feature to the “lipid profile” typical in Type 2 diabetes and also in the metabolic syndrome. Levels of LDL cholesterol (often referred to as “bad” cholesterol) are generally the same as those in the general population or only slightly elevated in people with diabetes, but it is a different kind of LDL. The concentrations of triglycerides in LDL cholesterol change it to a smaller, denser particle. Being smaller, these particles can more easily cross the endothelium—the lining of the arteries—and enter the walls of the vessels.
Three-quarters of people with diabetes will die of complications that arise from atherosclerosis. They have a 2–4 times higher risk of heart attack and stroke, and are more likely to die in the hospital while undergoing a cardiac procedure. They also do less well following a heart attack or surgery. Atherosclerosis in the peripheral circulation, primarily in the arteries of the legs, is 2–4 times more likely in people with diabetes. This can lead to dangerous clots, pain, and the need for amputation.
The growing understanding of the higher cardiac risk for people with diabetes has been reflected in the treatment guidelines published by the ADA, the National Cholesterol Education Program, and the American College of Physicians. In the 1990’s, for instance, ADA guidelines called for medication management if LDL levels were above 130 mg/dl. Current guidelines suggest starting lipid-lowering medicines for LDL levels above 100 mg/dl, and a target of less than 70 mg/dl if the person is known to have heart disease.
The National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines, published in 2004, call diabetes a “coronary heart disease risk equivalent.” People with diabetes carry an absolute risk of cardiac events similar to that of people without diabetes but with established heart disease. The NCEP recommends that people with diabetes be managed as if they already had known coronary artery disease.
Two follow-up studies using the TNT study reinforce this approach. The studies focused on those participants who had diabetes and those who had metabolic syndrome (a cluster of conditions that raises the risk of developing diabetes).
The first study examined the results for the 1,501 participants who had diabetes. At the end of the nearly five years of the study, their mean LDL levels were 98.6 mg/dl in the regular treatment group and 77 mg/dl in the intensive treatment group.
There was a higher incidence of cardiovascular events among the people with diabetes compared with those who didn’t have diabetes. However, the participants with diabetes on intensive atorvastatin therapy experienced a 25% reduction in the rate of major cardiovascular events compared with participants with diabetes on the regular therapy. So while the risk of the people with diabetes on the intensive therapy was still greater than that of the people who didn’t have diabetes, they experienced a similar reduction in their risk.
Of particular note was that the incidence of first stroke was reduced in the intensive-therapy group, and that risks were reduced for all in the intensive group, regardless of their level of blood glucose control (although those with a glycosylated hemoglobin [HbA1c] value of 7% or lower saw additional risk reduction).
The second study examined TNT participants who had metabolic syndrome, including most of the participants with diabetes. Metabolic syndrome is defined as having at least three of the following: a body-mass index above 28, a fasting plasma glucose over 100 mg/dl, an HDL cholesterol level lower than 40 mg/dl for men and lower than 50 mg/dl for women, a blood pressure at or higher than 135/85 mm Hg, a triglyceride level at or over 150 mg/dl.
As with the previous study of participants with diabetes, those with metabolic syndrome experienced a significant—29%—reduction in risk of major cardiovascular events. In fact, their risk reduction was 7 percentage points greater than that of the overall group.
This study’s authors noted that more than half of the TNT study participants met the criteria for metabolic syndrome. The data from the study shows that they had a 44% increase in absolute risk of major cardiovascular events compared to those without metabolic syndrome, and that those with diabetes were at the highest risk.
Statins and LDL
The trials mentioned here were all conducted with a particular class of drug, the HMG-CoA reductase inhibitors, or “statins.” These include pravastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, and atorvastatin. There is good reason for investigating these drugs, given their dramatic effect on LDL cholesterol. They are the drugs of choice for reducing the risk of heart disease. In fact, an editorial in the prestigious New England Journal of Medicine suggested that “if ever there were a perfect marriage of drug with disease, it might be between statins and atherosclerosis.”
Early studies of the statins established their usefulness in people with diabetes with dramatic reductions in cardiovascular events. The Heart Protection Study, for instance, used simvastatin and reduced cardiovascular events by about 25% in people with diabetes. Trials of the other statins have had similarly convincing results, with mean reductions in cholesterol of 20%, average reductions in the incidence of coronary artery disease of 30%, and average reductions in mortality of 29%.
The statins also have the bonus effect of lowering triglycerides and raising HDL levels.
There has been concern about the safety of statins because of consistent though rare reports of muscle weakness and aches in people taking statins. The National Lipid Association created a Statin Safety Task Force to investigate the issue, and its report was published in 2006. The authors concluded their review of clinical trials, published case studies, and voluntary notification to regulatory agencies with the statement that “by any standard, statins are remarkably safe drugs.”
Rhabdomyolysis, a breakdown of muscle fibers, was reported to be low in people taking simvastatin, lovastatin, atorvastatin, pravastatin, or fluvastatin, with an estimated incidence of from 3 to a maximum of 7 cases per 100,000 person-years. A more serious muscle condition, myopathy, was attributed to statins at a rate of 11 per 100,000 person-years. The drugs rarely if ever cause liver disease, and no link could be found to kidney disease or cognitive decline. They may cause peripheral neuropathy, a nerve disease that primarily affects the lower limbs, but only at a rate of 12 per 100,000 person-years. (“Person-years” are calculated by adding up the number of years each person in a study or a population has taken a particular drug. For example, if 100 people take drug A for 10 years each, a study of these people would cover 1,000 person-years.)
Blood tests can monitor the development of the muscle-related disorders and provide early warning of developing problems.
There are other drugs to bring down LDL cholesterol levels, though none is as popular as the statins. Bile acid sequestrants such as cholestyramine, colestipol, and colesevelam modestly lower LDL levels but can have gastrointestinal side effects. Nicotinic acid, or niacin, similarly has a modest effect on LDL levels. Both can be used in combination with statins. In one study, simvastatin and niacin reduced LDL levels by 42%, increased HDL levels by 26%, and reduced coronary events by 90%.
A new target for treatment?
Recent research suggests that the benefits of statins may not be entirely due to their effect on LDL levels. Statin therapy is most effective, it seems, when levels of a particular marker of inflammation are higher. C-reactive protein (CRP) is a sign of inflammation, and it appears to play a role in heart disease. It is thought that statins have anti-inflammatory properties, offering protection particularly to the blood vessel walls that are damaged by inflammation in the development of atherosclerosis.
A research team using data from the PROVE IT–TIMI 22 study found that not only did those who reached LDL levels below 70 mg/dl have fewer cardiovascular events, but that those who had CRP levels below 2 mg/l (milligrams per liter) also had fewer cardiovascular events, and to the same degree of difference. What’s more, the association of lower CRP values and fewer events was detected regardless of the person’s LDL level. Lowering CRP values with statins, therefore, was independently associated with decreased risk.
The authors are careful to point out that these findings should not be generalized from their study population—people who had already been diagnosed with an acute coronary syndrome—to people who have not received such a diagnosis.
However, if diabetes is considered a coronary heart disease equivalent, it might be logical to suggest that, as the earlier studies found, people with diabetes should consider intensive statin therapy.
The question might be answered for all people in a few years. The JUPITER trial will recruit 15,000 people who do not have heart disease but do have elevated CRP levels. The study will determine if rosuvastatin therapy will prevent heart disease in this population.
Lipids are not the only risk factor for heart disease, of course. Care guidelines from the American Diabetes Association also recommend keeping blood pressure under 130 systolic and 80 diastolic (130/80 mm Hg), and starting medication if it exceeds 140 systolic or 90 diastolic. Several classes of drugs used to lower blood pressure have been shown to reduce cardiac events in people with diabetes, including ACE inhibitors, angiotensin receptor blockers (ARB’s), diuretics, and calcium channel blockers.
Antiplatelet therapy, using aspirin or another drug such as clopidogrel, is also recommended for many people with diabetes. These medicines help prevent the blood clots that cause heart attacks, and aspirin is recommended for people with diabetes over the age of 40, or those under 40 who have additional risk factors such as family history and high cholesterol levels.
Finally, the recommendations advise all people with diabetes to not smoke cigarettes. Smoking is associated with a number of health problems, including heart disease.
