The news out of the United Kingdom in June 2003 was a call to action for people with diabetes and their physicians. Investigators in the Heart Protection Study had reported a year earlier that the drug simvastatin had lowered cholesterol levels in study subjects and reduced the risk of heart attack and stroke by 25%. The researchers then looked at the subgroup of subjects who had diabetes, and published their findings in June 2003.
They found that lowering levels of low-density lipoprotein (LDL) cholesterol (often referred to as “bad” cholesterol) by 39 mg/dl resulted in a 22% reduction in the likelihood of a first heart attack or stroke in people with diabetes. Significant cardiac benefits were found even in people who entered the study with no signs of arterial hardening and those whose LDL levels were within ranges that don’t automatically suggest the need for LDL-lowering drugs. These results led the researchers to conclude their report with a declaration that “statin therapy should now be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol concentrations.”
The relationship between heart disease and the various forms of lipids (blood fats such as cholesterol and triglycerides) was described as early as the 1930’s and confirmed in the Framingham Heart Study in the 1970’s and by many other studies since then. Cholesterol is a key contributor to atherosclerosis, the “hardening of the arteries” that leads to heart disease, stroke, and peripheral vascular disease.
This is particularly important to people with diabetes, in whom atherosclerosis is much more prevalent. 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 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 amputation.
People with diabetes, in particular Type 2 diabetes, have a characteristic dyslipidemia (lipid disorder) that puts them at higher risk of atherosclerosis. They tend to have high blood levels of triglycerides and low levels of high-density lipoprotein (HDL) cholesterol. HDL cholesterol is often referred to as “good” cholesterol, because it appears to protect against atherosclerosis. Although people with diabetes tend to have levels of LDL cholesterol that are the same (or only slightly elevated) as people who don’t have diabetes, their LDL particles are of a different and more dangerous kind.
The LDL particles in people with diabetes are different because they contain more triglycerides. “When you increase the concentration of triglycerides in LDL cholesterol, its structure changes and it becomes a smaller, denser particle,” says Leonard M. Keilson, MD, MPH, a lipids specialist practicing in Portland, Maine. “These dense LDL particles are particularly dangerous, because they can more easily cross the endothelium — the lining of the arteries — and enter the wall of the vessels.” Fatty deposits in arterial walls lead to atherosclerosis.
Diet modification and exercise can help with this dyslipidemia, although Dr. Keilson cautions that they are most effective in people who have metabolic syndrome (a group of problems including cholesterol abnormalities, abdominal obesity, high blood pressure, and insulin resistance that increase the risk of diabetes, heart disease, and stroke) as opposed to full-blown Type 2 diabetes.
“You can ‘convert’ a person with metabolic syndrome to what is essentially a nondiabetic state with diet modification and exercise,” Dr. Keilson says. “In true diabetes, though, the risk of heart disease is profound, and many physicians will go directly to pharmaceutical therapy to give their patients maximum protection.”
Even with the known benefits of diet and exercise and the existence of a variety of medicines, however, many people with diabetes are still at increased risk. At least half of the people with diabetes in the United States have total cholesterol levels above 200 mg/dl, which is the upper limit of the desirable range.
This disturbing report comes from a January 2004 review of data in the National Health and Nutrition Examination Survey 1999–2000. The review found that 51.8% of the people with diabetes in the survey had total cholesterol levels above 200 mg/dl. This was improved from a similar survey conducted between 1988 and 1994, but it means that millions are still above current cholesterol-lowering treatment goals.
The primary focus of dyslipidemia treatment in all people, with diabetes or not, is LDL cholesterol. Overwhelming evidence from clinical trials, experimental animals, laboratory research, and epidemiology points to LDL cholesterol as the form of cholesterol most likely to cause atherosclerosis.
Current standards call for lowering levels of LDL cholesterol below 100 mg/dl for people with known atherosclerosis. Diabetes is now considered a “coronary heart disease risk equivalent,” so people with diabetes are managed as if they already have atherosclerosis.
There are two ways to lower LDL levels: lifestyle changes and drug therapy. The American Diabetes Association (ADA) recommends starting diet and exercise changes if one’s LDL level is over 100 mg/dl and adding drug therapy if it exceeds 130 mg/dl. For people with diabetes who already have cardiovascular disease, however, drug therapy should be started along with lifestyle changes if their LDL levels are above 100 mg/dl.
Observational studies have concluded that people who adopt healthier diets and get more exercise have fewer heart attacks and other such cardiac events. Both diet modification and exercise have been shown to improve the dyslipidemia of diabetes, so by extension they are considered the best first-line treatment.
The ADA calls diet modification “medical nutrition therapy,” or MNT, and the American Heart Association includes it with exercise in what it calls “therapeutic lifestyle changes,” or TLC. Both recommendations call for reducing saturated fat in the diet and replacing it with an increased intake of carbohydrate or monounsaturated fat. Intensively following such a diet has been shown to result in a 15–25 mg/dl reduction in LDL levels.
“Diet and exercise can be expected to reduce LDL levels by no more than about 10%,” Dr. Keilson says. “Appropriate drug therapy, on the other hand, can bring about a 30% to 50% decrease. Exercise and diet are still important, for a variety of reasons, but the risk of heart disease is so high in people with diabetes that most should probably have drug therapy as well.”
Drugs for lowering LDL cholesterol
The first drug of choice to lower LDL cholesterol levels is usually an HMG CoA reductase inhibitor, or “statin.” These drugs, including pravastatin (brand name Pravachol), simvastatin (Zocor), lovastatin (Mevacor), fluvastatin (Lescol), rosuvastatin (Crestor), and atorvastatin (Lipitor), are well tolerated with few short-term or long-term side effects. The Heart Protection Study used simvastatin and reduced cardiovascular events by 25% in people with diabetes. (The authors of the study note that the 25% reduction was observed in people who didn’t always take their statin properly; taking simvastatin as prescribed 100% of the time, they predict, could reduce cardiac events by 33%.) 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%. Statins also have the bonus effect of lowering triglycerides as much as 35% and raising HDL levels 10%. The newest statin, rosuvastatin, appears to be the most powerful of all, with significantly greater effect on all the lipids than other members of the family.
There are consistent, though uncommon, reports of muscle weakness and aches in people taking statins, though the incidence has been the same in clinical trial participants taking placebos. One in every thousand people taking a statin develops a condition called myositis, with an elevated level of the muscle enzyme creatine kinase (CPK) accompanying the muscle aches. Rarer still, about one in every 10,000 people taking a statin progresses to serious muscle disease and acute kidney failure, although the early signal from raised CPK levels should give plenty of time to stop therapy before that happens.
The benefits of statins nonetheless far outweigh the rare serious side effects, according to a clinical advisory from the American College of Cardiology, the American Heart Association, and the National Heart, Lung, and Blood Institute.
“Given a one-in-five chance of heart disease in diabetes,” Dr. Keilson says, “the one-in-10,000 chance of serious side effects from the statins shouldn’t keep anyone from reaping the benefits of the therapy.”
A five-year study funded by the National Institutes of Health comparing the side effects of simvastatin and pravastatin against placebo is due to be completed this year. The $5 million study is investigating issues such as muscle pains and anecdotal reports of cognitive dysfunction in people taking statins.
Alternative LDL-lowering drugs include the bile acid sequestrants, such as cholestyramine (Questran, Questran Light) and colestipol (Colestid). These drugs lower LDL cholesterol and have few serious side effects, though they have been associated with bothersome gastrointestinal side effects. Some may also find cholestyramine and some forms of colestipol unpalatable because they are powders or granules that must be mixed with water. (A tablet form of colestipol is available.) A newer drug in this class, colesevelam (WelChol), comes in tablet form and may be better tolerated and as effective as its predecessors.
The bile acid sequestrants can raise triglyceride levels, so in a person with high triglycerides, nicotinic acid, or niacin, is sometimes used instead because it has been shown to decrease levels of LDL cholesterol and triglycerides and to raise levels of HDL cholesterol. The Coronary Drug Project examined the benefits of niacin in people who had had heart attacks and found an 11% lower mortality after 15 years. The side effects of therapeutic niacin treatment include flushing, gastrointestinal upset, and liver damage. Flushing can be reduced by using extended-release (Niaspan) or sustained-release formulations of niacin, but risks of liver damage increase with use of sustained-release (but not extended-release) niacin.
Niacin can also cause high blood glucose levels in some people, so there has been concern about using it in people with diabetes. However, a study published in 2000 concluded that niacin could be safely used in people with diabetes, increasing HDL levels by 29% while lowering LDL levels by 8% and triglycerides by 23%. Current guidelines for people with diabetes allow for its use with mindfulness of the potential side effects.
Ezetimibe (Zetia) is the first in a new class of drugs called cholesterol absorption inhibitors. In clinical trials, it has significantly lowered LDL levels and moderately lowered triglyceride levels and raised HDL levels. Ezetimibe is much better tolerated than the bile acid sequestrants and may ultimately replace them in routine therapy.
Once LDL levels are brought under control, the next step is to address elevated triglyceride levels. The drugs of choice for this therapy are the fibrates: gemfibrozil (Lopid), clofibrate, and fenofibrate (Lofibra, Tricor). In addition to lowering triglycerides, they also moderately lower LDL cholesterol and can change the size of LDL particles from the small, dense type that is more likely to cause atherosclerosis to a larger type. The most common side effects of the fibrates are primarily gastrointestinal symptoms.
The Helsinki Heart Study of gemfibrozil demonstrated a 10% drop in total cholesterol, an 11% drop in LDL, a 35% drop in triglycerides, and an 11% increase in HDL. The Diabetes Atherosclerosis Intervention Study (DAIS) used fenofibrate therapy and measured the progress of atherosclerosis using angiography, documenting a 40% reduction in the progress of the disease.
Other triglyceride-lowering agents include fish oils that have high levels of omega-3 fatty acids. In addition to lowering triglycerides, omega-3 fatty acids also help reduce blood clotting and improve other facets of heart function. Flaxseed oil is also rich in omega-3 fatty acids and has the advantage of not having a fishy taste.
The role of diabetes drugs
There are a number of drugs that are often prescribed for people with diabetes for other purposes but which have some positive effect on lipids as well. Since people with diabetes may be taking these medicines anyway, Dr. Keilson feels they can be an important part of the management of dyslipidemia.
The thiazolidinediones (TZDs), rosiglitazone (Avandia) and pioglitazone (Actos), are used primarily to reduce the insulin resistance common in Type 2 diabetes. In people taking a TZD, the size of LDL particles increases, and HDL levels rise. Pioglitazone also lowers triglyceride levels, but rosiglitazone raises LDL levels.
The primary side effects of the TZDs are weight gain and fluid retention. The American Heart Association and the ADA have recommended caution in using them in people with congestive heart failure or risk factors for it and additionally recommend that they not be used in people with advanced congestive heart failure.
At higher doses, metformin (Glucophage, Glucophage XR) is able to reduce total cholesterol levels. Metformin is also linked to some weight loss, which can have a beneficial effect on lipids.
Acarbose (Precose) is used primarily to slow the absorption of complex starches in the intestine, helping to reduce high blood glucose levels after a meal. It also appears to lower LDL levels and raise HDL levels in the process. The evidence for lipid benefits from miglitol (Glyset), which is in the same drug class as acarbose, is inconclusive.
The anti-obesity drugs orlistat (Xenical) and sibutramine (Meridia) are primarily used for weight loss but may have positive effects on blood lipids as well. Orlistat blocks the enzymes that break down fat in food, preventing as much as 30% of the fat from being absorbed. Treatment with orlistat has produced statistically significant lowering of total cholesterol, LDL cholesterol, and triglycerides in a clinical trial.
Sibutramine works through the central nervous system to suppress appetite. The Sibutramine Trial of Obesity Reduction and Maintenance (STORM) found that in addition to its weight-loss benefits, sibutramine lowered levels of triglycerides and increased levels of HDL cholesterol.
The complex dyslipidemia of diabetes often calls for a combination of drugs to achieve target levels of cholesterol. Most common are combinations of statins, which are effective for lowering LDL levels, with other drugs that address high triglycerides and low HDL levels.
“If you have a person with a low LDL level but who has high triglycerides and a low HDL level,” Dr. Keilson says, “you need to treat him differently than a person with high LDL levels. You can attempt to control his problem with more intensive blood sugar control, which will lower triglycerides, and with dietary modifications that reduce carbohydrates. After that, the next step would be to add a fibrate, fish oil or flaxseed oil, or niacin. The addition of ezetimibe to statin therapy may be especially helpful in raising HDL levels.”
In one study that added ezetimibe to statin therapy, for instance, LDL levels were reduced, HDL levels were increased, and triglyceride levels were lowered compared to statin plus placebo therapy.
Combination therapy also can have an additive effect on lowering LDL levels. The addition of the bile acid sequestrant colesevelam to statin therapy has been shown to result in an 8% to 12% greater reduction in LDL levels than statin therapy alone.
Niacin is also used with statin therapy, because the two drugs have complementary effects. A combination drug that contained both extended-release niacin and lovastatin (Advicor) was put to the test against atorvastatin and simvastatin in the Advicor Versus Other Cholesterol-modulating Agents Trial Evaluation (ADVOCATE). The combination drug lowered LDL levels, increased HDL levels, and decreased triglyceride levels better than atorvastatin or simvastatin alone.
Niacin plus statin combination therapy was also explored in the HDL-Atherosclerosis Treatment Study (HATS). Subjects who had already had coronary artery disease were given either placebo or niacin and simvastatin, with or without antioxidant vitamins. The group on niacin and simvastatin that did not receive antioxidants achieved a 42% reduction in LDL levels, a 36% decrease in triglycerides, a 26% increase in HDL levels, and a 90% reduction in coronary events. (The group taking antioxidants with niacin and simvastatin had slightly lesser improvements in cholesterol, but more important, the reduction in cardiovascular events disappeared.) LDL levels in the placebo groups were unchanged.
The goal of lipid therapy in diabetes is to return the levels of all lipids to as close to normal as possible. (See “Metabolic Sydrome and Lipid Goals.”) It is achievable in nearly every person, and the arsenal of drugs that can add to the benefits of diet and exercise is growing steadily.