Diabetes and Dyslipidemia
Diabetes mellitus is associated with significant increases in ASCVD. In T1DM, increased ASCVD is linked to hyperglycemia, renal disease, and hypertension, with dyslipidemia contributing when present. In T2DM, although the aforementioned complications of diabetes may each contribute to increased ASCVD, the dyslipidemia plays a more important role. Optimal glycemic control with diabetes medications can normalize plasma lipid levels in most individuals with T1DM. Insulin resistance is central to the pathophysiology of dyslipidemia in T2DM, with obesity and independently inherited detrimental lipid genes exacerbating the phenotype. Aggressive LDL lowering is key in individuals with T2DM because of their very high risk for ASCVD. High doses of potent statins are the first line of therapy followed by ezetimibe, which will be required to achieve LDL cholesterol levels well below 100 mg/dl. Therapy with lifestyle, and if needed, TG-lowering agents such as fibrates and omega-3 fatty acid concentrates can be used to treat hypertriglyceridemia, with the understanding that these agents have not consistently reduced ASCVD events. When individuals with T2DM also have very high levels of LDL cholesterol, PCSK9 inhibitors should be considered.
KeywordsDiabetes mellitus Dyslipidemia Hypertriglyceridemia Hypercholesterolemia Very-low-density lipoproteins Chylomicrons Low-density lipoproteins High-density lipoproteins Apolipoprotein B Apolipoprotein A-I
Numerous prospective cohort studies have indicated that diabetes mellitus (DM) is associated with a 3–4-fold increase in risk for atherosclerotic cardiovascular disease (ASCVD) (Kannel et al. 1990; Haffner 1998; Haffner et al. 1998). Furthermore, patients with DM have a 50% greater in-hospital mortality and a 2-fold increased rate of death within 2 years of surviving a myocardial infarction. This increased risk is particularly evident in both younger age groups and women. Females with Type 2 diabetes mellitus (T2DM) appear to lose a great deal of the protection from ASCVD that characterizes nondiabetic females. Of particular concern is the finding that the incidence and prevalence of T2DM have doubled between 1980 and 2012 with further rises noted in minorities such as Hispanics and African Americans (Geiss et al. 2014). In the USA in 2014, the number of newly diagnosed cases of T2DM was approximately 1.4 million. ASCVD is the major cause of morbidity and mortality in people with T2DM (Low Wang et al. 2016).
Although much of this increased risk is associated with the presence of well-characterized risk factors for ASCVD, a significant proportion remains unexplained. Patients with DM, particularly those with T2DM, have abnormalities of plasma lipids and lipoprotein concentrations that are less common in nondiabetics (Taskinen 1990; Dunn 1990; Ginsberg 1998). These lipid abnormalities include high triglycerides (TG), decreased high-density lipoprotein (HDL) cholesterol, and presence of small cholesteryl ester depleted low-density lipoprotein (LDL) particles and have been called the diabetic dyslipidemia. Patients with poorly controlled Type 1 DM (T1DM) can also have a dyslipidemic pattern. In this chapter, we will focus on approaches to the diabetic patient with significant dyslipidemia. Normal lipid and lipoprotein physiology will be reviewed briefly as a base from which we will examine the approach to treating the dyslipidemia commonly associated with diabetes.
Physical-chemical characteristics of the major lipoprotein classes
Characteristics of the major apolipoproteins
Structural component of HDL; LCAT activator
Unknown; possibly facilitates transfer of apos between HDL and chylomicrons apo A5
Necessary for assembly and secretion of chylomicrons from the small intestine
VLDL, IDL, LDL
Necessary for the assembly and secretion of VLDL from the liver; structural protein of VLDL, IDL, and LDL; ligand for the LDL receptor
Chylomicrons, VLDL, IDL, HDL
May inhibit hepatic uptake of chylomicrons and
Chylomicrons, VLDL, IDL, HDL
Activator of lipoprotein lipase
Chylomicrons, VLDL, IDL, HDL
Inhibitor of lipoprotein lipase; inhibits hepatic uptake of chylomicron and VLDL remnants
Chylomicrons, VLDL, IDL, HDL
Ligand for binding of several lipoproteins to the LDL receptor, LRP, and proteoglycans
Composed of LDL apoB linked covalently to apo(a); function unknown but is an independent predictor of coronary artery disease
Transport of Dietary Lipids on apo B48-Containing Lipoproteins in Diabetes Mellitus
After ingestion of a meal, dietary fat (TG) and cholesterol are absorbed into the cells of the small intestine and are incorporated into the core of nascent chylomicrons. The newly formed chylomicrons are secreted into the lymphatic system and then enter the circulation via the thoracic duct into the superior vena cava. In the lymph and the blood, chylomicrons acquire apo C-II, apo C-III, and apo E. In the capillary beds of adipose tissue and muscle, chylomicrons interact with the enzyme lipoprotein lipase (LpL), which is activated by apo C-II, and the chylomicron core TG is hydrolyzed. The lipolytic products, free fatty acids (FAs), can be taken up by fat cells and reincorporated into TG or into muscle cells where they can be used for energy. Some fatty acids can bind to albumin and circulate in the blood with uptake by the liver, where they are used for energy or synthesized back to TG for secretion in VLDL. apo C-III can inhibit lipolysis, and the balance of apo C-II and apo C-III determines, in part, the efficiency with which LpL hydrolyzes chylomicron TG. Three other proteins, apo A-V and the angiopoietin-like proteins (angptl3 and angptl4), are also important; apo A-V facilitates LpL-mediated lipolysis whereas angptl3 and angptl4 inhibit lipolysis. Recently, a protein called glycosylphosphoinositol HDL-binding protein-1 (GPIHBP1) was identified as critical component of LpL transport from adipose tissue or muscle to the luminal surface of capillary endothelial cells, where it anchors LpL. Absence of GPIHBP1 renders LpL inactive. Mutations in the gene for lipase maturation factor 1 are another rare cause of severe hypertriglyceridemia. Overall, in the past 15 years, the complexity of the processes removing TG from chylomicron (and VLDL) has become much better appreciated (GM et al. 2010; Olivecrona 2016).
Under normal conditions, apo B48-containing chylomicron remnants, which are the products of this lipolytic process, have lost about 80–85% of their TG and are relatively enriched in cholesteryl esters (both from the original dietary sources and from HDL-derived cholesteryl ester which has been transferred to the chylomicron by cholesteryl ester transfer protein [CETP]). The chylomicron remnants are also enriched in apo E, and this protein is important for the interaction of chylomicron remnants with several receptor and nonreceptor pathways on hepatocytes that rapidly remove them from the circulation. Uptake of chylomicron remnants involves binding to the LDL receptor, the LDL receptor related protein (LRP), hepatic lipase, and cell surface proteoglycans (Cooper 1997; Bishop et al. 2008).
apo E is thought to play a critical role in the hepatic uptake of chylomicron remnants. The gene for apo E has three variants, E2, E3, and E4, which among other difference, bind to the LDL receptor with varying affinity. apo E2 that is found in about 10% of the population and is defective in binding to the LDL receptor and individuals with both T2DM and either one or two apo E2 isoforms can have more severe dyslipidemia. Hepatic triglyceride lipase (HTGL), which both hydrolyzes chylomicron- and VLDL-remnant TG, as well as acting on HDL TG and phospholipids, may also play a role in remnant removal (Kobayashi et al. 2015). Deficiency of HTGL might, therefore, be associated with reduced remnant clearance. However, several studies have indicated that HTGL is elevated in T2DM and may, because it can hydrolyze phospholipids on the surface of HDL leading to instability of the lipoprotein, be an important contributor to low HDL cholesterol levels in this disease.
Chylomicron and chylomicron-remnant metabolism can be altered significantly in diabetes. In untreated T1DM, LpL will be low, and postprandial TG levels will, in turn, be increased. Insulin therapy increases LpL, resulting in improved clearance of chylomicron TG from plasma. In well-controlled T1DM, LpL measured in postheparin plasma (heparin releases LpL from the surface of endothelial cells where it is usually found), as well as adipose tissue LpL, can be normal or increased, and chylomicron TG clearance can be normal.
In T2DM, metabolism of dietary lipids is complicated by coexistent obesity and the hypertriglyceridemia associated with insulin resistance. Studies in diabetic animal models have demonstrated increased intestinal secretion of apo B48-containing lipoproteins, accompanied by increased expression, mass, and activity of intestinal microsomal TG transfer protein (MTP) (Adeli and Lewis 2008). Similar findings have been reported in humans with insulin resistance (IR) with or without T2DM and seem to be driven both by increased FA levels in plasma that can be taken up by enterocytes and the insulin-resistant state itself (Dash et al. 2015). Very recent studies indicate roles for the glucagon-like proteins in chylomicron assembly and secretion: GLP-1 inhibits and GLP-2 increases secretion of chylomicrons (Dash et al. 2015). Thus, there are more, possibly smaller, chylomicrons entering the circulation after consumption of a fatty meal by individuals with T2DM, raising the possibility of competition amongst chylomicrons (and VLDL) for LpL (Brunzell et al. 1973). The possibility of decreased efficiency of LpL-mediated lipolysis due to increased numbers of chylomicron T2DM is increased by modestly decreased LpL activity in IR states as well as increased apo C-III relative to apo C-II levels. Increased apo C-III secretion into plasma has been demonstrated in patients with diabetes and hypertriglyceridemia (Cohn et al. 2004; Nagashima et al. 2005), and this may also reduce hepatic uptake of chylomicron remnants. There have also been reports of alterations in hepatic heparin sulfate proteoglycans in mouse models of diabetes, further affecting negatively remnant removal by the liver.
Transport of Endogenous Lipids on apo B100-Containing Lipoproteins in Diabetes Mellitus
Whereas the role of chylomicrons is to transport dietary nutrients from the small intestine to adipose tissue, skeletal muscle, and the liver, the role of VLDL appears to be the transport of excess energy from the liver to adipose tissue and skeletal muscle. This extra energy is in the form of TG that can derive from amino acids via gluconeogenesis and hepatic de novo lipogenesis (DNL), glucose via DNL, and FAs taken up from the circulation. Three major sources of hepatic FAs can be involved in VLDL assembly; the first is increased hepatic FA flux to the liver from adipose tissue in IR with or without DM due to reduced anti-lipolytic effects of insulin on adipocytes. The importance of FA uptake by the liver for VLDL secretion has been demonstrated in mice infused with oleic acid bound to albumin (Zhang et al. 2004) and in humans receiving lipid emulsions and heparin (Lewis et al. 1995). Second is uptake of TG-containing chylomicrons and VLDL remnants can also stimulate assembly and secretion of VLDL (Cooper 1997). Finally, in animal models, increased hepatic DNL stimulates VLDL TG secretion but, unlike increased uptake of FA or remnants from the circulation, which stimulate secretion of both apo B100 and TG, increases in DNL are associated with secretion of the same number of larger, more TG-rich particles (Horton et al. 1999; Grefhorst et al. 2002). These findings are consistent with increased rates of DNL in people with T2DM (Ma et al. 2015) and increased secretion of the more buoyant and TG-rich VLDL1 subclass in the same group (Adiels et al. 2005). In fact, the major factors correlating with secretion of VLDL1 are hepatic fat and the level of glycemia. Importantly, however, IR/T2DM is also associated with assembly and secretion of VLDL particles as measured by secretion rates of apo B100.
Throughout the day, during both fasting and postprandial states, the liver assembles and secretes VLDL. VLDL is assembled in the endoplasmic reticulum of hepatocytes. As described above, VLDL TG derives from the combination of glycerol with circulating FAs derived from adipose tissue and taken up by the liver, FAs derived from chylomicron and VLDL remnants uptake by the liver, and FAs produced from glucose by hepatic de novo lipogenesis (DNL). Of these three, circulating FAs are by far the major source of TG-FAs in the liver (Donnelly et al. 2005). VLDL cholesterol is either synthesized in the liver from acetate or delivered to the liver by lipoproteins, mainly chylomicron remnants an LDL. The driving force for VLDL secretion is mainly the maintenance of normal hepatic TG levels, although hepatic cholesterol metabolism also can affect VLDL production. apo B100 and phospholipids form the surface of VLDL; there is one apo B100 on each VLDL particle and, therefore, the rate of secretion of apo B100 determines the number of VLDL particles entering the circulation. Since VLDL is the precursor of LDL, high rates of VLDL apo B100 secretion usually result in increased levels of LDL. Although some apo C-I, apo C-II, apo C-III, and apo E are present on the nascent VLDL particles as they are secreted from the hepatocyte, the majority of these molecules are probably added to VLDL after their entry into plasma. Importantly, a significant proportion of newly synthesized apo B100 may be degraded before secretion, and this degradation is inhibited when hepatic lipids are abundant (Ginsberg and Fisher 2009).
Once in the plasma, hydrolysis of VLDL TG by LpL is key for the delivery of VLDL TG-FA to adipose tissue and muscle, and this process can be modulated by all the factors that affected chylomicron lipolysis: apo C-II, apo C-III, apo A-V, the angptl proteins, and GPIHBP1. The result is generation of smaller, denser, cholesterol ester-enriched VLDL called VLDL remnants. IDL are very closely related to VLDL remnants but for the purposes of this review will be considered to be products of further lipolysis of VLDL remnants. VLDL remnants are similar to chylomicron remnants except that they carry apo B100 rather than apo B48. Additionally, unlike chylomicron remnants, not all VLDL remnants are removed by the liver but can be converted to IDL and LDL. IDL particles can also be taken up by the liver or undergo further catabolism to become LDL. Some LpL activity appears necessary for normal functioning of the metabolic cascade from VLDL to IDL to LDL. It also appears that apo E, HTGL, apo C-III, LDL receptors, and hepatic cell surface proteoglycans all play important roles in this process, with HTGL having roles in both uptake of VLDL remnants and IDL by the liver and further lipolysis of IDL to produce LDL. apo B100 is essentially the sole protein on the surface of LDL, and the lifetime of LDL in plasma appears to be mainly determined by the availability of LDL receptors. Overall, about 80% of LDL catabolism from plasma occurs via the LDL receptor pathway, while the remaining tissue uptake is by nonreceptor or alternative-receptor pathways. One of these alternative pathways may recognize glycosylated and/or oxidatively modified lipoproteins, which can be present in increased amounts in the blood of patients with DM (Ginsberg 1991).
Diabetic patients commonly have elevated plasma levels of VLDL TG, in the range of 150–250 mg/dl. In T1DM, TG levels correlate closely with glycemic control, and marked hyperlipemia can be found during episodes of ketoacidosis. The basis for increased VLDL levels in poorly controlled but nonketotic T1DM subjects is usually overproduction of these lipoproteins (Dunn 1990). Reduced clearance plays a more significant role in severe cases of high TG in uncontrolled T1DM. This results from a reduction of LpL, which returns to normal with adequate insulinization. Plasma TG can actually be “low-normal” with intensive insulin treatment in T1DM, and lower than average production rates of VLDL have been observed in such instances. Several qualitative abnormalities in VLDL composition may persist, however, including enrichment in free and esterified cholesterol and an increase in the ratio of free cholesterol to lecithin. The latter may be an indication of increased risk for ASCVD.
Overproduction of VLDL, with increased secretion of both triglyceride and apo B100, seems to be the central etiology of increased plasma VLDL levels in patients with T2DM (Adiels et al. 2008). As described above, there are three sources of fatty acids that can stimulate VLDL assembly and secretion, and they can all be increased in T2DM: increased FA flux to the liver resulting from adipose tissue IR, uptake of VLDL and chylomicron remnants that are more TG-enriched than normal because of somewhat reduced LpL activity, and increased DNL. As noted above, the first two increase secretion of both VLDL TG and apo B100 whereas the third only increases VLDL TG secretion. Thus, greater rates of DNL in people with T2DM are associated with larger, more TG-enriched VLDL. Of these three, circulating FAs are by far the major source of TG-FAs in the liver (Donnelly et al. 2005). It is important to note that hepatic IR pertains to loss of the inhibitory effects of insulin on hepatic gluconeogenesis, whereas insulin seems to maintain its lipogenic effects. Additionally, increased assembly and secretion of VLDL occur despite the demonstration that acute hyperinsulinemia targets apo B100 for degradation in cultured liver cells. The loss of that action of insulin results from the development of IR in the pathway of apo B100 degradation during chronic hyperinsulinemia (Moon et al. 2012).
Because obesity, IR, and independently inherited familial forms of hyperlipidemia are common in T2DM, study of the pathophysiology is difficult. The interaction of these overlapping traits also makes therapy less effective. In contrast to T1DM, where intensive insulin therapy normalizes (or even “super-normalizes”) VLDL levels and metabolism, therapy of T2DM with either insulin or oral agents only partly corrects VLDL abnormalities in the majority of patients. Therapies for the diabetic dyslipidemia will be discussed later in this chapter.
If glycemic control is good, LDL cholesterol levels and LDL metabolism are usually normal in patients with T1DM. In fact, with intensive insulin treatment, LDL production falls concomitant with reduced VLDL production (Dunn 1990). The LDL receptor is regulated to some extent by insulin, and severe insulin deficiency may lead to reduced catabolism of LDL. Patients with T1DM may have increased ratios of free cholesterol:lecithin even when glycemic control is adequate. Glycosylation of LDL does appear to occur in poorly controlled patients with DM, and reduced catabolism of LDL via the LDL receptor pathway has been observed in some, but not all, in vitro studies using diabetic LDL and cultured fibroblasts.
In T2DM, regulation of plasma levels of LDL, like that of its precursor VLDL, is complex. In the presence of hypertriglyceridemia, dense, triglyceride-enriched and cholesteryl ester depleted LDL is present. Thus individuals with T2DM and mild to moderate hypertriglyceridemia may have the pattern B profile of LDL described by Austin and Krauss (Austin et al. 1990). Patients with T2DM can be shown to have overproduction of LDL apo B100 even with mild degrees of hyperglycemia, particularly if there is concomitant elevation of VLDL. This situation is made more complex by the observation that there is both reduced VLDL conversion to LDL and direct LDL entry into plasma in T2DM (Kissebah et al. 1982).
Fractional removal of LDL, mainly via LDL receptor pathways, can be increased, normal, or reduced in T2DM. Increased LDL fractional catabolism is often seen in nondiabetics with significant hypertriglyceridemia, and while the basis for this is uncertain, elevated plasma triglyceride levels can probably also increase LDL catabolism in patients with T2DM. As insulin seems to be required for normal LDL receptor function, reduced LDL fractional removal from plasma has, therefore, been observed in poorly controlled T2DM. This could also be a consequence of glycosylation of LDL. These multiple potential effects on LDL metabolism make it difficult to predict what level of LDL will be present in any individual with T2DM. Overall, LDL elevations are not more commonly present in men with T2DM, although women with T2DM tend to have higher levels of LDL than women without diabetes. Of course, any one individual could have a high LDL-C based on unrelated genetic influences, and with increasing obesity, T2DM is becoming more common in people with familial hypercholesterolemia.
Some investigators have suggested that glycosylated LDL can be taken up by macrophage scavenger receptors and contribute to foam cell formation. Other studies indicate that LDL from patients with diabetes, particularly small, dense LDL, may be more susceptible to oxidative modification and catabolism via macrophage scavenger receptors.
In summary, T1DM may be associated with elevations of VLDL triglyceride and LDL cholesterol if diabetic control is very poor or if the patient is actually ketotic. In contrast, T2DM is usually almost always associated with lipid abnormalities, most common of which are high TG, reduced HDL-C levels, and the presence of smaller, cholesteryl ester depleted LDL.
Transport of apo A-Containing Lipoproteins in Diabetes Mellitus
HDL may be the most complex of all the lipoprotein class. Subclasses of HDL, varying in size, density, lipid composition, and apolipoprotein components, have been isolated by a variety of physical-chemical techniques. Although we refer to HDL as the “apo A”-containing lipoproteins, as noted earlier there are approximately 100 proteins associated with HDL (Gordon et al. 2010).
Nascent HDL is secreted from the liver and the small intestine as phospholipid discs mainly containing apo A-I; they are called pre-beta HDL. The liver is the source of about 70% of these nascent HDLs (Timmins et al. 2005; Brunham et al. 2006). These disc-like HDLs, particularly those with apo A-I, appear to be the best acceptors of membrane free cholesterol and may be the initial HDL particles involved in RCT. The initial step in this process begins with the ATP-binding cassette transporter A1 (ABCA1) transferring intracellular and plasma membrane free (unesterified) cholesterol to pre-beta HDL. The next step, which begins the process of generating mature HDL, involves the conversion of free cholesterol to CE by LCAT, which is activated by apo A-I. CEs move from the surface to the core of the maturing HDL particle, allowing addition of more free cholesterol to the surface, followed by more CE generation. As HDL particles mature, additional free cholesterol can also be added via ATP-binding cassette transporter G1 (ABCG1) and scavenger receptor B1 (SR-B1), giving rise to mature, CE-rich HDL. Mature HDL particles can deliver both free and esterified cholesterol to the liver via interaction with SR-B1 (Trigatti et al. 2000; Shen et al. 2017). It has yet to be proven, however, that RCT is critical for “clearing” cholesterol from peripheral tissues, including foam cells in arterial plaques, to the liver (Tall and Rader 2018).
In humans, the CETP-mediated transfer of cholesteryl ester from HDL to triglyceride-rich lipoproteins (chylomicrons and VLDL in the fed and fasted states, respectively) appears to be an alternative pathway for RCT as the cholesteryl esters can then be taken up by the liver; chylomicron remnants, VLDL remnants or IDL, and finally LDL are all active participants in this pathway. However, if hepatic LDL receptors are downregulated, the CE enriched apoB lipoproteins will circulate for extended periods of time and can deliver their CE back to the vessels from which they originally came.
In T2DM, multiple factors acting in concert result in lower levels of HDL-C and apo A-I. CETP-mediated exchange of TG for CE in both the fasting and postprandial states clearly plays an important role in altering HDL levels in T2DM (Riemens et al. 1998). TG enrichment of HDL is followed by lipolysis of TG, mainly by HTGL, leading to generation of smaller HDL particles from which apo A-I can dissociate (Horowitz et al. 1993). The free apo A-I can be filtered through the glomerulus and then taken up and degraded by renal tubular cells (Horowitz et al. 1993); this increased clearance of apo A-I from plasma, confirmed by HDL turnover studies demonstrating increased apo A-I fractional removal rates, is the hallmark of low levels of the protein and HDL-C in states of IR and low HDL (Horowitz et al. 1993; Brinton et al. 1994). Thus, CETP-mediated mechanisms result in both less CE in HDL and fewer HDL particles. However, IR itself lowers HDL levels by pathways that are not fully understood. Recent studies demonstrated that when hepatic insulin signaling is reduced, apo A-I gene expression and protein synthesis are decreased by a mechanism involving type 1 deiodinase in the liver (Liu et al. 2016). Increased hydrolysis of HDL phospholipids by HL activity, which is increased in IR/T2DM, results in disruption of particles with loss of CE and apo A-I (Deeb et al. 2003). The decrease in HDL particles available for participation in RCT may be important to the atherogenicity of the dyslipidemia associated with T2DM.
In T1DM, HDL cholesterol levels are often normal, and studies of the relationship between HDL cholesterol levels and degree of glycemic control in these patients have been inconsistent. HDL levels may actually be increased in individuals receiving intensive insulin therapy, and this may be linked to increased LpL activity and/or reduced HTGL activity. Lipoprotein turnover studied indicate that there are no differences in apo A-I metabolism between patients with T1DM and nondiabetics when they are matched for a wide range of HDL cholesterol concentrations.
Reduced plasma HDL cholesterol levels do not seem to be related to control or mode of treatment in patients with T2DM. Once again, however, understanding the metabolism of HDL in T2DM is complicated by the common presence of obesity and insulin resistance-associated dyslipidemias in this group. A consistent finding is the inverse relationship between plasma insulin (or C-peptide) concentrations, which are measures of insulin resistance, and HDL-C levels.
Treatment of Diabetic Dyslipidemia
The centerpiece of therapy for the treatment of diabetes is always diet, irrespective of the absence or presence of dyslipidemia (American Diabetes Association 2018). However, the presence of dyslipidemia increases the rationale for intensive diet intervention. It is important to remember that improvements in plasma triglyceride and total cholesterol levels during dietary intervention can be observed even in the absence of weight loss. Thus, reductions in dietary saturated fat intake, along with reduced cholesterol consumption, can lower plasma TG and LDL cholesterol levels even if caloric intake is unchanged. Which nutrients to use as replacement for saturated fats, i.e., carbohydrates or mono- and polyunsaturated fats, has been one of the longest ongoing controversies in the field of nutrition. However, when the patient also has diabetes, the issue becomes less contentious because of the need to control carbohydrate intake. We will not discuss this further, other than to say that simultaneous control of both plasma glucose and lipids (particularly triglycerides) is possible with judicious use of high fiber carbohydrates balanced with moderate increases in mono- and polyunsaturated fats as replacements for saturated fats.
Of course, achievement of optimum weight, which for many people with T2DM and dyslipidemia requires a BMI of 27 or less, is probably as important, or more important, than the exact balance of nutrients. Unfortunately, the optimal weight loss diet in anyone, and in particular in people with diabetes and dyslipidemia, is even more controversial than the optimal isocaloric nutrient mix (American Diabetes Association 2018). One exception would be patients with severe hypertriglyceridemia (>1000 mg/dl), who are at risk or have already had episodes of pancreatitis. These patients require very low fat diets (<15% calories) with high fiber carbohydrates as replacement calories. In the most extreme cases, or when glucose control is difficult to achieve because of the increased carbohydrate intake, medium chain triglycerides, which are not carried in chylomicrons, can be used to allow for less carbohydrate intake without affecting plasma triglyceride levels. Many of these individuals would benefit from weight loss, so reduction in dietary fat intake without nutrient replacement is a good option.
The omega-3 fatty acids are unique polyunsaturated fatty acids that continue to arouse considerable interest (American Heart Association 2017). These fatty acids, found mostly in fatty fish, are comprised mainly of eicosapentaenoic acid and docosahexaenoic acid. Alpha-linolenic acid, present in vegetables such as linseed, is also an omega-3 FA. When consumed in large quantities (3–4 gm/day), the omega-3 FAs can cause a very significant decrease in plasma VLDL concentrations in subjects with severe (>1000 mg/dl) hypertriglyceridemia. In milder forms of hypertriglyceridemia, reductions in VLDL are often associated with increases in plasma LDL and apoB levels. These responses to increased intake of omega-3 FA, whether as fish or supplements, have been observed in both nondiabetics and diabetics. Several cohort studies and intervention trials suggest that diets high in omega-3 fatty acids are associated with reduced rates of ASCVD in high-risk populations (American Heart Association 2017). Although ingestion of increased quantities of fish should be recommended, the evidence for use of large doses of omega-3 FA supplements is, at best, minimal and not recommended for the prevention of most types of cardiovascular disease (American Heart Association 2017). This recommendation may change in the near future if two large, ongoing ASCVD outcome trials with high doses of omega-3 fatty acid concentrates are positive.
Lipid Lowering Therapies
Current Treatment Guidelines
In the past 30 years, a series of guidelines, both in the USA and other countries, have progressively addressed accumulating data demonstrating the efficacy of lowering LDL cholesterol levels to prevent ASCVD. Most guidelines have recognized the significantly increased risk of ASCVD in people with diabetes mellitus, although not necessarily considering them to have coronary heart disease (CHD) equivalence (Low Wang et al. 2016). In the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, which markedly altered approaches to lowering LDL-C in people at risk for CVD in the USA (Stone et al. 2014), diabetes was considered to be a high risk category and treatment with high doses of potent statins recommended for secondary prevention patients and moderate to high dose treatment for those who have not had an event yet, depending on overall risk. The recently released 2015 ACC/AHA report (Drozda et al. 2015) suggested that individuals with diabetes receive moderate-intensity statin therapy for adults 40–75 years, with high-intensity statin therapy to be considered for such individuals with a ≥7.5% estimated 10-year ASCVD risk or a prior CVD event. In adults with diabetes, who are <40 years of age or >75 years of age, or who have a LDL <70 mg/dL, it was recommended that health providers evaluate the potential for ASCVD benefits and for adverse effects and drug–drug interactions and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy. Similar recommendations have been issued by the European Atherosclerosis Society (EAS), European Society of Cardiology (ESC) (ESC/EAS 2016), and the European Association for the Study of Diabetes (EASD) (Ryden et al. 2007). Fortunately for our patients, we have outstanding pharmacologic therapies for those patients requiring more than nutrition and exercise prescriptions. As noted above, this applies to almost everyone with diabetes mellitus.
Statin therapy is considered first-line treatment for hyperlipidemia in all patients, including those with diabetes (Stone et al. 2014). In a meta-analysis of 14 RCTs which included 18,686 patients with T2DM, statin monotherapy resulted in a 9% reduction in all-cause mortality and a 21% reduction in the incidence of major cardiovascular incidents per mmol/L of LDL lowered (Kearney et al. 2008). There are several agents available for clinical use: lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, and pitavastatin. These agents lower LDL-C by 18–55% depending on dose and statin, increase HDL-C by 5–10%, and reduce TG levels by 7–30% (Ginsberg 2006).
Statins lower LDL-C by inhibiting cholesterol biosynthesis, which by reducing hepatic cholesterol concentrations, leads to upregulation of hepatic LDL receptors and increased LDL particle clearance. In insulin-resistant individuals with dyslipidemia, statins can also reduce the hepatic assembly and secretion of apo B-containing lipoproteins (Ginsberg 2006).
Ezetimibe: This drug reduces plasma LDL cholesterol by inhibiting intestinal absorption of both dietary cholesterol and cholesterol entering the intestinal track from the biliary tree. The loss of cholesterol in feces leads to an upregulation in the liver of both cholesterol synthesis and the synthesis of LDL receptors. The latter effect predominates, resulting in greater LDL receptor-mediated uptake of circulating LDL particles and, therefore, lowering of plasma LDL cholesterol levels. After several studies of the effects of ezetimibe on ASCVD risk that produced mixed outcomes, the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated reduced ASCVD events with lowering of LDL cholesterol from 67 to 54 mg/dl (Cannon et al. 2015). Although the relative benefit was small (about 7%), it was concordant with what would be expected based on the meta-analysis of all statin trials, where a lowering of LDL cholesterol of about 39 mg/dl results in about a 23% reduction event. This trial was not only crucial because it supported the use of a nonstatin drug in combination with statin treatment but because it supported the LDL hypothesis, which is that lowering LDL cholesterol by any means will reduce rates of ASCVD events (MG et al. 2016). Importantly, and consistent with many of the statin-monotherapy trials, participants with diabetes mellitus had the highest event rates and the best therapeutic response to LDL lowering.
PCSK9 Inhibitors: Serum proprotein convertase/subtilisin kexin 9 (PCSK9) binds to low-density lipoprotein receptors and targets them to the lysosome, along with LDL, instead of allowing them to recycle efficiently. This results in fewer LDL receptors on the surface of cells, particularly the liver, increasing serum LDL-C (Seidah 2011). In response to a rapid series of preclinical studies and population genetics (Cohen et al. 2006), several companies developed monoclonal antibodies that bind PCSK9 in the circulation, rendering them unable to bind to the LDL receptor. Two fully human monoclonal antibodies to PCSK9, evolocumab and alirocumab, have shown the ability to reduce LDL levels between 50–70% in short-term studies and were approved by the FDA and the EMA. Secondary analyses of the OSLER and ODYSSEY LONG TERM studies of the efficacy of evolocumab and alirocumab, respectively, published in 2015, demonstrated evidence of improving patient outcomes by reducing the rate of major adverse cardiovascular events (MACE) compared to standard statin therapy (Sabatine et al. 2015; Robinson et al. 2015). They were followed by the publication by the full Fourier outcome trial (Sabatine et al. 2017a) and a secondary analysis of Fourier subjects with and without diabetes mellitus (Sabatine et al. 2017b) that both showed significant reductions in MACE with evolocumab therapy in patients already receiving statins. The Odyssey Outcomes trial with alirocumab will be reported in the near future (Schwartz et al. 2014). Development of a siRNA is ongoing and may allow fewer injections with similar efficacy (Ray et al. 2017). PCSK9 inhibitors may be a major advance in the treatment of individuals with T2DM who have very high plasma LDL cholesterol levels in addition to the typical diabetic dyslipidemia.
Fibrates: Although fibrates have been available for more than 40 years as effective agents to lower triglyceride and raise HDL cholesterol levels, their efficacy as cardioprotective drugs remains in doubt. Several early studies of fibrate monotherapy to reduce CVD events, including the Helsinki Heart Study, the VA-HIT Study, and the Bezafibrate Infarction Prevention Trial, gave variable results (Frick et al. 1987; Rubins et al. 1999; Bezafibrate Infarction Prevention (BIP) Study 2000). Two fibrate trials that focused on patients with T2DM, FIELD (Keech et al. 2005) and ACCORD (Ginsberg et al. 2010), failed to meet their primary outcomes, although a prespecified subgroup analysis of ACCORD patients defined by TG levels in the upper tertile (>204 mg/dl) and HDL-C levels in the lower tertile (<34 mg/dl) had 29% fewer events than those without dyslipidemia. This dyslipidemic group comprised 17% of the total participants. The latter results remained constant in a 6 year observational follow-up of the trial (Elam et al. 2017). Importantly, post-hoc analyses of the Helsinki Heart Study (Frick et al. 1987), the Bezafibrate Infarction Prevention Trial (Bezafibrate Infarction Prevention (BIP) Study 2000), and FIELD (Scott et al. 2009) both showed marked benefits in groups with baseline TG levels greater than 200 mg/dl with or without low HDL-C levels. A study with a new fibrate, pemafibrate, is just starting and will enroll 10,000 participants, all with TG levels >200 mg/dl and HDL-C <40 mg/dl. It will take several years for the trial to be completed.
Niacin: Niacin was a mainstay of the treatment of patients with familial hypercholesterolemia in the pre-statin era. In the 1970s, the Coronary Drug Project Niacin arm showed a significant reduction in CVD events in men who had survived prior events. In the ensuing years, niacin was used for treatment of hypertriglyceridemia and low HDL-C. Niacin has many side effects that are annoying but harmless (flushing, itching), but it can also be hepatotoxic and can worsen preexisting diabetes or convert individuals with prediabetes to full diabetes. Because of the latter problems, niacin was used very sparsely and with care in individuals with T2DM, despite its excellent effects on all the classes of lipoproteins. Two recent studies, Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) (Boden et al. 2011) and the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) (Landray et al. 2014), in which niacin was added to statin therapy, failed to show benefit over statin alone and confirmed the diabetogenic effects of niacin. As a result, use of niacin has fallen to very low levels overall and is rarely used in people with prediabetes or diabetes.
Bile Acid Binding Resins: Interrupting the enterohepatic recirculation of bile acids causes the liver to increase both cholesterol synthesis and LDL receptors to bring more cholesterol into the liver. The result is a lowering of circulating LDL cholesterol ranging from 10% to 25% depending on the dose taken. Early versions of the binding resins, cholestyramine and colestipol, were difficult to take and had significant gastrointestinal side effects. However, both were demonstrated to reduce ASCVD in large randomized trials (National Cholesterol Education Program 2002). A drawback to their use was an increase in hepatic VLDL triglyceride production and plasma triglyceride levels. A new agent in this class is colesevelam, which has greater tolerability and fewer drug interactions than the other resins. GI side effects seem to be significantly reduced compared to the older bile acid sequestrants. All of the bile acid binding resins work very well with statins and with ezetimibe. Importantly, colesevelam reduces blood glucose concentrations with HbA1c reductions of about 0.5% achieved in people with diabetes (Hansen et al. 2017). This added benefit makes the bile acid sequestrants a good choice as a second drug in individuals with very high baseline LDL cholesterol levels who do not reach LDL goals on statin monotherapy.
Diabetes mellitus is associated with significant increases in all types of ASCVD. In T1DM, increased ASCVD is linked to hyperglycemia, renal disease, and hypertension, with dyslipidemia contributing when it is present. In T2DM, although the aforementioned complications of diabetes may each contribute to increased ASCVD, the dyslipidemia, which is almost universally present, plays a more important role. The dyslipidemia of T2DM affects both the intestinal and the hepatic lipoprotein pathways, with increased levels of apo B48 and apo B100 TG-rich lipoproteins (VLDL and chylomicrons and their remnants). LDL levels can vary and are linked both to abnormalities in VLDL metabolism and to common genes for hypercholesterolemia that can be independently inherited in individuals with either T1DM or T2DM. Treatments of lipid abnormalities in patients with T1DM are directed to glucose control: optimal therapy with diabetes medications can normalize plasma lipid levels in most instances. In T2DM, the dyslipidemia is most closely linked to the underlying insulin resistance in this patient population, with obesity and independently inherited detrimental lipid genes exacerbating the insulin-resistant dyslipidemia. Treatment options are both numerous and effective, with statin therapy of critical importance to lower risk for ASCVD. Because of the very high risk for ASCVD events in people with T2DM, aggressive LDL lowering is key, with high doses of potent statins the first line of therapy followed by ezetimibe, which will be required to achieve LDL cholesterol levels well below 100 mg/dl. Therapy with lifestyle, and if needed TG-lowering agents such as fibrates and omega-3 fatty acid concentrates, can be used to treat hypertriglyceridemia, with the understanding that these agents have not consistently reduced ASCVD events. For individuals with T2DM unfortunate enough to also have very high levels of LDL cholesterol, either on a polygenic basis or because they also have familial hypercholesterolemia, PCSK9 inhibitors should be considered.
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