Endocrinology Metabolism

Diabetes and Lipid Management

Diagnosis of Cholesterol Issues in the Diabetic Patient

In the patient with diabetes mellitus (DM), the diabetes itself is a well-established coronary risk equivalent, with a risk of a coronary heart disease (CHD) event greater than 20% in 10 years. Coronary artery disease (CAD) is the leading cause of death in patients with diabetes over the age of 35. It is critical to view the control of lipids to be as important as blood glucose and blood pressure management in these patients. Over time, studies such as the CARE trial and the Heart Protection Study have shown benefit with aggressive lipid control in the diabetic population.

Women with type 2 DM appear to lose the "protection" that is seen in age-controlled nondiabetic women. Patients with DM have a 50% greater in-hospital mortality, and a two-fold increased rate of death within 2 years of surviving a myocardial infarction (MI). Although much of this increased risk is due to established risk factors for CAD, a significant proportion remains unexplained. Patients with DM, particularly those with type 2 DM, have abnormalities of plasma lipids and lipoprotein concentrations that are less commonly present in nondiabetics. This has been called diabetic dyslipidemia.

The Third Report of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III) noted other coronary risk equivalents including: symptomatic carotid artery disease, peripheral artery disease, abdominal aortic aneurysm, and multiple risk factors that confer a 10-year risk of CHD >20 percent. The ATP-III guidelines recommended the use of statin therapy for primary prevention in patients on the basis of LDL cholesterol and the 10-year risk of CAD based on the Framingham risk calculator.

The 2013 guidelines of the American College of Cardiology and the American Heart Association (ACC-AHA) for the treatment of cholesterol expanded the indications for statin therapy for the prevention of cardiovascular disease. These guidelines differ from the ATP guidelines, primarily looking at the 10-year risk for CAD as opposed to primarily looking at LDL levels to guide therapy. For patients with known CAD, it expands treatment to all patients. The current standards of medical care for diabetes from the American Diabetes Association uses the same recommendations.

The ADA recommends that treatment should include lifestyle modification, focusing on reduced intake of saturated fat, trans fat, cholesterol, increased intake of omega-3 fatty acids, viscous fiber, plant stenols/sterols, weight loss (if indicated), and increased physical activity. Diet and exercise modifications should be recommended to all patients. Studies have shown up to a 30% reduction in LDL in 6 months with lifestyle changes. The role of the nutritionist in the diabetes education team is critical and has a great influence on diet-directed goals for treatment.

The traditional lipid markers include total cholesterol (TC), high density lipoprotein (HDL-C) and triglycerides (TGs). The low density lipoprotein (LDL-C) can be calculated from these values. The total cholesterol and the HDL can be obtained in the fasting or non fasting state as there is little variability in them related to meals. Triglycerides are much more impacted by the postprandial state and should be obtained in the fasting state. When the LDL is calculated, it is done with the Friedewald formula: LDL-C = Total cholesterol - Very low density lipoprotein cholesterol (VLDL-C) - HDL-C . This calculation is not accurate with TG >400 mg/dL, and in these cases would need to be directly measured. When measuring fasting lipids, a 12-hour fast is recommended.

The role of evaluating non-HDL cholesterol has evolved as a factor to be considered as important as LDL cholesterol in the role of assessing cardiac risk. This measurement is the difference between the total cholesterol and HDL cholesterol. This includes all the particles that are considered atherogenic including VLDL, intermediate density lipoprotein (IDL) and LDL.

In the Lipid Research Clinics Program, the LDL-C fraction was a slightly weaker predictor of cardiovascular death than the non-HDL-C fraction. ATP III identifies the non-HDL-C concentration as a secondary target of therapy in people who have high triglycerides. The goal for non-HDL-C is a concentration that is 30 mg/dL higher than that for LDL-C.

Markers like apolipoprotein B have limited use in the population at large, but may be helpful in a subset of patients with type 2 diabetes and high cardiometabolic risk. LDL cholesterol levels may not accurately reflect the number of LDL particles, particularly in patients with small LDL size. There is a strong association between LDL particles and cardiovascular disease. Studies have shown that higher LDL particle number is consistently associated with increased cardiovascular risk.

However, measuring LDL subfractions and size do not add risk prediction beyond what is noted with traditional risk factors, in most patients. The 2010 American College of Cardiology Foundation/American Heart Association guideline for the assessment of cardiovascular risk in asymptomatic adults does not recommend the use of this testing in assessing risk.

C-reactive protein (CRP) has become the most studied of the inflammatory markers associated with atherosclerosis. High sensitivity CRP (hs-CRP) assays are used to assess cardiovascular risk. These correlate with risk factors such as diabetes. Consider hs-CRP testing in patients with intermediate cardiovascular risk by the Framingham risk score. Increased CRP correlates with the presence of cardiovascular risk factors and may reflect the effect of these to vascular inflammation.

Strategy for Treatment

As noted above, the goals for therapy have changed since the ATP III guidelines first appeared. There is a general consensus over the use of the ACC AHA recommendations for statin and combination therapy.

Patients with diabetes are evaluated as to treatment and intensity of treatment by two primary factors: age and presence of risk factors for atherosclerotic cardiovascular disease (ASCVD) or the presence of ASCVD. ASCVD risk factors include LDL cholesterol > or = to 100 mg/dl, high blood pressure, smoking, chronic kidney disease, albuminuria, and family history of premature ASCVD. Table I is adapted from the current standards of medical care for diabetes from the American Diabetes Association.

Table I.

Current standards of medical care for diabetes from the American Diabetes Association.

The ADA guidelines are in keeping with the ACC-AHA recommendations. As per the guidelines, in diabetics not on statins, screening for lipid disorders is recommended at the time of diagnosis, at initial medical evaluation and every 5 years thereafter, or more frequently if indicated.

To improve the lipid profile in diabetics, a strong emphasis is placed on lifestyle changes, which include weight loss (if indicated), increased physical activity, reduced intake of saturated/trans fat and cholesterol; as well as increased intake of omega-3 fatty acids, viscous fiber and plant stanols/sterols.

In addition to the lifestyle modifications, all diabetics with ASCVD and individuals under 40 years of age with ASCVD risk factors should be on a statin. While over the age of 40 years, all diabetics should be initiated on statin therapy, with the intensity of therapy based on ASCVD risk factors (LDL-C >/= 100 mg/dL, high blood pressure, smoking, obesity/overweight individuals, family history of premature ASCVD). Patients between the ages 40-75 without ASCVD risk factors can be placed on moderate intensity statins, while those with positive risk factors may fare better with high intensity therapy. Similarly, patients over 75, irrespective of their ASCVD can be started on either high or moderate intensity statins, tailoring therapy based on their response.

Even in the absence of weight loss, dietary changes can improve total cholesterol, triglycerides, and LDL levels. Fibrate therapy can be helpful when the low HDL is concurrent with a high TG level, but there is an increased risk of muscle toxicity. These drugs can increase HDL by up to 20%. Nicotinic acid is the most effective for high-risk patients who have a primary low HDL-cholesterol. Studies have shown increases in HDL by up to 30%. The combination of gemfibrozil and nicotinic acid can potentially raise HDL-cholesterol by as much as 45%.

Fibrate therapy can be helpful when the low HDL is concurrent with a high TG level, but there is an increased risk of muscle toxicity. These drugs can increase HDL by up to 20%. Nicotinic acid is the most effective for high-risk patients who have a primary low HDL-cholesterol. Studies have shown increases in HDL by up to 30%. The combination of gemfibrozil and nicotinic acid can potentially raise HDL-cholesterol by as much as 45%.

Medical therapy is needed in most patients to reach the current lipid goals. Lipid-reducing drugs include statins, fibric acid derivatives, bile acid sequestrants, nicotinic acid, and cholesterol absorption inhibitors. The choice of drug is dependent on the individual patient lipid abnormality. The statins have shown improvements in overall mortality in primary and secondary prevention. Based on this data, statins are the first choice in patients with LDL hypercholesterolemia, with the goal of reduction in primary or secondary cardiovascular risk.

The statins can produce an LDL-C reduction of 20% to 60%. The less potent statins such as pravastatin and lovastatin can be titrated up for LDL-lowering effect, but still do not reach the lowering seen with the more potent atorvastatin or rosuvastatin. Over time, with more generic statin options, these medications are also becoming more affordable.

The statin drugs work by competitively inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, and by upregulation of LDL receptors. The overall effect is a dramatic lowering of plasma levels of LDL cholesterol. VLDL triglyceride concentrations are also reduced in many subjects with hypertriglyceridemia directly related to the reduction of LDL cholesterol.

In regard to HDL, the directly-targeted HDL therapies have been limited and not successful as they have evolved through the clinical trial process. Low HDL can be seen in a number of scenarios, including familial conditions like familial primary hypoalphalipoproteinemia. It can also be caused by drugs such as beta blockers, anabolic steroids or benzodiazepines. Most commonly, it is found in insulin resistant states such as type 2 diabetes, obesity and hypertension.

Elevated triglycerides are often found in the insulin resistant state. Emerging data has suggested that elevated triglyceride levels are independently associated with coronary risk. The goal of treatment is to decrease this risk. Treatments include weight loss in obese patients, exercise, diet modification, and medication review (hormone-based treatments, etc). In patients with diabetes, strict glycemic control is needed, as well as hypertension and smoking cessation. With triglycerides less than 500 mg/dL, statins can be used as primary therapy. Beyond this level, fibrates can be used.

Results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial have put into question the addition of fenofibrate and niacin respectively as add on therapy to a statin agent. At the very least there was no benefit in the primary analysis. At this time, combination therapy of a statin with niacin is not recommended. Combination therapy of a statin with a fibrate is generally not recommended.

However, in sub-group analyses there may be benefit or harm depending on the subgroup studied. As a result, statin therapy with fenofibrate may be considered in men with a triglyceride level >204 mg/dL and HDL cholesterol level <34 mg/dL. Future studies will need to be performed to determine those individuals who would benefit most from and those who might be harmed by combination therapy with a statin or fibrate or a statin and niacin Additional studies are needed to determine optimal lipid lowering therapy in those patients who cannot tolerate any statin agent.

One new class of agents that may prove to be valuable in patients with diabetes as an add-on to statin therapy or those intolerant of statins are PCSK9 inhibitors. The FOURIER trial demonstrated that in patients taking a statin and having a LDL cholesterol of 70 mg/dl or higher and having ASCVD there was a reduction in the risk of the primary cardiovascular endpoint. Of note about 36% of the patients in this study had diabetes. The data from this trial did not demonstrate an increased risk for developing diabetes in patients who did not have diabetes. However, longer follow-up while on treatment with a PSCK9 inhibitor and evaluation of other agents in this class of drugs for the development of diabetes are still needed.

Monitoring response to statins and safety profile

The method of monitoring the effects of lipid-lowering therapy is not clear. Rather than take a rigid approach to measuring lipid profiles in patients with diabetes, current recommendations suggest that a lipid profile be obtained at the time of diagnosis of diabetes, the initial medical evaluation, and at a minimum every 5 years beyond the initial evaluation. A lipid profile is recommended prior to starting treatment with a statin. The major change in monitoring the effects of lipid lowering therapy is to individualize the testing frequency for LDL cholesterol to the patient rather than set intervals. With statins, lipid levels stabilize within weeks after dose adjustment. Routine monitoring of serum creatine kinase (CK) levels is not recommended in patients on statins. It may be helpful to have a baseline CK level to assess for any change if the patient develops symptoms later on.

The main clinical side effect with the statins is myalgia. The American College of Cardiology/American Heart Association/National Heart, Lung and Blood Institute Advisory defines myopathy as any disease of muscles, myalgia as muscle aching or weakness, myositis as muscle symptoms with increases in CK, and rhabdomyolysis as muscle symptoms with a 10-fold increase in CK, with increases in serum creatinine.

As the statins are still a desirable class to use if able, consider using statins such as pravastatin, which appears to have a lower risk of myalgia/myopathy. Pravastatin is not metabolized by CYP3A4. In patients who do not tolerate any statin and are being treated for secondary prevention, other options include bile acid sequestrants, fenofibrate niacin, and ezetimide. Muscle injury is an important concern, particularly in patients who are also treated with cyclosporine, fibrates, and HIV medications.

Muscle injury is uncommon when statin therapy is used alone, with a frequency of up to 11% for myalgias, 0.5% for myositis, and less than 0.1% for rhabdomyolysis. Patients can have myalgias without an elevation in serum CK. Muscle symptoms can begin within weeks to months after starting the statins. These symptoms are reversible, and myalgias and serum CK usually return to normal over days to weeks after the drug is stopped. Of note, the CK value can also elevate in multiple contexts, including exercise and high impact sports. Patients treated with high doses of potent statins, those who are older, female, have a genetic predisposition all have a higher risk for myopathy particularly when statins are given with drugs that interfere with drug metabolism.

The risk of muscle injury is increased when the drugs are metabolized by cytochrome P-450 3A4 and drugs that interfere with CYP3A4. Grapefruit juice inhibits CYP3A4, and there is an increased risk of muscle injury in renal failure, obstructive liver disease, and hypothyroidism. In patients treated with gemfibrozil who need a statin, pravastatin or fluvastatin are preferred. Fenofibrate is the preferred fibrate in patients who require combined therapy with a statin.

Without clinical symptoms, a CK level >10 times the upper limit of normal is an indication for discontinuing the medication. In patients with moderate symptoms or with a CK elevated to more than 5-fold, the statin should be stopped. Awareness of these issues is key. Fortunately, the more severe manifestations are uncommon, as noted.

Statin intolerance

Cholesterol goals can be met by moving to an alternate statin such as fluvastatin or pravastatin, with careful dose titration when the patient is asymptomatic. There are a number of different options that can be tried to help get the appropriate patient back on a statin if desired.

An alternate more potent statin, given daily or weekly, such as rosuvastatin or atorvastatin, can be attempted. This often requires a lot of counseling with the patient to attempt such a trial. Also, the combination of the lowest tolerated statin with a cholesterol absorption inhibitor or bile acid sequestrant can be attempted. Red yeast rice is an over-the-counter agent with statin-like properties that can also be used, but may also cause myopathy. Some have suggested that if a patient requires a statin and experiences muscle pain while on pravastatin or fluvastatin, a trial of supplementation with CoQ10 at a dose of 150 mg daily may help with the ability to tolerate the statin.

Other Issues

When should you reduce the statin dose because the cholesterol is too low?

This is an interesting and evolving area. Some patients achieve very low LDL-C levels on while on therapy. There is little evidence by which to determine the optimal low limit of LDL-C. In the JUPITER trial, patients on rosuvastatin with LDL less than 50 mg/dL had a slightly higher rate of adverse events than those who did not. Though there is not consistent recommendation, consider reducing the statin dose in patients who have an LDL less than 25 mg/dL.

What is the role of colesevelam (Welchol®)?

Colesevelam is a bile acid sequestrant that lowers LDL cholesterol in patients with primary hypercholesterolemia. In short-term trials, colesevelam reduced A1C levels by 0.4% in patients with type 2 diabetes and poor control with oral agents or insulin. Colesevelam's mechanism of action to improve glycemic control is unknown. One hypothesis is that it reduces gastrointestinal glucose absorption. In contrast to its effects on LDL cholesterol, colesevelam can increase triglyceride concentrations by 20%.

What is the effect of statins on diabetes?

The data on the increased incidence of diabetes with statins has been noted, but data from the JUPITER trial showed that even with increased incidence, those individuals who did develop diabetes did better on a statin. Current data suggests that statin therapy may lead to a small increased risk of developing diabetes, and that the risk is slightly greater with intensive statin therapy than moderate statin therapy. A 2011 meta-analysis of five randomized trials looking at this noted one additional case of diabetes for every 500 patients treated with intensive rather than moderate statin therapy.

The JUPITER study assigned 17,802 healthy patients with LDL-C level < 130 mg/dL and a C-reactive protein > 2.0 mg/L to treatment with rosuvastatin 20 mg daily or placebo. The trial was stopped early for benefit after a follow-up of 1.9 years. Treated patients had lower levels of LDL-C and lower levels of C-reactive protein. Patients treated with rosuvastatin had a slightly higher rate of newly diagnosed diabetes despite these beneficial effects.

As mentioned above, more data is needed to assess if the newly approved class of cholesterol lowering drugs, PSCK9 inhibitors, increase the rate of developing newly diagnosed diabetes. The FOURIER study did not demonstrate an increase rate of developing diabetes in the subjects taking evolocumab.

How does type 1 versus type 2 diabetes compare in regard to the lipid panel?

The patient with type 1 diabetes tends to have a lipid panel that parallels the nondiabetic patient and becomes more abnormal with poor glycemic control. This leads to a high TG and low HDL.

The patient with type 2 diabetes reflects the insulin-resistant state: high LDL, low HDL, high TG. For the same lipid panel, the diabetic patient has more coronary disease compared with the nondiabetic patient.

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