ABSTRACT

Atherosclerotic cardiovascular disease (ASCVD) is a major cause of morbidity and mortality in both men and women with T1DM and T2DM. In patients with T1DM, intensive glycemic control results in a reduction in ASCVD. However, intensive glycemic control does not have a major impact in reducing ASCVD in patients with T2DM. Metformin, pioglitazone, SGLT2 inhibitors, and certain GLP-1 receptor agonists have been shown to decrease major cardiovascular events in patients with T2DM to a greater extent than other treatment modalities. In patients with T2DM other risk factors including, hypertension and dyslipidemia, play a major role in inducing ASCVD and control of these risk factors is paramount. In patients with T1DM in good glycemic control, the lipid profile is very similar to the general population. In contrast, in patients with T2DM, even with good glycemic control, there are frequently lipid abnormalities (elevated TG and non-HDL-C, decreased HDL-C, and an increase in small dense LDL). In both T1DM and T2DM, poor glycemic control increases TG levels and decreases HDL-C levels with modest effects on LDL-C levels. Extensive studies have demonstrated that statins decrease ASCVD in patients with diabetes. Treatment with high doses of potent statins reduces ASCVD events to a greater extent than low dose statin therapy. Adding fibrates or niacin to statin therapy has not been shown to further decrease ASCVD events. In contrast, studies have shown that the combination of a statin and ezetimibe or a statin and a PCSK9 inhibitor result in a greater decrease in ASCVD events than statins alone. Studies have suggested that EPA, an omega-3-fatty acid, when added to statins also reduces ASCVD events but this result is controversial. In statin intolerant patients with T2DM bempedoic acid decreases ASCVD events. Current recommendations state that most patients with diabetes should be on statin therapy. In certain patients with diabetes ezetimibe, PCSK9 inhibitors, and bempedoic acid can play a role in reducing ASCVD. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Atherosclerotic cardiovascular disease (ASCVD) is a major cause of morbidity and mortality in both men and women with diabetes (1-5). In addition to coronary disease, ASCVD includes stroke and peripheral arterial disease (PAD). PAD is common in diabetes, may be the first presentation of ASCVD and should be recognized as needing aggressive treatment of risk factors. The risk of ASCVD is increased approximately 2-fold in men and 3-4-fold in women (2-4,6,7). In the Framingham study, the annual rate of ASCVD was similar in men and women with diabetes, emphasizing that woman with diabetes need as aggressive preventive treatment as men with diabetes (2,6). In addition, several but not all studies, have shown that patients with diabetes with no history of ASCVD have a similar risk of having a myocardial infarction as non-diabetic patients who have a history of ASCVD, i.e., diabetes is an equivalent risk factor as a history of a previous cardiovascular event (8,9). The duration of diabetes and the presence of other risk factors or complications of diabetes likely determine whether a patient with diabetes has a risk equivalent to patients with a history of previous ASCVD events (10,11). In one study patients with T2DM who had the following risk factors within the target range, HbA1c, LDL-C, albuminuria, smoking, and blood pressure, the risk of an acute myocardial infarction or stroke was similar to individuals without diabetics (12). Moreover, numerous studies have shown that patients with diabetes who have ASCVD are at a very high risk of having another event, indicating that this population of patient’s needs especially aggressive preventive measures (1,8). This increased risk for the development of ASCVD in patients with diabetes is seen both in populations where the prevalence of ASCVD is high (Western societies) and low (for example, Japan) (2). However, in societies where the prevalence of ASCVD is low, the contribution of ASCVD as a cause of morbidity and mortality in patients with diabetes is relatively low compared to Western societies (2).

While the database is not as robust, the evidence indicates that patients with T1DM are also at high risk for the development of ASCVD (1,13-15). Interestingly, women with T1DM have twice the excess risk of fatal and nonfatal vascular events compared to men with T1DM (16,17). Additionally, developing T1DM at a young age increases the risk of ASCVD to a greater degree than late onset T1DM (17). Approximately 50% of patients with T1DM are obese or overweight and between 8% and 40% meet the criteria for the metabolic syndrome, which increases their risk of developing ASCVD (18).

While the development of diabetes at a young age increases the risk of ASCVD in patients with both T1DM and T2DM the deleterious impact is greater in patients with T2DM (19). Lastly, in patients with both T1DM and T2DM the presence of renal disease increases the risk of ASCVD (4,14). Of note is that the risk of developing ASCVD events in patients with diabetes has decreased recently, most likely due to better lipid and blood pressure control, which again reinforces the need to aggressively treat these risk factors in patients with diabetes (5,7,20).

ROLE OF GLYCEMIC CONTROL

Epidemiological studies have shown an association between the level of glycemic control and the development of ASCVD in both T1DM and T2DM (1,4,5,21,22). However, the association of glycemic control with ASCVD is considerably weaker than the association of glycemic control with the microvascular complications of diabetes, such as retinopathy and nephropathy (4). 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 ASCVD. For example, patients with poor glycemic control may not undertake other preventive measures that could reduce ASCVD such as exercise, healthy diet, etc. Furthermore, the patients with poor glycemic control may have less compliance with therapies that reduce lipids and blood pressure. Therefore, randomized studies are essential in determining the role of glycemic control on ASCVD.

Early randomized studies, such as the University Group Diabetes Project (UGDP) and VA cooperative study, did not demonstrate a reduction in cardiovascular events in patients who were aggressively treated for glucose control (23-25). In fact, the data from these early studies 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 ASCVD.

THE EFFECT OF GLUCOSE LOWERING DRUGS ON ASCVD

ROLE OF OTHER RISK FACTORS IN ASCVD

Numerous studies have demonstrated that the traditional risk factors for ASCVD play an important role in patients with diabetes (2,4,5,110). Patients with diabetes without other risk factors have a relatively low risk of ASCVD (in most studies higher than similar non-diabetic patients), whereas the increasing prevalence of other risk factors markedly increases the risk of developing ASCVD (2). The major reversible traditional risk factors are hypertension, cigarette smoking, and lipid abnormalities (2,4,5,14,111). Other risk factors include obesity (particularly visceral obesity), insulin resistance, small dense LDL, elevated TG, low HDL-C, procoagulant state (increased PAI-1, fibrinogen), family history of early ASCVD, homocysteine, Lp (a), renal disease, albuminuria, and inflammation (C-reactive protein, SAA, cytokines) (2,4,5,110,111). In the last decade, it has become clear that to reduce the risk of ASCVD 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 chapter, I will focus on the dyslipidemia that occurs in patients with diabetes.

ROLE OF LIPIDS IN ASCVD

As in non-diabetic populations, epidemiological studies have shown that increased LDL-C and non-HDL-C levels and decreased HDL-C levels are associated with an increased risk of ASCVD in patients with diabetes (2,4,110,111). In the UKPDS cohort LDL-C levels were the strongest predictor of coronary artery disease (112). While it is universally accepted that elevated levels of LDL-C and non-HDL-C cause atherosclerosis and ASCVD the role of HDL-C is uncertain. Genetic studies and studies of drugs that raise HDL-C have not supported low HDL-C levels as a causative factor for atherosclerosis (113). Rather it is currently thought that HDL function is associated with atherosclerosis risk and that this does not precisely correlate with HDL-C levels (113). In patients with diabetes, elevations in serum triglyceride (TG) levels also are associated with an increased risk of ASCVD (4,111,114). With regard to TG, it is not clear whether they are a causative factor for ASCVD or whether the elevation in TG is a marker for other abnormalities (4,111,114,115). Recent Mendelian randomization studies have provided support for the hypothesis that elevated TG levels play a causal role in atherosclerosis (115,116). Unfortunately, as will be discussed later in this chapter lowering TG levels in patients on statin therapy has not decreased cardiovascular events.

LIPID ABNORMALITIES IN PATIENTS WITH DIABETES

In patients with T1DM in good glycemic control, the lipid profile is very similar to lipid profiles in the general population (110). In some studies HDL-C levels are modestly increased in patients with T1DM (117). In contrast, in patients with T2DM, even when in good glycemic control, there are abnormalities in lipid levels (118-121). It is estimated that 30-60% of patients with T2DM have dyslipidemia (5,122). Specifically, patients with T2DM often have an increase in serum TG levels, increased VLDL and IDL, and decreased HDL-C levels. Non-HDL-C levels are increased due to the increase in VLDL and IDL. LDL-C levels are typically not markedly different than in normal subjects but there is an increase in small dense LDL, a lipoprotein particle that may be particularly pro-atherogenic (123). As a consequence, there are more LDL particles, which coupled with the increases in VLDL and IDL, leads to an increase in apolipoprotein B levels (118-121). Additionally, the postprandial increase in serum TG is accentuated and elevations in postprandial lipids may increase the risk of ASCVD (118-121).

It should be recognized that the lipid changes in patients with T2D are characteristic of the alterations in lipid profile seen in obesity and the metabolic syndrome (insulin resistance syndrome) (124). Since a high percentage of patients with T2DM are obese, insulin resistant, and have the metabolic syndrome, it is not surprising that the prevalence of increased TG and small dense LDL and decreased HDL-C is common in patients with T2DM even when these patients are in good glycemic control. Obesity is also accompanied by increased systemic inflammation. The increasing prevalence of obesity/overweight in patients with T1D will likely result in an increased prevalence of dyslipidemia in this population.

Studies have shown that the anti-oxidant and anti-inflammatory functions of HDL isolated from patients with T1DM and T2DM are reduced (117,125). Additionally, the ability of HDL to facilitate cholesterol efflux is reduced in patients with T1DM and T2DM (126,127). Together these findings indicate that HDL-C levels per se may not fully reflect risk of ASCVD in patients with diabetes and that HDL function is perturbed in patients with diabetes.

In both T1DM and T2DM, poor glycemic control increases serum TG levels, VLDL, and IDL, and decreases HDL-C levels (119). Poor glycemic control can also result in a modest increase in LDL-C, which because of the elevation in TG is often in the small dense LDL 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 T1DM and T2DM (128). Some studies have observed no impact of diabetes mellitus on Lp(a) concentrations while other studies reported an elevation or a decrease in Lp(a) concentrations (128). The development of microalbuminuria and the onset of renal disease are associated with an increase in Lp (a) levels (129). Of note low Lp(a) levels are associated with an increased risk of developing T2DM (128). A recent very large case control study found that an Lp(a) concentration in the bottom 10% increases T2DM risk (130).

EFFECT OF GLUCOSE LOWERING DRUGS ON LIPIDS

Some therapies used to improve glycemic control may have an impact on lipid levels above and beyond their effects on glucose metabolism. In reviewing the literature, it is often very difficult to separate improvements in glycemic control vs. direct effects of drugs. Additionally, many of the changes induced by drug therapy result in only small changes in LDL-C, HDL-C, and TG levels, are variable from study to study, and are of questionable clinical significance. Insulin, sulfonylureas, meglinitides, DPP4 inhibitors, and alpha-glucosidase inhibitors do not appear to markedly alter fasting lipid profiles other than by improving glucose control (there are data indicating that DPP4 inhibitors and acarbose decrease postprandial triglyceride excursions, but they do not markedly alter fasting lipid levels) (131). In contrast, metformin, thiazolidinediones, GLP1 receptor agonists, bromocriptine-QR, and SGLT2 inhibitors have effects independent of glycemic control on serum lipid levels.

Metformin may decrease serum TG levels and LDL-C levels without altering HDL-C levels (131). In a meta-analysis of 37 trials with 2,891 patients, metformin decreased TG by 11.4mg/dL when compared with control treatment (p=0.003) (132). In an analysis of 24 trials with 1,867 patients, metformin decreased LDL-C by 8.4mg/dL compared to control treatment (p<0.001) (132). In contrast, metformin did not significantly alter HDL-C levels (132). It should be noted that in the Diabetes Prevention Program 3,234 individuals with impaired glucose metabolism were randomized to placebo, intensive lifestyle, or metformin therapy. In the metformin therapy group no significant changes were noted in TG, LDL-C, or HDL-C levels compared to the placebo group (133). Thus, metformin may have small effects on lipid levels.

The effect of thiazolidinediones depends on which agent is used. Rosiglitazone increases serum LDL-C levels, increases HDL-C levels, and only decreases serum TG if the baseline TG levels are high (131). In contrast, pioglitazone has less impact on LDL-C levels, but increases HDL-C levels, and decreases TG (131). In the PROactive study, a large randomized cardiovascular outcome study, pioglitazone decreased TG levels by approximately 10%, increased HDL-C levels by approximately 10%, and increased LDL-C by 1-4% (134). 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 thiazolidinediones (131). In a randomized head-to-head trial, it was shown that pioglitazone decreased TG levels and increased serum HDL-C levels to a greater degree than rosiglitazone treatment (135,136). Additionally, pioglitazone increased LDL-C levels less than rosiglitazone. In contrast to the differences in lipid parameters, both rosiglitazone and pioglitazone decreased A1c and C-reactive protein to a similar extent. The mechanism by which pioglitazone induces more favorable changes in lipid levels than rosiglitazone despite similar changes in glucose levels is unclear, but differential actions of ligands for nuclear hormone receptors are well described.

Treatment with SGLT2 inhibitors results in a small increase in LDL-C and HDL-C levels (131). In a meta-analysis of 48 randomized controlled trials SGLT2 inhibitors significantly increased LDL-C (3.8mg/dL, p < 0.00001), HDL-C (2.3mg/dL, p < 0.00001), and decreased TG levels (8.8mg/dL, p < 0.00001) (137). The mechanism for these increases in LDL and HDL cholesterol is unknown but could be due to a decrease in plasma volume. The decrease in TG levels could be secondary to weight loss.

Bromocriptine-QR (Cycloset) treatment decreases TG levels but has no significant effect on LDL-C or HDL-C levels (138,139). The decrease in TG levels is thought to be due to a decrease in hepatic TG synthesis, likely due to a decrease in adipose tissue lipolysis resulting in decreased blood free fatty acid levels and reduced delivery of fatty acids to the liver for TG synthesis (140).

Colesevelam, a bile acid sequestrant that is approved for glucose lowering, lowers LDL-C levels by 15-20% and has only a modest effect on HDL-C levels (101,141). The effect of bile acid sequestrants on TG levels varies (141). In patients with normal TG levels, bile acid sequestrants increase TG levels by a small amount. However, as baseline TG levels increase, the effect of bile acid sequestrants on TG levels becomes greater, and can result in substantial increases in TG levels (141). In patients with TG > 500mg/dL the use of bile acid sequestrants is contraindicated (141).

Finally, GLP-1 receptor agonists can favorably affect the lipid profile by inducing weight loss (decreasing TG and very modestly decreasing LDL-C levels) (131). In a review by Nauck and colleagues it was noted that GLP-1 receptor agonists lowered TG levels by 18 to 62mg/dL depending upon the specific GLP-1 receptor agonist while decreasing LDL-C by 3-8mg/dL and increasing HDL-C by less than 1mg/dL (142). Additionally, GLP-1 receptor agonists reduce postprandial TG by reducing circulating chylomicrons by decreasing intestinal lipoprotein production (131,142). DPP4 inhibitors have a similar effect on postprandial TG levels as GLP-1 receptor agonists while having minimal effects on fasting lipid levels (142).

In the SURPASS trials, tirzepatide studies TG levels were consistently decreased by 13-25% (83,143). In most studies with the exception of SURPASS 5, HDL cholesterol levels increased by 3-11% (83,143). Total cholesterol and LDL cholesterol levels were modestly decreased in most studies (83,143). Not unexpectedly given the decrease in TG levels small LDL particles were decreased. For details see the Endotext chapter Oral and Injectable (Non-Insulin) Pharmacological Agents for the Treatment of Type 2 Diabetes (83).

PATHOPHYSIOLOGY OF THE DYSLIPIDEMIA OF DIABETES

Figure 1.

Pathophysiology of the Dyslipidemia of Diabetes

Multiple mechanisms account for the dyslipidemia seen in patients with T2DM, which are affected both by the level of glucose control and by factors such as obesity and inflammation that also contribute to dyslipidemia.

EFFECT OF LIPID LOWERING ON ASCVD EVENTS IN PATIENTS WITH DIABETES

CURRENT GUIDELINES FOR SERUM LIPIDS

There are several different guidelines for treating lipids in patients with diabetes. While they all focus on lowering LDL-C there are differences between the various guidelines.

TREATMENT OF LIPID ABNORMALITIES IN PATIENT WITH DIABETES

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