Dyslipidemia in diabetes mellitus
Are You Sure the Patient Has Dyslipidemia?
In general lipid disorders do not cause any symptoms. The diagnosis is dependent on laboratory testing. The main exception is the chylomicronemia syndrome, which is characterized by marked elevations in serum triglyceride levels (>1000mg/dl). In this syndrome patients can develop a skin rash, eruptive xanthoma, which is typically located over the buttocks, shoulders, and extensor surfaces of the extremities. The skin lesions appear as white to yellow papules with an erythematous base. They often appear suddenly in association with marked increases in serum triglyceride levels.
The chylomicronemia syndrome can also cause abdominal pain that may be due to pancreatitis. Hyperlipidemias lead to an increased risk of cardiovascular disease and the cardiovascular disease can result in the typical symptoms associated with cardiovascular disease.
In general lipid disorders do not cause any abnormalities on physical examination. The main exception is the chylomicronemia syndrome which can cause eruptive xanthoma, which appears as 1-5mm white to yellow papules with an erythematous base located over the buttocks, shoulders, and extensor surfaces of the extremities. Lipemia retinalis is seen when serum triglyceride levels are greater than 1000- 2000mg/dl and is characterized by retinal arteries and veins having a pink color on fundoscopic examination. Lipid disorders can also cause a number of other types of xanthomas (for example tendonous xanthomas) but these lesions are not induced by or related to the diabetes.
Lipid disorders are diagnosed by laboratory testing. In patients with Type 1 diabetes in good glycemic control the lipid profile is very similar to that seen in the general population. Poor glycemic control in patients with Type 1 diabetes can result in marked increases in serum triglyceride, Very Low Density Lipoprotein (VLDL), and Intermediate Density Lipoprotein (IDL) levels. Poor glycemic control also can lead to a decrease in High Density Lipoprotein (HDL). Very poor glycemic control can result in an increase in Low Density Lipoprotein (LDL), which because of the increase in triglycerides is usually due to an increase in the small dense LDL subfraction.
In patients with Type 1 diabetes Lipoprotein (a) (Lp(a)) levels are frequently elevated and improvements in glycemic control lead to a decrease. Renal disease and microalbuminuria are associated with increases in Lp(a) levels.
In patients with Type 2 diabetes abnormalities in serum lipid levels are frequently observed even when they have good glycemic control. Patients with Type 2 diabetes typically have an increase in serum triglycerides, VLDL, and IDL and a decrease in HDL. Additionally, there is an increase in small dense LDL, a lipoprotein particle that may be particularly atherogenic. The lipid abnormalities that are seen in patients with type 2 diabetes are the same lipid abnormalities that characterize patients with the metabolic syndrome (insulin resistance syndrome; obesity syndrome). Poor glycemic control will exacerbate these abnormalities leading to further increases in serum triglycerides, decreases in HDL, and if severe enough, increases in LDL levels. In patients with Type 2 diabetes Lp(a) levels are usually within the normal range and are not altered by changes in glycemic control. However, renal disease or microalbuminuria can result in an increase in Lp(a) levels.
In diabetic patients with poor glycemic control the chylomicronemia syndrome may develop if they have an underlying genetic abnormality in triglyceride metabolism, which predisposes them to marked elevations in serum triglyceride levels. One such abnormality is heterozygosity for mutations in the enzyme lipoprotein lipase. The chylomicronemia syndrome is characterized by marked elevations in serum triglycerides (>1000mg/dl) and chylomicrons. The blood can appear pink and the plasma turbid. If the plasma is incubated overnight in the refrigerator a cream layer may be seen at the top.
Several of the drugs used to lower glucose levels also have effects on serum lipid levels. Insulin, sulfonylureas, meglinitides, DPP4 inhibitors, and alpha glucosidase inhibitors do not typically effect serum lipid levels beyond the effects that are seen with improved glucose control (predominantly decrease in serum triglycerides). In contrast, metformin and thiazolidinediones have effects on serum lipid levels that are independent of their effects on glucose metabolism. Metformin typically lowers serum triglyceride and LDL levels without effecting HDL.
Pioglitazone, the only thiazolidinedione (TZD) currently widely available in the US, lowers serum triglyceride levels and raises HDL. However, pioglitazone also increases LDL levels but the density of the LDL increases (i.e. a shift from small dense LDL to large buoyant LDL). Glucagon Like Protein-1 (GLP-1) analogues can favorable effect serum lipid levels by inducing weight loss (decreased triglycerides and increased HDL). Finally, SGLT2 inhibitors increase LDL and HDL levels.
What Else Could the Patient Have?
Many factors in addition to diabetes effect serum lipid levels. Genetic factors are very important and there is a number of mutations and polymorphisms that lead to profound alterations in serum lipid levels. For example mutations in the LDL receptor can result in marked elevations in serum LDL levels while mutations in lipoprotein lipase can result in marked elevations in serum triglyceride levels. In patients with diabetes with marked alterations in serum lipid levels it is very important to consider the possibility of a genetic disorder and the first step is to obtain a detailed family history.
In addition to genetic factors other disease states can lead to elevations in serum lipid levels. For example, hypothyroidism can result in marked elevations in serum LDL levels while ethanol use can result in elevations in serum triglyceride levels. Finally, commonly used drugs can often contribute to abnormalities in serum lipid levels. For example, estrogen therapy can raise triglyceride levels while high doses of androgens can lower HDL levels. It is therefore important in patients with diabetes who have abnormalities in serum lipid levels to consider the possibility of underlying genetic disorders, other disease states, or the use of medications which can adversely affect lipids.
Key Laboratory and Imaging Tests
The key to the diagnosis of lipid disorders is the measurement of serum cholesterol, triglycerides and HDL cholesterol levels. LDL cholesterol levels are typically calculated from the above results (LDLc = Total cholesterol - HDLc- triglycerides/5). In situations where the triglyceride levels are > 400 the calculation of LDLc is inaccurate. In these situations one should utilize direct LDLc assays. Finally, non-HDL cholesterol levels are a very useful measurement and can be an important therapeutic goal (non HDLc = total cholesterol - HDLc). Non HDLc is considered to reflect all of the pro-atherogenic lipoproteins in the serum.
Other Tests That May Prove Helpful Diagnostically
There is a number of alternative measurements that are advocated by various experts as better indicators for determining the risk of developing atherosclerosis than the standard lipid profile. Measurement of apolipoprotein B levels is considered to be a good indicator of pro-atherogenic lipoproteins. Apolipoprotein A1 measurements are a good indicator of HDL levels. Lp(a) measurement determines the number of these pro-atherogenic particles.
In addition a number of experts advocate obtaining lipid studies that determine other parameters.
The VAP test provides information on the amount of cholesterol in various lipoprotein particles including IDL, Lp(a), VLDL1/2, VLDL3, HDL2, HDL3, and remnant lipoproteins. In addition it classifies patients on whether they have an abundance of small dense LDL (pattern B) or a predominance of large LDL (pattern A). NMR testing measures the number of LDL particles, small LDL particles, HDL particles, large HDL particles, and large VLDL particles. In addition it provides information on the average size of VLDL, LDL, and HDL particles. Finally gradient gel electrophoresis can be used to measure LDL and HDL size.
While everyone agrees that these additional tests are very useful in research studies their role in the day to day management of patients with lipid disorders is not clear. Many experts feel that these more sophisticated tests are unnecessary and do not alter management except in unusual situations. Additionally, the guidelines for lipid management utilize the standard lipid panel and not these more sophisticated tests. In my practice I seldom utilize these tests and do not feel that I need the extra information to treat lipid disorders in most of my patients with diabetes.
Management and Treatment of the Disease
The main purpose of treating lipid disorders in patients with diabetes is to reduce the risk of cardiovascular disease. The American Diabetes Association has provided guidelines to help clinicians diagnose and manage lipid disorders. It is recommended that all adult patients with diabetes have their lipid profile checked at the time of diagnosis and then every five years if not on statin therapy. This profile includes total cholesterol, HDL cholesterol, triglycerides, and calculated LDL cholesterol. A direct LDL measurement should be obtained if the serum triglyceride levels are elevated.
The American Diabetes Association (ADA) recommends that all patients with diabetes should follow a diet that reduces the intake of saturated fats, trans fats, and cholesterol and increases omega-3-fatty acids, viscous fiber, and plant stanol/sterol intake. In overweight patients a weight loss diet should be instituted. In the absence of contraindications physical activity is recommended for all patients (150 minutes per week of moderate intensity aerobic activity spread over at least three days per week with no more than two consecutive days without exercise; resistance training at least two times per week).
The ADA recommends that intensive statin therapy (atorvastatin 40-80mg, rosuvastatin 20-40mg) should be added to lifestyle therapy regardless of lipid levels in all patients with overt cardiovascular disease. . For patients with diabetes aged <40 years with additional risk factors one should consider using moderate or intensive statin therapy. For patients aged >40 years without additional risk factors one should consider using moderate intensity statin therapy. For patients aged 40-75 years with additional risk factors one should consider using intensive statin therapy. For patients > 75 years with additional risk factors for cardiovascular disease one should consider using moderate or intensive statin therapy. In practice this means that virtually all patients with diabetes over the age of 40 should be treated with statins. There are occasional exceptions but most patients with diabetes over the age of 40 have at least one additional risk factor for cardiovascular disease.
The ACC/AHA published guidelines on the treatment of blood cholesterol to reduce cardiovascular risk. They recommend that patients with diabetes between 40-75 years of age with an LDL > 70mg/dl be treated with statin therapy. If the 10 year risk of developing atherosclerotic cardiovascular disease is > 7.5% they recommend intensive statin therapy to lower the LDL by at least 50% (atorvastatin 40-80mg or rosuvastatin 20-40mg). If the 10 year risk of developing atherosclerotic cardiovascular disease is < 7.5% they recommend moderate intensity statin therapy to lower the LDL by 30-50%. The 10 year risk can be calculated by using a calculator available on line (http://my.americanheart.org/cvriskcalculator) or by downloading an app for an I-phone or I-pad (ASCVD app). In patients with diabetes < 40 years of age or > 75 years of age they recommend that therapy be individualized based on risk of cardiovascular disease, potential for adverse effects, and patient preferences.
It should be noted that the ADA and the ACC/AHA recommendations do not have treatment goals. In contrast the National Lipid Association (NLA) has treatment goals for patients with diabetes In patients with type 1 or type 2 diabetes with pre-existing atherosclerotic cardiovascular disease, two or more risk factors for atherosclerotic cardiovascular disease (risk factors are age >45 for males, >55 for females; family history of early coronary heart disease; current cigarette smoking; high blood pressure >140/>90 mm HG; or low HDL < 40mg/dl males, < 50mg/dl females), or evidence of end organ damage (retinopathy, albumin/creatinine ratio > 30mg/g, or chronic kidney disease) the goal LDL is <70mg/dl and the goal non-HDL cholesterol is < 100mg/dl. In patients with diabetes with 0-1 risk factors and no end organ damage, the LDL goal is < 100mg/dl and the non-HDL cholesterol goal is < 130mg/dl. The NLA guidelines recommend considering drug therapy if a patient with diabetes is not at goal.
Thus, different organizations have proposed somewhat different recommendations for the treatment of lipids in patients with diabetes. Despite these differences it is clear that the vast majority of patients with diabetes will need to be treated with statins regardless of which guidelines one elects to follow.
One approach is to combine these recommendations. Begin with the ACC/AHA approach and calculate the 10 risk of developing cardiovascular disease in patients 40-75 years of age without pre-existing cardiovascular disease. Initiate intensive statin therapy if the 10 year risk is > 7.5% or moderate statin therapy if the risk is < 7.5%. In patients with diabetes who have pre-existing cardiovascular disease initiate intensive statin therapy. Eight to twelve weeks after initiating statin therapy obtain a lipid panel to determine if the LDL and non-HDL cholesterol levels are at goal. In patients with pre-existing cardiovascular disease or multiple risk factors the goal should be an LDL < 70mg/dl and a non HDLc < 100mg/dl. In patients that are not at high risk the goal should be an LDL < 100mg/dl and a non-HDLc < 130mg/dl. If the levels are not at goal either adjust the statin dose or consider adding additional medications.
As discussed above the cornerstone of therapy is lifestyle changes. The major problem of course is compliance and it is often extremely difficult for patients to make the necessary lifestyle changes. In most patients with type 2 diabetes weight loss is a key element but success in getting patients to lose weight is difficult. There is a large number of different weight loss diets recommended by various "experts" but in practice few of our patients are capable of achieving significant long term weight loss. If successful weight loss will decrease serum triglyceride levels, increase HDL cholesterol levels, and modestly reduce LDL cholesterol levels.
Because of the relative lack of success of lifestyle changes, drug therapy is often required. The effect of statins, fibrates, niacin, ezetimibe, and bile resin binders on lipid levels in patients with diabetes are very similar to that seen in non-diabetic patients. There are very strong data that statins reduce cardiovascular disease in patients with diabetes similar to what occurs in patients without diabetes. It is because of this robust outcome data that statins are the first line drug for lowering LDL cholesterol levels.
The data for fibrates is not clear. In some monotherapy studies a reduction in cardiovascular disease was observed with fibrate therapy but this was not a consistent or robust effect. In the single study where a fibrate was added to statin therapy a reduction in cardiovascular events was not noted. In an analysis of subgroups there was a suggestion that adding a fibrate to a statin might be of benefit in patients with diabetes whose triglyceride levels were greater than 204 and HDL levels less than 34. Further studies are required to clarify the benefits of adding a fibrate to statin therapy in patients with diabetes.
There is a single niacin monotherapy study carried out from 1966-1974 that demonstrated a decrease in cardiovascular outcomes in patients with diabetes. When used in combination with a statin niacin therapy did not have any benefits on cardiovascular events. However, similar to observations with fenofibrate in the subset of patients with TG > 198mg/dl and HDL < 33mg/dl niacin showed a trend towards benefit (hazard ratio 0.74; p=0.073). There are no data addressing the effects of bile resin binders on cardiovascular outcomes in patients with diabetes.
The IMPROVE-IT trial tested whether the addition of ezetimibe to statin therapy will provide an additional beneficial effect in patients with the acute coronary syndrome. This was a large trial with over 18,000 patients randomized to statin therapy vs. statin therapy + ezetimibe. Approximately 27% of the patients in this trial had diabetes. On treatment LDL cholesterol levels were 70mg/dl in the statin alone group vs. 53mg/dl in the statin + ezetimibe group. There was a small but significant 6.4% decrease in major cardiovascular events. Cardiovascular death, non-fatal MI, or non-fatal stroke were reduced by 10%. These beneficial effects were particularly pronounced in the patients with diabetes. The results of this study have a number of important implications. First, it demonstrates that combination therapy may have benefits above and beyond statin therapy alone. Second, it provides further support for the hypothesis that lowering LDL per se will reduce cardiovascular events. Third, it suggests that lowering LDL levels into the 50s will have benefits above and beyond lowering LDL levels to the 70mg/dl range. These results have implications for determining goals of therapy.
Statins, fibrates, and ezetimibe are drugs that are easy to use and generally well tolerated in patients with diabetes. Bile resin binders are more difficult to use in patients with diabetes because they increase serum triglyceride levels and many patients with diabetes already have elevated triglyceride levels. Additionally, bile resin binders can bind other drugs and interfere with their absorption. Most patients with diabetes are on multiple drugs and thus these drug interactions can pose difficulties. Colesevelam (Welchol) is a bile resin binder that comes in pill or powder form and appears to cause fewer side effects and has fewer drug-drug interactions.
Notably, bile resin binders can have favorable effects on glycemic control and in several studies have been shown to lower the A1c level by approximately 0.5%. In contrast, niacin increases insulin resistance and can potentially worsen glycemic control. Studies have shown that low doses of niacin (< 2,000mg / day) are well tolerated in patients with good glycemic control. High doses of niacin or the use of niacin in patients with poor glycemic control niacin are more likely to adversely affect glucose levels
Niacin can also increase serum uric acid levels and induce gout. Patients with type 2 diabetes have an increased prevalence of gout and niacin may increase the frequency of gouty attacks. Advantages of niacin include its ability to lower Lp(a) and it is the most effect drug in increasing HDL levels.
The first priority in treating lipid disorders in patients with diabetes is to lower LDL cholesterol levels. The reason for focusing on LDL is that the data linking LDL with cardiovascular disease is very strong and we have very effective agents to lower LDL cholesterol levels. Statins are the first choice drug for lowering LDL cholesterol levels. The effectiveness of different statins in lowering LDL levels varies but one can achieve with high dose statins greater than a 50% decrease in LDL levels. Inexpensive generic statins can be used initially and if these are not successful one can then use more expensive branded statins.
If statins are not tolerated or maximum statin therapy does not reach LDL goal one can employ additional drugs. The main choices are ezetimibe, niacin, or bile resin binders. In general I tend to use ezetimibe first because it is easiest for patients to take and has few side effects. If the patient does not have hypertriglyceridemia and glycemic control needs improvement bile resin binders are a good choice. In patients who cannot tolerate statins it will often require combination therapy (for example ezetimibe, bile acid binders, and niacin) to reach LDL goals.
After the LDL cholesterol is at goal the second priority is the non-HDL cholesterol (non HDLc = total cholesterol - HDLc). The non-HDL cholesterol goal is 30mg/dl greater than the LDL cholesterol goal. For example if the LDL goal is < 100mg/dl the non-HDLc goal is < 130mg/dl; if the LDL goal is < 70mg/dl the non-HDLc goal is < 100mg/dl. One often finds that the LDL is at goal but the non-HDL is not at goal when the triglyceride levels are elevated (>200mg/dl).
Numerous studies have shown that non-HDLc is a strong risk factor for the development of cardiovascular disease and that lowering non-HDLc levels with drug therapy predicts a reduction in cardiovascular events. In patients whose LDL is at goal but their non-HDLc levels are still elevated the addition of drugs that lower serum triglyceride levels can be very effective. Fibrates, niacin, or fish oil (3-4 grams per day of EPA/DHA) are typically used. Niacin or a fibrate are good choices if HDLc are low.
If serum triglyceride levels are markedly elevated (> 500mg/dl) initial therapy should be directed at lowering serum triglyceride levels to prevent the development of the chylomicronemia syndrome. Lifestyle changes including avoiding ethanol intake is the first step and can be very effective. Fibrates, niacin, and fish oil are the initial drugs that should be used. It will often take multiple drugs to effectively lower the serum triglyceride levels. Once the serum triglyceride levels are lowered reductions in LDL cholesterol become an important priority and statin therapy is often added.
Patients with diabetes often have mixed lipid disorders (elevated LDL and triglycerides and low HDL) and therefore require multiple medications. The addition of certain drugs to statins can increase the risk of myositis. Specifically gemfibrozil is not the fibrate of choice in combination with statins because it increases the risk of myositis. Rather fenofibrate should be used because the risk of myositis is not markedly increased. While fenofibrate is approved by the FDA in combination with statins I tend to avoid the highest doses of statins if possible. In addition, niacin may also interact with statins and increase the risk of myositis and therefore I try to avoid using the maximum statin dose in combination with niacin.
What’s the Evidence?/References
" Standards of medical care in diabetes--2016". Diabetes Care. vol. 39. 2016. pp. S60-S71.(This presents the recommendations of the American Diabetes Association on the diagnosis and management of lipid disorders.)
Baigent, C, Blackwell, L, Emberson, J, Holland, LE, Reith, C, Bhala, N. " Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials". Lancet. vol. 376. 2010. pp. 1670-81.(This paper is a meta-analysis that examined the ability of statins to reduce cardiovascular disease. They found that a 38mg/dl reduction in LDL cholesterol resulted in a 22% decrease in major vascular events. Moreover, intensive statin therapy reduced events to a greater extent than usual therapy. Finally, this very large data base did not demonstrate that statins increase the risk of cancer or death from non vascular causes.)
Boden, WE, Probstfield, JL, Anderson, T, Chaitman, BR, Desvignes-Nickens, P, Koprowicz, K. " Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy". N Engl J Med. vol. 365. 2011. pp. 2255-67.(This paper presents the results of the AIM-HIGH study. The addition of extended release niacin to statin therapy favorably affected lipid levels but did not reduce cardiovascular events.)
Boekholdt, SM, Arsenault, BJ, Mora, S, Pedersen, TR, LaRosa, JC, Nestel, PJ. " Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis". JAMA. vol. 307. 2012. pp. 1302-9.(This is a meta-analysis of 8 statin trials with over 60,000 patients. They found that on treatment levels of LDLc, non-HDLc, and apoB were associated with the risk of major cardiovascular events but the association was strongest for non-HDLc, demonstrating the importance of non-HDLc.)
Canner, PL, Furberg, CD, Terrin, ML. "McGovern ME Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project)". Am J Cardiol. vol. 95. 2005. pp. 254-7.(This paper describes the results of the Coronary Drug Project that examined the effect of niacin and other drugs as monotherapy on cardiovascular disease. They report in this paper that niacin monotherapy reduced cardiovascular events and mortality in patients with elevated glucose levels.)
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Guyton, JR, Slee, AE, Anderson, T, Fleg, JL, Goldberg, RB, Kashyap, ML, Marcovina, SM, Nash, SD, O'Brien, KD, Weintraub, WS, Xu, P, Zhao, XQ, Boden, WE. "Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes)". J Am Coll Cardiol. vol. 62. 2013. pp. 1580-4.(In a subgroup of patients with high TG and low HDL there was a suggestion that niacin therapy reduced cardiovascular events.)
Handelsman, Y. "Role of bile acid sequestrants in the treatment of type 2 diabetes". Diabetes Care. vol. 34. 2011. pp. S244-50.(This paper reviews the beneficial effects of bile acid sequestrants on glycemic control in patients with type 2 diabetes.)
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Kearney, PM, Blackwell, L, Collins, R, Keech, A, Simes, J, Peto, R. " Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis". Lancet. vol. 371. 2008. pp. 117-25.(This is a meta-analysis of statin trials examining the effect in patients with diabetes. They report that the beneficial effects of statins on cardiovascular disease is very similar in patients with diabetes as compared to non-diabetics.)
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