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The Role Of Lipids In Increasing Cardiovascular Diseases
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last edited
by Dhemy Padilla 14 years, 6 months ago
THE ROLE OF LIPIDS IN INCREASING CARDIOVASCULAR DISEASES
Kenneth R Feingold, MD
Last Author Revision: October 2009
EPIDEMIOLOGY OF CARDIOVASCULAR DISEASE IN PATIENTS WITH DIABETES
Cardiovascular disease is the major cause of morbidity and mortality in both men and women with diabetes (approximately 60-70% of deaths). The risk of cardiovascular disease is increased approximately 2 fold in men and 3-4 fold in women. In the Framingham study, the annual rate of cardiovascular disease was similar in men and women, emphasizing that woman with diabetes need as aggressive preventive treatment as men with diabetes. In addition, several but not all studies have shown that patients with diabetes who have no history of cardiovascular disease have approximately the same risk of having a myocardial infarction as non-diabetics who have a history of cardiovascular disease, i.e., diabetes is an equivalent risk factor as a history of a previous cardiovascular event. Moreover, numerous studies have shown that patients with diabetes who have cardiovascular disease are at a very high risk of having another event, indicating that this population of patient’s needs especially aggressive preventive measures. This increased risk for the development of cardiovascular disease in patients with diabetes is seen in populations where the prevalence of cardiovascular disease is high (Western societies) and low (for example, Japan). It should be noted though, that in populations where cardiovascular disease is more modest, indicating the importance of other risk factors in modulating the impact of diabetes (see below). While the database is not as robust, the evidence indicates that patients with Type 1 diabetes are also at high risk for the development of cardiovascular disease. Lastly, in patients with both Type 1 and Type 2 diabetes the presence of renal disease increases the risk of cardiovascular disease.
Most, but not all, epidemiological studies have shown an association between glycemic control and the development of cardiovascular disease. However, the association of glycemic control with cardiovascular disease is considerably weaker than the association of glycemic control with the microvascular complications of diabetes, such as retinopathy and nephropathy. Additionally, the association of hypertension and dyslipidemia with cardiovascular disease is stronger than the association of hyperglycemia with cardiovascular disease. It must be recognized that epidemiological studies can only demonstrate associations and that confounding variables could account for the association between poor glycemic control and cardiovascular disease. For example, patients with poor glycemic control may not undertake other preventive measures that could reduce cardiovascular disease such as exercise, healthy diet, etc. Therefore, randomized studies are essential in determining the role of glycemic control on cardiovascular disease.
Early randomized studies, such as the UGDP and VA cooperative study, did not demonstrate a reduction in cardiovascular events in aggressively treated patients and in fact suggested that improvements in glycemic control (VA cooperative study) or the use of certain drugs to treat diabetes (oral sulfonylureas in UGDP) may actually increase the risk of cardiovascular disease. More recent studies, the DCCT in patients with Type 1 diabetes and the Kumamoto study in patients with Type 2 diabetes, while demonstrating a decrease in cardiovascular events in the subjects randomized to improved glycemic control did not have enough cardiovascular disease events to demonstrate a statistically significant reduction (DCCT studied a population at low risk for cardiovascular disease and the Kumamoto study had a very small number of subjects). In contrast, both the DCCT and the Kumamoto study clearly demonstrated that improvements in glycemic control resulted in a reduction in microvascular disease. Recently a long term follow-up of the DCCT has demonstrated that improvement in glycemic control reduces cardiovascular disease. The initial DCCT compared intensive vs. conventional therapy for a mean of 6.5 years. At the end of the study a very large proportion of subjects agreed to participate in a follow-up observational study (Epidemiology of Diabetes Interventions and Complications- EDIC). During this follow-up period glycemic control was relatively similar between the intensive therapy and conventional therapy group (glycosylated hemoglobin 7.9% vs. 7.8%) but during the trial there was a large difference in glycosylated hemoglobin levels (7.4% vs. 9.1%). After a mean 17 years of observation the risk of any cardiovascular event was reduced by 42% and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease was reduced by 57% in the intensive control group. This study demonstrates that intensive glycemic control (for 6.5 of the 17 years of observation) is sufficient to have long term beneficial effects on the risk of developing cardiovascular disease in patients with Type 1 diabetes. This beneficial effect was not entirely due to the prevention of microvascular complications as the differences between the intensive and conventional treatment groups persisted after adjusting for microalbuminuria and albuminuria.
The UKPDS studied a large number of patients with Type 2 diabetes at high risk for cardiovascular disease. In this study improved glycemic control, with either insulin or sulfonylureas, reduced cardiovascular disease by 16%, which just missed being statistically significant (p=0.052). In the UKPDS the improvement in glycemic control was modest (HbA1c reduced by approximately 0.9%) and the 16% reduction in cardiovascular disease was in the range predicted based on epidemiological studies. Very recently the results of a 10 year follow-up of the UKPDS study have been reported (total duration of observation 25 years). After termination of the study glycosylated hemoglobin levels became very similar between the control and treatment groups. Nevertheless, risk reductions for MI became statistically significant for the insulin or sulfonylurea group compared to controls (15% decrease, p=0.01).
Similarly, the DiGami study, which used insulin infusion during the peri MI period to improve glycemic control followed by long-term glycemic control, demonstrated that survival post MI was significantly improved by good glycemic control. While this study focused on a very selected population and time period (patients undergoing a MI) the results are consistent with the hypothesis that improvements in glycemic control will reduce cardiovascular disease. However, a recently reported DiGami 2 study did not confirm the benefits of tight glucose control beginning in the peri MI period on outcomes. It most be noted though that the differences in glucose control achieved in DiGami 2 were much smaller than planned and the number of patients recruited was less than anticipated. Together these deficiencies could account for the failure to demonstrate significant differences in cardiovascular disease events.
Very recently the results of three large randomized trials, the ACCORD, ADVANCE, and VA Diabetes Trial, have been reported. Much to everyone’s surprise and disappointment improvement in glycemic control did not result in a reduction in cardiovascular disease in these trials. The ACCORD study randomized 10,251 subjects with Type 2 diabetes in the US and Canada with either a history of cardiovascular disease or at increased risk for the development of cardiovascular disease. Multiple different treatment protocols were used with the goal of achieving an A1c level < 6% in the intensive group and between 7-7.9% in the standard glycemic control group. During trial the A1c levels were 6.4% in the intensive group and 7.5% in the standard group. As expected the use of insulin therapy was much greater in the intensive group as was the occurrence of hypoglycemia and weight gain. After a mean duration of 3.5 years this study was stopped early by the data safety monitoring board due to an increased mortality in the intensive treatment group (1.41 vs. 1.14% per year; hazard ration 1.22 CI 1.01- 1.46). The primary outcome (MI, stroke, cardiovascular disease death) was reduced by 10% in the intensive control group but this was not statistically significant (p=0.16). The explanation for the increased death rate in the intensive treatment arm remains unknown but it has been speculated that the increased deaths might have been due to hypoglycemia, weight gain, rapidly lowering A1c levels, or unrecognized drug toxicity.
The ADVANCE study randomized 11,140 subjects with Type 2 diabetes in Europe, Asia, Australia/New Zealand and Canada who either had cardiovascular disease or at least one risk factor for cardiovascular disease. In the intensive group the goal A1c was <6.5%. The achieved A1c levels during the trial were 6.3% in the intensive group and 7.3% in the standard treatment group. Of note is that compared to the ACCORD study less insulin use was required to achieve these A1c levels. With regards to macrovascular disease (MI, stroke, and cardiovascular death) no significant differences were observed between the intensive and standard treatment groups (HR 0.94, CI 0.84-1.06, p=032). In contrast to the ACCORD trial, no increase in overall or cardiovascular mortality in the intensive treatment group was observed in the ADVANCE study.
The VA Diabetes Trial randomized 1,791 subjects with poor glycemic control on maximal oral agent therapy or insulin (entry A1c 9.4%). In the intensive group the goal A1c was <6.0%. The achieved A1c levels during the trial were 6.9% in the intensive group and 8.5% in the standard treatment group. Similar to the other trials a significant reduction in cardiovascular disease was not observed in the intensive glycemic control group (HR 0.88, CI 0.74-1.05, p=0.12). Notably there were more cardiovascular disease deaths and sudden deaths in the intensive treatment group but this increase was not statistically significant.
Thus, while the epidemiological data strongly suggests that glycemic control would favorably impact cardiovascular disease the recent randomized trials that were designed to specifically to prove this hypothesis have failed to demonstrate a clear link. There are a number of explanations for why these trials may not have worked as planned. First, in the ACCORD, ADVANCE, and VA Diabetes Trial other cardiovascular risk factors were aggressively treated (lipid and BP lowering, ASA therapy). Because of this the expected number of cardiovascular events was considerably less than expected in these trials. This may have reduced the ability to see a beneficial effect of glucose control. Additionally, the beneficial effects of glucose control maybe more robust if other risk factors are not aggressively controlled. In this regard it is worth noting that in the UKPDS both BP and lipid treatment were not adequate by current standards (systolic BP 135-140mm Hg, LDL cholesterol 135-142mg/dl) and this could be one factor that resulted in this older trial showing a small benefit on cardiovascular disease. Second, these recent trials were comparing relatively low A1c levels in both the intensive and usual control groups (A1c in intensive from ~6.4-6.9% and usual control group from ~7.0-8.4%). It is possible that this is on the “flatter” portion of the glycemic control-cardiovascular risk curve and that if one compared patients with higher A1c values one would see more impressive results. Third, all three trials were carried out in patients with long standing diabetes who either had pre-existing cardiovascular disease or were at high risk for cardiovascular disease. It is possible that patients with a different clinical profile would be more likely to benefit from intensive glucose control. Subgroup analysis from these trials have suggested that patients with a shorter duration of diabetes, less severe diabetes, or the absence of pre-existing cardiovascular disease actually benefited from intensive control. It maybe that glycemic control is most important prior to the development of significant atherosclerosis. Clearly additional studies on different types of patients (i.e. newly diagnosed without evidence of cardiovascular disease) will be necessary to definitively determine the role of glycemic control in different diabetic populations. Fourth, the duration of these studies was relatively short and it is possible that a much longer duration of glycemic control is required to show benefits on cardiovascular disease. In the UKPDS study the beneficial effects of intensive glucose control was not seen early but required an extended duration of time (15-25 years). Fifth, it may be that glycemic control will be more important in patients with Type 1 diabetes where abnormalities in glucose metabolism are a major reason for the increased risk of atherosclerosis. In contrast, patients with Type 2 diabetes have multiple risk factors for atherosclerosis (dyslipidemia, hypertension, inflammation, coagulation disorders) and glucose may play only a minor role in the increased risk. This could account for why intensive glycemic control produced a marked reduction in cardiovascular disease in the DCCT (Type 1 trial) and had only minimal effects in the trials carried out in patients with Type 2 diabetes. Finally, it is possible that our current treatments have side effects that mask the beneficial effects of glucose control. For example, hypoglycemia and weight gain could counterbalance the beneficial effects of improvements in glycemic control. It is possible that different treatment strategies could lead to more profound benefits (see below).
Thus, the currently available data do not indicate that glycemic control will have major effects on reducing cardiovascular disease in patients with Type 2 diabetes. In contrast, in patients with Type 1 diabetes intensive glucose control appears to be very beneficial based on the results of the DCCT. Of note is that in the UKPDS, metformin, while producing a similar improvement in glycemic control as insulin or sulfonylureas, markedly reduced cardiovascular disease by approximately 40%. This indicates that effects of metformin other than improving glucose control, such as decreasing lipids, decreasing insulin resistance, preventing weight gain, etc., may account for the beneficial effects on cardiovascular disease. Along similar lines a very recent study compared the effect of adding metformin or placebo in patients already on insulin therapy. After a mean follow-up of 4.3 years this study also observed a reduction in macrovascular events (HR 0.61 CI- 0.40-0.94, p=0.02), which was partially accounted for by metformin’s beneficial effects on weight. Additionally, these studies demonstrate that the method by which one improves glycemic control may be very important. Studies with thiazolidindiones, such as rosiglitazone and pioglitazone, have suggested that they may have anti-atherogenic properties (reduction of proatherogenic lipid profile, decreases in C-reactive protein, decreases in PIA-1, reduction in carotid intimal media thickness, etc). Moreover, a recent randomized controlled trial (ProActive Study) examined the effect of pioglitazone vs. placebo over a 3 year period in type 2 diabetics with pre-existing macrovascular disease. With regards to the primary endpoint ( a composite of all-cause mortality, non-fatal myocardial infarction including silent MI, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle) there was a 10% reduction in events in the pioglitazone group but this difference was not statistically significant (p=0.095), However, the pioglitazone treated group did demonstrate a 16% reduction in the main secondary endpoint (composite of all cause mortality, non-fatal myocardial infarction, and stroke) that was statistically significant (p=0.027). In the pioglitazone treated group the blood pressure, HBA1c, triglyceride, and HDL levels were all improved compared to the placebo group making it very likely that the mechanism by which pioglitazone decreased vascular events was multifactorial. Further support for the beneficial effects of pioglitazone on atherosclerosis is provided by studies that have examined the effect of pioglitazone on carotid intima-media thickness. Both the Chicago and Pioneer studies demonstrated favorable effects on carotid intima-media thickness in patients treated with pioglitazone compared to patients treated with sulfonylureas. Similarly, Periscope, a study that measured atheroma volume by intravascular ultrasonography, also demonstrated less atherosclerosis in the pioglitazone treated group compared to patients treated with sulfonylureas. Finally, while the data from a variety of different types of studies strongly suggests that pioglitazone is anti-atherogenic the results with rosiglitazone are not as clear. Several meta-analyses of rosiglitazone trials suggested that rosiglitazone was associated with an increased risk of adverse cardiovascular outcomes. However, the final results of the RECORD study, a randomized trial comparing rosiglitazone vs. either metformin or sulfonylurea therapy, have recently been published and did not reveal a difference in cardiovascular disease death, myocardial infarctions, or stroke. Thus, while the available data suggests that pioglitazone is anti-atherogenic the data for rosiglitazone suggests either a neutral effect or perhaps even an increased risk of atherosclerosis.
Recently the Bari 2D study was published. This study compared the effect of insulin sensitizers (metformin/TZD- mostly rosiglitazone) vs. insulin provision therapy (sulfonylureas/insulin) on cardiovascular outcomes in patients with Type 2 diabetes and coronary artery disease (> 50% stenosis and positive stress test or > 70% stenosis and classic angina). In this study no differences in survival or cardiovascular endpoints were observed between metformin/TZD therapy vs. sulfonylurea/insulin therapy. Why in this study the metformin/TZD group did not derive benefit is unknown. It should be noted that the vast majority of patients on TZD therapy were treated with rosiglitazone and as discussed above the effects of rosiglitazone on cardiovascular disease do not appear to be as beneficial as pioglitazone.
ROLE OF OTHER RISK FACTORS
Numerous studies have demonstrated that the traditional risk factors for cardiovascular disease play an important role in patients with diabetes. Patients with diabetes without other risk factors have a relatively low risk of cardiovascular disease whereas the increasing prevalence of risk factors markedly increases the risk of developing cardiovascular disease. The major reversible risk factors are hypertension, cigarette smoking, HDL cholesterol, and LDL cholesterol. Other risk factors include obesity (particularly visceral obesity), insulin resistance, small dense LDL, elevated triglycerides, procoagulent state (increased PAI-1, fibrinogen), homocystine, Lp (a), renal disease, microalbuminuria, and inflammation (C-reactive protein, SAA, cytokines). In the last decade it has become clear that to reduce the risk of cardiovascular disease in patients with diabetes one will not only need to improve glycemic control but also address these other cardiovascular risk factors. In the remainder of this section we will focus on the dyslipidemia that occurs in patients with diabetes.
LIPID ABNORMALITIES IN PATIENTS WITH DIABETES
In patients with Type 1 diabetes in good glycemic control the lipid profile is very similar to lipid profiles in the general population. In contrast, in patients with Type 2 diabetes, even when in good glycemic control, there are abnormalities in lipid levels. Specifically, patients with Type 2 diabetes often have an increase in serum triglyceride levels, increased VLDL and IDL, decreased HDL, and an increase in small dense LDL, a lipoprotein particle that may be particularly atherogenic. It should be recognized that these lipid changes are characteristic of the metabolic syndrome (insulin resistance syndrome). Since a high percentage of patients with Type 2 diabetes are to some degree insulin resistant and have the metabolic syndrome, it is not surprising that the prevalence of increased triglycerides and small dense LDL and decreased HDL is common in patients with Type 2 diabetes even when these patients are in good glycemic control. In both Type 1 and Type 2 diabetes poor glycemic control increases serum triglyceride levels, VLDL and IDL, and decreases HDL. Poor glycemic control can also result in a modest increase in LDL cholesterol, which because of the elevation in triglycerides is often in the small dense subfraction. It is therefore important to optimize glycemic control in patients with diabetes because this will have secondary beneficial effects on lipid levels. Lp (a) levels are usually within the normal range in patients with Type 2 diabetes and do not appear to be greatly effected by glycemic control. In patients with Type 1 diabetes Lp (a) levels are frequently elevated and improvements in glycemic control result in decreases in Lp (a) levels. The development of microalbuminuria and the onset of renal disease are associated with an increase in Lp (a) levels.
The methods used to improve glycemic control may have an impact on lipid levels above and beyond their effects on glucose metabolism. Specifically, insulin, sulfonylureas, meglinitides, DPP4 inhibitors, and alpha-glucosidase inhibitors do not consistently alter lipid profiles other than by effecting glucose control. In contrast, metformin and thiazolidindiones have effects independent of glycemic control on serum lipid levels. Metformin decreases serum triglyceride levels and may modestly decrease LDL cholesterol without altering HDL cholesterol. The effect of thiazolidindiones appears to depend on which agent is used. Rosiglitazone increases serum LDL cholesterol levels, increases HDL cholesterol levels, and only decreases serum triglycerides if the baseline levels are high. In contrast, pioglitazone has less impact on LDL cholesterol levels, increases HDL cholesterol levels, and decreases serum triglyceride levels. It should be noted that reductions in the small dense LDL subfraction and an increase in the large buoyant LDL subfraction are seen with both thiazolidindiones. In a recent randomized head to head trial it was shown that pioglitazone decreased serum triglyceride levels and increased serum HDL cholesterol levels to a greater degree than rosiglitazone treatment. Additionally, pioglitazone increased LDL cholesterol levels less than rosiglitazone. In contrast to the differences in lipid parameters, both rosiglitazone and pioglitazone decreased HBA1c and c-reactive protein to a similar extent. The mechanism by which pioglitazone induces more favorable changes in lipid levels than rosiglitazone is unclear. Whether the different effects of rosiglitazone and pioglitazone on lipid metabolism accounts for the differences seen in preventing cardiovascular disease remains to be determined. Finally, exenatide can favorably affect the lipid profile by inducing weight loss (decreased triglycerides and increased HDL).
EFFECT OF LIPID LOWERING ON CARDIOVASCULAR EVENTS
As in the non-diabetic population, epidemiological studies have shown that increased LDL cholesterol and decreased HDL cholesterol levels increase the risk of cardiovascular disease in patients with diabetes. In patients with diabetes, elevations in serum triglyceride levels also are associated with an increased risk of cardiovascular disease. With regards to triglycerides, it is not clear whether they are an independent risk factor for cardiovascular disease or whether the elevation in triglycerides is a marker for other abnormalities, such as decreased HDL cholesterol levels. As discussed above, while epidemiology can provide great insights, because of the potential for unrecognized confounding variables, randomized controlled trials are required to demonstrate that reductions in lipid levels will result in a decrease in cardiovascular disease.
With the exception of one study, CARDS, the large randomized statin outcome studies have not specifically focused on the effect of statins on cardiovascular disease in patients with diabetes. As shown in Table 1, these diverse statin trials, including both primary and secondary prevention trials, have consistently shown the beneficial effect of statins on cardiovascular disease, presumably primarily by lowering LDL levels. The reduction in cardiovascular disease observed was of a similar magnitude in the diabetic subjects as in the non-diabetic subjects. Thus, the available data indicates that statins are beneficial in reducing cardiovascular disease in subjects with diabetes. Because of the large number of patients with diabetes included in the Heart Protection Study (HPS) and CARDS we will discuss these two studies in greater depth.
Table 1. Statin Trials- Diabetic Subgroups
Study
|
Drug
|
% Decrease
|
|
Controls
|
Diabetics
|
2º Prevention
|
4S
|
Simvastatin
|
32
|
55
|
CARE
|
Pravastatin
|
23
|
25
|
LIPID
|
Pravastatin
|
25
|
19
|
LIPS
|
Fluvastatin
|
20
|
43
|
HPS
|
Simvastatin
|
24
|
26
|
1º Prevention
|
AFCAPS
|
Lovastatin
|
37
|
42
|
HPS
|
Simvastatin
|
24
|
24
|
ASCOT
|
Atorvastatin
|
44
|
16
|
CARDS
|
Atorvastatin
|
--
|
37
|
The HPS was a double blind randomized trial that focused on patients at high risk for the development of cardiovascular events including patients with a history of myocardial infarctions, other atherosclerotic lesions, diabetes, and/or hypertension. Patients were between 40 and 80 years of age and had to have a total serum cholesterol levels greater than 135mg/dl (thus very few patients were excluded because they did not have a high enough cholesterol level). The major strength of this trial was the large number of patients studied (>20,000). The diabetes subgroup included 5,963 subjects and thus was as large as many trials. The study was a 2x2 study design comparing simvastatin 40mg a day vs. placebo and anti-oxidant vitamins (vitamin E 600mg, vitamin C 250mg, and beta-carotene 20mg) vs. placebo and lasted approximately 5 years. Analysis of the group randomized to the anti-oxidant vitamins revealed no beneficial or harmful effects. In contrast, simvastatin therapy (40mg per day) reduced cardiovascular events, including myocardial infarctions and strokes, by approximately 25% in all participants and to a similar degree in the diabetic subjects (total cardiovascular disease reduced 27%, coronary mortality 20%, myocardial infarction 37%, stroke 24%). Further analysis of the subjects with diabetes revealed that the reduction in cardiovascular events with statin therapy was similar in individuals with diabetes diagnosed for a short duration (<6 years) and for a long duration (>13 years). Similarly, subjects with diabetes in good control (HbA1c <7%) and those not in ideal control (HbA1c >7%) also benefited to a similar degree with statin therapy. Moreover, both Type 1 and Type 2 diabetic patients had a reduction in cardiovascular disease with simvastatin therapy. The decrease in cardiovascular events in patients with Type 1 diabetes was not statistically significant because of the small number of subjects. Nevertheless this is the only trial that included Type 1 diabetics and suggests that if Type 1 patients are over the age of 40 years of age that they will benefit from statin therapy similar to Type 2 diabetics. In general, statin therapy reduced cardiovascular disease in all subgroups of subjects with diabetes (females, males, older age, renal disease, hypertension, high triglycerides, low HDL, ASA therapy, etc) i.e. statin therapy benefits all patients with diabetes. Of particular note subjects with diabetes with baseline LDL cholesterol levels less than 116mg/dl treated with simvastatin had a reduction in cardiovascular events. Moreover, analysis of all study patients similarly demonstrated that subjects with LDL cholesterol levels less than 100mg/dl benefited from statin therapy. These results are of particular clinical importance because they demonstrate that high-risk patients with LDL cholesterol levels at goal (LDL< 100mg/dl) would nevertheless benefit from statin therapy. Because of the results of this and other studies (see below) guidelines for treating patients have been updated.
The CARDS trial is the only statin trial that specifically focused on subjects with diabetes. The subjects in this trial were males and females with Type 2 diabetes between the ages of 40 to 75 years of age who were at high risk of developing cardiovascular disease based on the presence of hypertension, retinopathy, renal disease, or current smoking. Of particular note the subjects did not have any evidence of clinical atherosclerosis (myocardial disease, stroke, peripheral vascular disease) and hence this study is a primary prevention trial. Inclusion criteria included LDL cholesterol levels less than 160mg/dl and triglyceride levels less than 600mg/dl. Of note is that the average LDL cholesterol in this trial was approximately 118mg/dl indicating relatively low LDL cholesterol levels. A total of 2838 Type 2 diabetic subjects were randomized to either placebo or atorvastatin 10mg a day. Atorvastatin therapy resulted in a 40% decrease in LDL cholesterol levels with over 80% of patients achieving LDL cholesterol levels less than 100mg/dl. Most importantly, atorvastatin therapy resulted in a 37% reduction in cardiovascular events. In addition strokes were reduced by 48% and coronary revascularization by 31%. As seen in the HPS, subjects with relatively low LDL cholesterol levels (LDL <120mg/dl) benefited to a similar extent as subjects with higher LDL cholesterol levels (>120mg/dl). CARDS, in combination with the other statin trials, provide conclusive evidence that statin therapy will reduce cardiovascular events in patients with diabetes. Of note the benefits of statin are seen in patients with diabetes in both primary and secondary prevention trials.
A few studies have compared the effect of different magnitudes of LDL lowering on the reduction in cardiovascular events in patients with diabetes. The Post-CABG study compared very low dose lovastatin (2.5-5.0mg per day) vs. high dose lovastatin (40-80mg per day) in 1,351 subjects post bypass surgery. Starting LDL cholesterol levels were between 130-174mg/dl. As expected the high dose of lovastatin reduced LDL cholesterol levels to a much greater degree than the low dose lovastatin (low dose LDL approx 135 vs. high dose LDL approx 95). The main comparison in this trial was the change in atherosclerosis in the grafts measured by comparing baseline angiography to angiography after 4.3 years. In the entire population the mean percentage of grafts with progression of atherosclerosis was 27 percent in the high dose lovastatin group and 39 percent in the low dose lovastatin group. Additionally, the rate of revascularization was reduced by 29 percent in the high dose lovastatin group. When the patients with diabetes were analyzed separately, similar beneficial effects were observed. These results indicate that lowering LDL to less than 100mg/dl would slow the angiographic changes to a greater extent than lowering the LDL to 135mg/dl. Of note though is that even with LDL levels less than 100mg/dl progression of atherosclerosis still occurred.
Recent studies have compared reductions of LDL to approximately 100mg/dl to more aggressive reductions in LDL. The Reversal Trial studied 502 symptomatic coronary artery disease patients with an average LDL of 150mg/dl. Patients were randomized to moderate LDL lowering therapy with pravastatin 40mg per day or to aggressive lipid lowering with atorvastatin 80mg per day. As expected LDL levels were considerably lower in the atorvastatin treated group (pravastatin LDL= 110 vs. atorvastatin LDL= 79mg/dl). Additionally, C-reactive peptide was reduced by 36.4% in the atorvastatin group vs. 5.2% in the pravastatin group. Most importantly, when one analyzed the change in atheroma volume determined after 18 months of therapy using intravascular ultrasound, the group treated aggressively with atorvastatin had a much lower progression rate than the group treated with pravastatin. Compared with baseline values, patients treated with atorvastatin had no change in atheroma burden (there was a very slight regression of lesions), whereas patients treated with pravastatin showed progression of lesions. When one compares the extent of the reduction in LDL cholesterol to the change in atheroma volume, a 50% reduction in LDL (LDL levels of approximately 75mg/dl) resulted in the absence of lesion progression. This study suggests that lowering the LDL to levels well below 100mg/dl is required to prevent disease progression as measured by intravascular ultrasound.
The Prove-It trial determined in patients recently hospitalized for an acute coronary syndrome whether aggressively lowering of LDL cholesterol with atorvastatin 80mg per day vs. moderate LDL lowering with pravastatin 40mg per day would have a similar effect on cardiovascular end points such as death, myocardial infarction, documented unstable angina requiring hospitalization, revascularization, or stroke. As expected the on-treatment LDL cholesterol levels were significantly lower in patients aggressively treated with atorvastatin compared to the moderate treated pravastatin group (atorvastatin LDL= approximately 62 vs. pravastatin LDL= approximately 95mg/dl). Of great significance, death or major cardiovascular events was reduced by 16% over the two years of the study in the group aggressively treated with atorvastatin. Moreover, the risk reduction in the patients with diabetes in the aggressive treatment group was similar to that observed in non-diabetics.
In the treat to new target trial (TNT) patients with stable coronary heart disease and LDL cholesterol levels less than 130mg/dl were randomized to either 10mg or 80mg atorvastatin and followed for 4.9years. As expected LDL cholesterol levels were lowered to a greater extent in the patients treated with 80mg atorvastatin (77mg/dl vs. 101mg/dl). Impressively, the occurrence of major cardiovascular events was reduced by 22% in the group treated with atorvastatin 80mg (p<0.001). Once again the risk reduction in the patients with diabetes randomized to the aggressive treatment group was similar to that observed in non-diabetics.
Finally, the IDEAL trial was a randomized study that compared atorvastatin 80mg vs. simvastatin 20-40mg in 8,888 patients with a history of cardiovascular disease. As expected LDL cholesterol levels were reduced to a greater extent in the atorvastatin treated group than the simvastatin treated group (approximately 104mg/dl vs. 81mg/dl). Once again the greater reduction in LDL cholesterol levels was associated with a greater reduction in cardiovascular events. Specifically, major coronary events defined as coronary death, nonfatal myocardial infarction, or cardiac arrest was reduced by 11% (p=0.07) while nonfatal acute myocardial infarctions were reduced by 17% (p=0.02).
Combining the results of the Heart Protection Study, CARDS, Reversal, Prove-It, TNT, and IDEAL leads one to the conclusion that aggressive lowering of LDL cholesterol with statin therapy will be beneficial and suggests that in high risk patients lowering the LDL to levels well below 100mg/dl is desirable. As will be discussed below guidelines have recently been updated to reflect the results of these studies.
The beneficial effect of fibrates (e.g. gemfibrozil, fenofibrate) on cardiovascular disease in patients with diabetes is shown in Table 2. While the data are not perfect, the results of these randomized trials suggest that this class of drug also reduces cardiovascular events in patients with diabetes. The largest trial was the Field Trial which was recently published. In this trial, patients with type 2 diabetes between the ages of 50 and 75 not taking statin therapy were randomized to fenofibrate or placebo and followed for approximately 5 years. Fenofibrate therapy resulted in a 12% decrease in LDL cholesterol, a 29% decrease in triglycerides and a 5% increase in HDL. Coronary events (coronary heart disease death and non-fatal MI) were reduced by 11% in the fenofibrate group (p= 0.16). However, there was a 24% decrease in non-fatal MI in the fenofibrate treated group (p=0.01) and a non-significant increase in coronary heart disease mortality. Total cardiovascular disease events (coronary events plus stroke and coronary or carotid revascularization) were reduced 11% (p=0.035). These beneficial effects of fenofibrate therapy on cardiovascular disease were observed in patients without a previous history of cardiovascular disease. In patients with a previous history of cardiovascular disease no benefits were observed. Interestingly, fenofibrate treatment was associated with a decreased development of retinopathy requiring laser therapy and the progression of albuminuria was decreased. The mechanism by which fibrates reduce cardiovascular events is unclear. These drugs lower serum triglyceride levels and increase HDL cholesterol but it should be recognized that the beneficial effects of fibrates could be due to other actions of these drugs. Specifically, these drugs activate PPAR alpha, which is present in the cells that comprise the atherosclerotic lesions, and it is possible that these compounds directly affect lesion formation and development. In addition, fibrates are anti-inflammatory. In fact, analysis of the VA-HIT study suggested that much of the benefit of the fibrate was not due to changes in serum lipoprotein levels. To summarize, while in general the data to date suggests that fibrates reduce cardiovascular disease in patients with diabetes, the results are not as robust or consistent as seen in the statin trials.
Table 2. Fibrate Trials-Diabetic Subgroup
Study
|
Drug
|
#Diabetic subjects
|
% Decrease
|
|
|
|
controls
|
diabetics
|
* Not statistically significant
|
Helsinki Heart Study
|
Gemfibrizol
|
135
|
34
|
60*
|
VA-HIT
|
Gemfibrizol
|
620
|
24
|
24
|
DIAS
|
Fenofibrate (Tricor)
|
418
|
-
|
33*
|
Sendcap
|
Bezafibrate
|
164
|
-
|
70
|
Field
|
Fenofibrate
|
9795
|
|
11*
|
A single randomized trial, the Coronary Drug Project, has examined the effect of niacin monotherapy on cardiovascular outcomes. This trial was carried out from 1966 to 1974 in men with a history of a prior myocardial infarction and demonstrated that niacin therapy reduced cardiovascular events. Recently the results of this study were re-analyzed to determine the effect of niacin therapy in subjects with varying baseline fasting and 1-hour post meal glucose levels. It was noted that 6 years of niacin therapy reduced the risk of coronary heart disease death or nonfatal MI by approximately 15-25% regardless of baseline fasting or 1 hour post glucose challenge glucose levels. Particularly notable is that reductions in events were seen in the subjects who had a fasting glucose levels >126mg/dl or 1 hour glucose levels >220mg/dl (i.e. patients with diabetes). Thus, based on this single study, niacin reduces cardiovascular events both in normal subjects and patients with diabetes.
With regards to ezetimibe and the bile resin binders there have been no randomized studies that have examined the effect of these drugs on cardiovascular end points in subjects with diabetes. In non-diabetic subjects bile resin binders have reduced cardiovascular events. Since bile resin binders have a similar beneficial impact on serum lipid levels in diabetic and non-diabetic subjects one would anticipate that these drugs would also result in a reduction in events in the diabetic population. There are no outcome studies with ezetimibe (studies are in progress) but given that this drug reduces LDL cholesterol levels one would anticipate that ezetimibe will also reduce cardiovascular events.
With regards to combination therapy, studies are currently underway looking at the effect of adding either niacin or fibrates to statin therapy on cardiovascular outcomes. The ACCORD trial is adding fenofibrate to simvastatin therapy in patients with Type 2 diabetes while AIM HIGH and HPS2-THRIVE are adding niacin to statin therapy. The results of ACCORD should be available very soon while AIM HIGH and HPS2-THRIVE should be completed in 2011 and 2012 respectively.
CURRENT GUIDELINES FOR SERUM LIPIDS
The American Diabetes Association (ADA) recommends that all adult patients with diabetes have their lipid profile determined yearly. This profile includes total cholesterol, HDL cholesterol, triglycerides, and calculated LDL cholesterol. If the triglyceride level is high a direct LDL measurement should be strongly considered. If values are at low-risk levels (LDL <100 mg/dl, triglycerides <150 mg/dl, and HDL >50 mg/dl), assessment may be repeated every 2 years.
Current ADA recommendations are as follows. Lifestyle modification including a reduction in saturated fat, trans fat, and cholesterol intake, weight loss if indicated, and increased physical activity is indicated in all patients with diabetes. Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels in diabetic patients with overt cardiovascular disease or patients over age 40 who have one or more other cardiovascular risk factors. For low risk individuals (no overt cardiovascular disease and under age 40) statin therapy should be considered if LDL remains above 100mg/dl after lifestyle changes or patient has multiple cardiovascular risk factors. For patients without overt cardiovascular disease the LDL goal is <100mg/dl. In individuals with overt cardiovascular disease a LDL goal < 70mg/dl is an option. If one follows these recommendations almost all patients with diabetes over the age of 40 will be on statin therapy and many, if not most, under the age of 40 will also be treated with statins. Note that many patients with LDL levels less than 100mg/dl will still require statin therapy. For example a patient with overt cardiovascular disease and an LDL of 95mg/dl should be treated with statin therapy. Similarly, a 60 year old male with diabetes and more than one other cardiovascular risk factor should also be treated with statin therapy even if his LDL is <100mg/dl. Triglyceride levels <150mg/dl and HDL cholesterol levels > 40mg/dl in men and >50mg/dl in women are desirable.
TREATMENT OF LIPID ABNORMALITIES IN PATIENT WITH DIABETES
Initial treatment of lipid disorders should focus on lifestyle changes. There is little debate that exercise is beneficial and that all patients with diabetes should, if possible, exercise for at least 150 minutes per week ( for example 30 minutes 5 times per week). Exercise will decrease serum triglyceride levels and increase HDL cholesterol levels (an increase in HDL requires vigorous exercise). Diet is debated to a greater extent. Everyone agrees that weight loss in obese patients is essential. But how this can be achieved is hotly debated with many different "experts" advocating different approaches. The wide diversity of approach is likely due to the failure of any approach to be effective in the long term for the majority of obese patients with diabetes. If successful weight loss will decrease serum triglyceride levels, increase HDL cholesterol levels, and modestly reduce LDL cholesterol. To reduce LDL cholesterol levels it is important that the diet reduce saturated fat, trans fatty acid, and cholesterol intake.
It is also hotly debated whether a low fat, high complex carbohydrate diets vs. a high monounsaturated fat diet is ideal for patients with diabetes. One can find "experts" in favor of either of these approaches and there are pros and cons to each approach. I think it is essential to recognize that both approaches reduce saturated fat, trans fatty acids, and cholesterol intake and it is likely that these changes are the most important dietary alterations that our patients need to make. The high carbohydrate diet will increase serum triglyceride levels in some patients and if the amount of fat in the diet is markedly reduced serum HDL levels may decrease. In obese patients it has been postulated that a diet high in monounsaturated fats, because of the increase in caloric density, will lead to an increase in weight gain. Both diets reduce saturated fat and cholesterol intake that will result in reductions in LDL cholesterol levels. Additionally, both of these diets also reduce trans-fatty acid intake, which will have a beneficial effect on LDL and HDL cholesterol levels. Recently there has been increased interest in low carbohydrate, increased protein diets. Short-term studies have indicated that weight loss is superior with this diet however longer studies have demonstrated a similar weight loss to that observed with conventional diets. The major concern with the low carbohydrate, high protein diet is that they tend to be high in saturated fats and cholesterol. In the short-term studies during active weight loss this has not resulted in major perturbations in serum cholesterol levels but there is concern that when weight becomes stable these diets might adversely affect serum cholesterol levels. In general while weight loss and diet therapy are beneficial, in clinical practice they are seldom sufficient because long-term life style changes are very difficult for most patients to sustain. With the currently available weight loss drugs only modest effects on weight have been observed. In some patients weight loss drugs may be a useful adjuvant to diet therapy.
Lastly, some "experts" advocate the addition of fish oil in as part of the diet or as supplements. Fish oil will lower serum triglyceride levels (high doses are required; ~3 grams of DHA/EPA) and studies in non-diabetic subjects indicate a reduction in cardiovascular events (low doses; ~1 gram DHA/EPA). Most studies of fish oil in patients with diabetes have demonstrated that this is a safe approach but an occasional study has reported worsening of glycemic control in patients with diabetes treated with fish oil supplements. Additionally, in some patient's high dose fish oil increases LDL cholesterol levels.
The effect of statins, fibrates, niacin, ezetimibe and bile resin binders on lipid levels in patients with diabetes is virtually identical to that seen in the non-diabetic patients (Table 3). Statins, ezetimibe, and fibrates are easy to use and generally well tolerated by patients with diabetes. Bile resin binders are relatively difficult to take due to GI toxicity (mainly constipation). Diabetic subjects have an increased prevalence of GI symptoms and this maybe exacerbated by the use of bile resin binders. In diabetic patients with diarrhea the use of bile resin binders may be advantageous. Bile resin binders may increase serum triglyceride levels, which can be a problem in some patients with diabetes who are already hypertriglyceridemic. An additional difficulty in using bile resin binders is their potential for binding other drugs. Other drugs should be taken either two hours before or four hours after taking a bile resin binder to avoid the potential of decreased drug absorption. Diabetic patients are frequently on multiple drugs for glycemic control, hypertension, etc., and it can sometimes be difficult to time the ingestion of bile resin binders to avoid other drugs. Colesevelam (Welchol) is a bile resin binder that comes in pill form that appears to cause fewer side effects and has fewer interactions with other drugs than other preparations. The usual dose is 3 pills BID with meals. Of particular note is that a number of studies have shown that colesevelam improves glycemic control in patients with diabetes resulting in an ~0.5% decrease in A1c levels. Lastly, niacin reduces insulin sensitivity (i.e., causes insulin resistance), which can worsen glycemic control. Studies have shown that low doses of niacin (<2000mg/day) are well tolerated in diabetic subjects who are in good glycemic control. In patients with poor glycemic control, niacin is more likely to adversely impact glucose levels. High doses of niacin are also more likely to adversely affect glycemic control. Niacin can also increase serum uric acid levels and induce gout, an abnormality that is already common in obese patients with Type 2 diabetes. However, niacin is the most effective drug in increasing HDL cholesterol levels, which are frequently low in patients with diabetes.
Table 3. Effect of Lipid Lowering Drugs
|
LDL
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HDL
|
Triglycerides
|
*Patients with elevated TG have largest decrease
** In patients with high TG may cause marked increase
*** In some patients may increase LDL
|
Statins
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↓ 20-60%
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↑ 5-15%
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↓ 0-35%*
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Bile acid binders
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↓ 10-30%
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↑ 0-10%
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↑ 0-10%**
|
Fibrates (e.g. TRICOR)
|
↓ 0-15%***
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↑ 5-15%
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↓ 20-50%
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Niacin
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↓ 10-25%
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↑ 10-30%
|
↓ 20-50%
|
Ezetimibe
|
↓ 15-25%
|
↑ 1-3%
|
↓ 10-20%
|
The first priority in treating lipid disorders in patients with diabetes is to lower the LDL cholesterol levels to goal. LDL is the first priority because the database linking LDL with cardiovascular disease is extremely strong and we now have the ability to markedly decrease LDL cholesterol levels. Dietary therapy is the initial step but in most patients will not be sufficient to achieve the LDL goals. If patients are willing and able to make major changes in their diet it is possible to achieve remarkable reductions in LDL cholesterol levels but this seldom occurs in clinical practice. Statins are the first choice drugs to lower LDL cholesterol levels and the majority of diabetic patients will require statin therapy. There are six statins currently available in the US and one should be sure to choose a statin that is capable of lowering the LDL to goal. The effect of different doses of the various statins on LDL cholesterol levels is shown in Table 4. Currently three statins are available as generic drugs, lovastatin, pravastatin, and simvastatin, and these statins are relatively inexpensive. If a patient is unable to tolerate statins or statins as monotherapy are not sufficient to lower LDL to goal the second choice drug is ezetimibe. Ezetimibe can be added to any statin and is now available in a combination pill with simvastatin (Vytorin). If additional LDL lowering is required or a patient cannot tolerate ezetimibe one could add a bile resin binder. Both ezetimibe and bile resin binders additively lower LDL cholesterol levels when used in combination with a statin because the mechanism of action of these drugs is to increase hepatic LDL receptor levels thereby resulting in a reduction in serum LDL levels. Niacin and the fibrates also lower LDL cholesterol levels (see table 3).
Table 4. Comparative Efficacy of Available Statins
% LDL Reduction
|
Simvastatin (Zocor)
|
Atorvastatin (Lipitor)
|
Lovastatin (Mevacor)
|
Pravastatin (Pravachol)
|
Fluvastatin (Lescol)
|
Rosuvastatin (Crestor)
|
Vytorin (ezetimibe + simvastatin)
|
27
|
10
|
---
|
20
|
20
|
40
|
---
|
---
|
34
|
20
|
10
|
40
|
40
|
80
|
---
|
---
|
41
|
40
|
20
|
80
|
---
|
---
|
---
|
---
|
48
|
80
|
40
|
---
|
---
|
---
|
10
|
10/20
|
54
|
---
|
80
|
---
|
---
|
---
|
20
|
10/40
|
60
|
---
|
---
|
---
|
---
|
---
|
40
|
10/80
|
The second priority should be non-HDL cholesterol (total cholesterol – HDL cholesterol = non-HDL cholesterol), which is particularly important in patients with elevated triglyceride levels (>200mg/dl). Non-HDL cholesterol is a measure of all the pro-atherogenic apolipoprotein B containing particles. Numerous studies have shown that non-HDL cholesterol is a strong risk factor for the development of cardiovascular disease. The non-HDL cholesterol goals are 30mg/dl greater than the LDL cholesterol goals. For example, if the LDL goal is <100mg/dl then the non-HDL cholesterol goal would be <130mg/dl. Drugs that reduce either LDL cholesterol or triglyceride levels will reduce non-HDL cholesterol levels.
The third priority in treating lipid disorders is to increase HDL cholesterol levels. There is strong epidemiologic data linking low HDL cholesterol levels with cardiovascular disease but unfortunately our ability to increase HDL cholesterol levels is relatively limited. Life style changes are the initial step and include increased exercise, weight loss, and stopping cigarette smoking. The role of recommending ethanol is controversial but in patients who already drink moderately there is no reason to recommend that they stop. The first choice drug for increasing HDL levels is niacin (see Table 3). Fibrates and statins also raise HDL cholesterol levels but the increases are modest (usually less than 15%). Unfortunately, given the currently available drugs it is very difficult to significantly increase HDL levels and in many of our diabetic patients we are unable to achieve HDL levels in the recommended range.
The fourth priority in treating lipid disorders is to decrease triglyceride levels. Initial therapy should focus on glycemic control. Improving glycemic control can have profound effects on serum triglyceride levels. Fibrates, niacin, statins, and fish oil all reduce serum triglyceride levels (see Table 3).
Many diabetic patients have multiple lipid abnormalities. As discussed in detail above life style changes are the initial therapy. If life style changes are not sufficient in patients with both elevations in LDL and triglycerides (and elevations in non-HDL cholesterol) my approach to drug therapy is based on the triglyceride levels (Figure 1). If the serum triglycerides are very high (greater than 500mg/dl), where there is an increased risk for pancreatitis and hyperviscosity syndromes, initial pharmacological therapy is directed at the elevated triglycerides and the initial drug choice is either a fibrate, niacin, or high dose fish oil (3 grams EPA/DHA per day). If the serum triglycerides are less than 500mg/dl, statin therapy to lower the LDL level to goal is the initial therapy (see Figure 1). Studies have clearly demonstrated that statins are effective drugs in lowering triglyceride levels in patients with elevated triglycerides. In patients with normal triglyceride levels statins do not greatly affect serum triglyceride levels. If the triglyceride levels remain above goal one can then consider combination therapy.
Figure 1. Combined Hyperlipidemia. Increased LDL and TG
Often monotherapy is not sufficient to completely normalize the lipid profile. For example, often with statin therapy one lowers the LDL to goal but the HDL and triglycerides remain in the abnormal range. Currently, there are no randomized controlled trials demonstrating that combination therapy reduces cardiovascular disease to a greater extent than monotherapy. However, many experts believe that further improvements in the lipid profile will be beneficial. When using combination therapy one must be aware that the addition of either fibrates or niacin to statin therapy increases the risk of myositis. The increased risk of myositis is greatest when gemfibrizol is used in combination with statins. Fenofibrate seems to have a modest risk and recently the FDA approved the use of fenofibrate in combination with moderate doses of statins. The increased risk with niacin appears to be very modest and there is even a combination pill containing lovastatin and niacin available (Advicor). It is my opinion that the risks of combination therapy are relatively modest if patients are carefully selected and that in many patients at high risk for cardiovascular disease combination therapy is appropriate. One should be aware of the steps listed in Table 5 that can reduce the potential for toxicity when one uses combination therapy. As with many decisions in medicine one needs to balance the benefits of therapy with the risks of therapy and determine for the individual patient the best approach.
Table 5. When to Use Combination Therapy
In summary, modern therapy of patients with diabetes demands that we normalize lipid levels to reduce the high risk of cardiovascular disease in this susceptible population.
REFERENCES
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The Role Of Lipids In Increasing Cardiovascular Diseases
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