Curr Cardiol Rep (2015) 17: 32 DOI 10.1007/s11886-015-0589-5

DIABETES AND CARDIOVASCULAR DISEASE (S MALIK, SECTION EDITOR)

Role for Combination Therapy in Diabetic Dyslipidemia Haider J. Warraich & Nathan D. Wong & Jamal S. Rana

Published online: 18 April 2015 # Springer Science+Business Media New York 2015

Abstract Individuals with type 2 diabetes mellitus have a high residual risk of cardiovascular disease (CVD) despite maximal statin therapy and lifestyle interventions. In addition, adults with diabetes frequently exhibit the pattern of elevated triglycerides, small dense LDL, and reduced levels of high density lipoprotein cholesterol (HDL), also known as diabetic dyslipidemia. The role of combination therapy with an additional agent such as niacin, ezetimibe, fenofibrate, and n-3 fatty acids have been extensively studied with disappointing results. Review of key trials assessing benefit of combination therapy to reduce CVD risk from dyslipidemia is performed. While combination therapy frequently results in an improvement in lipid profile, to date, no consistent improvement in clinical outcomes has been observed. Therefore, current guidelines do not recommend combination therapy in individuals with diabetes, highlighting the role of intensifying statin therapy and lifestyle interventions. The recently released The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE IT) demonstrated a small but

This article is part of the Topical Collection on Diabetes and Cardiovascular Disease H. J. Warraich Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA N. D. Wong Division of Cardiology, Department of Medicine, University of California Irvine, Irvine, CA, USA J. S. Rana (*) Division of Cardiology, Kaiser Permanente Medical Center, 3600 Broadway, Oakland 94611, CA, USA e-mail: [email protected] J. S. Rana Department of Medicine, University of California San Francisco, San Francisco, CA, USA

significant improvement in clinical endpoints with addition of ezetimibe to statins in high-risk patients. Although this trial was not specifically targeted towards patients with diabetes, the results may influence the future role of a combination therapy in such a population. Keywords Type 2 diabetes mellitus . Dyslipidemia . Statins . Fibrates . Ezetimibe . Fish oil

Introduction Cardiovascular disease (CVD) continues to account for the greatest amount of morbidity and mortality in both developed and developing countries [1]. A significant proportion of this burden occurs in patients with type 2 diabetes mellitus (T2DM), who are carrying a very high lifetime risk of suffering from cardiovascular complications such as myocardial infarction and cerebrovascular accidents [2, 3]. Furthermore, the proportion of CVD that occurs due to diabetes is on the rise in the general population [4]. The prevalence of T2DM is rising in the USA and worldwide: the incidence and prevalence of T2DM has doubled between 1990 and 2008, with further rises noted in minorities such as Hispanics and African Americans [5]. Therefore, reducing the risk of adverse cardiovascular events in this population is a significant public health priority. Lifestyle modification and statin therapy are the cornerstone of cardiovascular risk reduction in patients with T2DM [6]. Lifestyle modifications are the first line intervention and include weight loss, dietary modification and aerobic exercise. Statins are the mainstay in the pharmacologic management of hyperlipidemia in all populations including diabetics.

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Despite the established role of lifestyle modifications and statin therapy, individuals with diabetes remain at considerable risk for cardiovascular disease [7, 8]. This residual risk of atherosclerotic cardiovascular disease is due to unique pathophysiology of dyslipidemia in patients with T2DM. In this review of the literature, we seek to briefly outline the mechanisms of dyslipidemia in diabetics and how it differs from patients without diabetes. We outline risk reduction obtained with traditional interventions and then review some of the major trials studying combination pharmacotherapy in diabetic dyslipidemia. Finally, we outline the positions of major cardiovascular associations regarding management of hyperlipidemia in this population and then touch upon some areas of further investigation that may shape this area in the future.

Pathophysiology of Dyslipidemia in Diabetics Diabetics are considerably higher risk of cardiovascular disease compared to matched controls with some even considering diabetes a coronary artery disease equivalent [9, 10]. In the general population, the increased risk of atherosclerosis is brought about chiefly by raised low density lipoprotein cholesterol (LDL). [11] However, the prevalence of LDL is similar between diabetics and non-diabetics [12, 13], and data suggests that the elevated risk of cardiovascular disease in T2DM occurs independently of the serum LDL level [14]. These findings point to the altered pathophysiology of dyslipidemia in diabetics. While diabetics have similar LDL levels compared to controls [12, 13], they demonstrate a uniquely altered lipid profile. Diabetics frequently exhibit the pattern of elevated triglycerides and small dense LDL and reduced levels of high density lipoprotein cholesterol (HDL) [15]. Patients with T2DM also have a higher prevalence of small dense LDL particles that are known to be more atherogenic and are associated with a higher rate of nephropathy in diabetics [16]. Population-based epidemiologic studies such as the Framingham Heart Study and the United Kingdom Prospective Diabetes Study (UKPDS) have demonstrated that the prevalence of hypertriglyceridemia in diabetics is almost twice that in non-diabetics [12, 13]. A similar trend of reduced HDL levels is also noted in diabetics compared to matched controls [17]. Insulin resistance, increased in T2DM, is the central driver of the typical lipid derangements noted in diabetes [18]. Insulin resistance increases the flux of free fatty acids from adipose tissue which are taken up by the liver. This hepatic uptake of free fatty acids increases the synthesis of triglycerides by the liver. The increase in triglyceride synthesis in the liver stimulates increased hepatic production of triglyceride-rich very low density lipoprotein cholesterol (VLDL), which is also augmented by hyperglycemia, another characteristic of insulin resistance [19]. Increased hepatic triglyceride synthesis is also

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associated with increased secretion of apoB. Furthermore, the normal inhibitory effect of hyperinsulinemia on hepatic apoB production is also reduced in T2DM [20]. Subsequently, via the action of the cholesterol ester transfer protein (CETP), triglyceride enrichment of LDL and HDL from triglyceride laden VLDL occurs, which in turn becomes more cholesterol rich [21]. Triglyceride-rich LDL is then hydrolyzed by hepatic or lipoprotein lipase which results in the production of small dense LDL while triglyceride rich HDL, when hydrolyzed by hepatic and lipoprotein lipase, results in the loss of apoA-1 (the primary protein component of HDL), which is filtered by the renal glomeruli. Insulin resistance therefore not only results in the increased production of triglycerides and small dense LDL but also impairs reverse cholesterol transport with reduction in the concentrations of HDL and apoA-1, which are responsible for the transport of cholesterol esters from atherosclerotic lesions in the vasculature back to the liver. Insulin resistance, which mediates this widespread disruption of lipid metabolism, is itself brought about by heightened inflammation brought about by cytokines such as TNFα and adipokines produced by adipose tissue [22]. This systemic inflammation is reflected by rises in the level of serum markers such as high-sensitivity C-reactive protein (hsCRP) is known to independently reduce production of components of reverse cholesterol transport such as HDL and apoA-1 as well as increase in triglyceride synthesis [23]. The particular pathophysiology of diabetic dyslipidemia has made it challenging to treat for physicians. Metabolic dyslipidemia, even among those without diabetes has been associated with an increased risk of CHD, and this relationship was found to be independent from LDL and other risk factors of the metabolic syndrome, especially for men [24]. Whereas the traditional focus of hyperlipidemia management has been on the reduction of LDL levels, the derangements characteristic of diabetic dyslipidemia have made it challenging to rely solely on conventional means.

Lifestyle Interventions Lifestyle interventions in patients with T2DM comprise dietary restriction and physical exercise. The central role of dietary restriction lies in achieving weight loss. To achieve sustained weight loss, caloric restriction remains the key and even modest degrees of weight loss are associated with an improvement in glycemic and lipid profile. In one study that randomized obese and overweight diabetics to caloric restriction versus usual care, improvements in all markers including glycemic control, Hba1c and lipid profile was noted [25]. What remains somewhat unclear is which dietary modification is best to optimize cholesterol metabolism and maximize weight loss. The American Diabetic Association (ADA) in its most recent guidelines, recommends a diet low in transfat,

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saturated fat, and cholesterol [26]. In a similar vein, the Adult Treatment Panel III (ATPIII) also recommends a diet low in monosaturated fats [27]. Recently, however, studies increasingly favor low carbohydrate diets over low fat diets. A large multicenter trial in Spain that randomized patients to a Mediterranean diet supplemented with extra virgin olive oil or nuts showed a significant reduction in cardiovascular events compared to patients advised a low fat diet (96 and 83 events vs. 109 events) [28]. A subgroup analysis of this study showed that patients randomized to a Mediterranean diet also had a lower incidence of T2DM [29]. A carbohydrate-restricted diet has also been shown to be associated with greater weight loss compared to a low fat diet [25]. Dietary interventions, while considered first line treatment for all patients with diabetes, have not been successful in demonstrating a mortality benefit. While Look AHEAD (Action for Health in Diabetes), a multi-center randomized control trial (RCT), which randomized overweight and obese patients with T2DM to either caloric restriction and physical exercise or usual care, resulted in improvement in several CVD risk factors including obesity, no reduction in cardiovascular events or mortality was noted even after a median follow-up of 9.6 years [30]. While small but significant differences were noted in either LDL, HDL, or triglyceride levels, no statistical difference was noted in lipid profiles between the arms at the end of the study. The study was limited by the fact that weight loss was greater initially but was not sustained over time and that weight loss also occurred in the control arm as well. Exercise mediates its beneficial effects chiefly by achieving and maintaining weight loss. However, exercise also has additional benefits over and above achieving weight loss and in diabetics is associated with better glycemic control [31] as well as improvements in lipid profiles [32–34]. A reduction in cardiovascular events or mortality however has not been demonstrated in diabetics with exercise training.

Statin Therapy and Residual Risk Statins, the class of drugs that comprise HMG-coA reductase inhibitors, are considered first-line treatment for hyperlipidemia in all patients including those with diabetes. In a metaanalysis 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, which was similar to that in those without diabetes [35]. Furthermore, the relative risk reduction in all major outcomes including coronary events, coronary revascularization, stroke and major vascular events was similar for patients with or without diabetes [35]. The risk factor reduction brought about by statins occurs in a dose-dependent fashion, with higher dose statins associated with a greater lowering of

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cardiovascular events [36]. Intensive lowering of statins results in a linear reduction of CVD risk in patients regardless of their initial lipid profile [37]. Furthermore, while the greatest risk factor reduction is noted in patients at the highest risk of CVD, diabetics across the spectrum of risk derive a benefit in hard outcomes such as mortality with statin use [38]. The substantial benefits of statins are somewhat tempered by reports of a rise in incident diabetes in individuals treated with statins. Multiple reports have shown a small but consistent increase in the incidence of T2DM in patients treated with statins with the greatest rise noted in patients already at high risk for diabetes [39]. In the JUPITER trial, 270 patients treated with rosuvastatin developed T2DM compared to 216 on placebo [40]. The increased incidence of diabetes with statin use is not very large and is greatly offset by the benefits of statin therapy. One meta-analysis of 91,140 patients enrolled in 13 RCTs demonstrated that it took 255 patients treated with statins for 4 years to have one patient develop diabetes most of whom were pre-diabetic to begin with; yet, 5.4 vascular events were avoided in these 255 patients [41]. In sum, thus given their favorable risk-benefit profile, statins are recommended for use in all patients, even those at risk for developing diabetes. Even with the implementation of lifestyle modifications and the institution of statin therapy, patients with T2DM carry a substantial residual risk of future CVD [42]. Despite a multifaceted approach as applied in the STENO-2 trial, 50 % of patients went on to have microvascular complications from atherogenic dyslipidemia [43]. Over a mean duration of 7.8 years, 24 of 160 diabetics provided intensive therapy died compared to 40 in the conventional arm on the STENO-2 study [44]. One in seven of all diabetics treated with statins go on to suffer cardiovascular events over 5 years [35]. This significant residual risk has been the impetus behind investigators trying to find additional agents to lower CVD risk in diabetics. These additional agents include ezetimibe, fibrates, niacin, and n-3 fatty acids [45]. With statin therapy well established, the role of these agents as monotherapy is miniscule. However, considerable interest remains in using these agents in combination with statins.

Combination Therapy Given the established role of statin as an agent known to reduce mortality in patients with dyslipidemia including those with diabetes is well established, the role of monotherapy with a non-statin agent is only indicated in patients who do not tolerate statins. However, given the high residual risk of future CVD events in patients despite statin therapy, the role of adding a medication to supplement the risk reduction brought about by statins has been extensively studied. The primary medications that have been studied as adjuncts to statins

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include niacin, fibrates, ezetimibe, and n-3 fatty acid ethyl esters and are summarized in Table 1.

Statins and Niacin Nicotinic acid derivatives like niacin function by slowing hepatic removal of HDL by downregulating hepatic HDLApoA1 receptors and increases HDL production by amplifying the expression and secretion of CETP. Clinical studies have demonstrated that niacin produces a very robust increase in serum HDL [46]. When compared to the combination of lovastatin and colestipol in the FATS trial, the combination of niacin and colestipol improved HDL more so than LDL; atherosclerotic progression however was better in the lovastatin and colestipol combination [47]. When antioxidants were added to simvastatin and niacin in the HATS trial, CIMT regression actually decreased without any metabolic or clinical benefit although these patients did not specifically analyze diabetics [48]. In ARBITER 2, patients were randomized to extended release once daily dosed niacin on top of preexisting statin therapy versus statin and placebo [49]. While an improvement in HDL profile was noted, only patients with insulin resistance were noted to have improvement in CIMT regression compared to the control arm. ARBITER 3, an extension of ARBITER 2, however, did show net difference in CIMT regression between the niacin-statin combo group compared to the statinplacebo group [50]. In the OXFORD-NIASPAN study, patients treated with statin and niacin experienced greater reduction in carotid wall area as seen on magnetic resonance imaging compared to statin and placebo group [51]. This study too did not specifically look at diabetics. The first trial powered to assess clinical benefit of the addition of niacin to statin therapy was AIM-HIGH, which randomized 3414 patients with known CVD to extended release niacin or placebo [52]. These patients were already on intensive statin therapy with goal LDL of 40–80 mg/dl with ezetimibe used if LDL goal was not reached with statin alone. AIM-HIGH was stopped after 3 years for lack of clinical efficacy. Not only was niacin unable to reach the primary outcome, a statistically significant increase was noted in serious infections and gastrointestinal disorders. This was followed in 2014 by HPS-2 Thrive, in which 25,673 patients were randomized to extended release niacin-laropiprant versus placebo in patients on statins and tight LDL control [53]. Laropiprant is a prostaglandin D2 receptor antagonist that prevents flushing in around two-thirds of patients, therefore increasing adherence to niacin [54]. This trial not only did not show any clinical benefit with niacin after 3.9 years of median follow-up but resulted in a wide array of serious adverse effects including new onset diabetes and worsening of preexisting diabetes. This compound, marketed by Merck under the brand name

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Tredaptive®, was removed from the market after these results were released. In both AIM-HIGH and HPS2-Thrive, a third of the patients had diabetes, but results were not affected by diabetic status. A subsequent post-hoc analysis of AIMHIGH suggested that patients in the highest tertile of triglycerides and the lowest tertile of HDL demonstrated a trend towards possible benefit with the addition of niacin to statin therapy [55]. This result points to the need to identify the benefit of using niacin in patients with well-controlled LDL and deranged HDL and TG, and many patients in these trials did not specifically have both elevated triglycerides and low HDL-C. Importantly, these trials also enrolled patients with known CVD who were already on many recommended preventive therapies and given they were already treated to an LDL-C < 70 mg/dl in many cases may have made it difficult to show further added benefit. However, given the lack of a significant result and the presence of a wide array of serious adverse events noted with niacin, the future role of niacin as an adjunct to statin therapy for dyslipidemia appears limited. Statins and Fibrates Fibrates increase peroxisome proliferator-activated alpha (PPAR-α) activity and increase the expression of transcription factors responsible for ApoA1 synthesis which results in increased levels of HDL and also reduce hepatic triglyceride synthesis [56]. In the FIELD trial, which randomized 9795 diabetics to fenofibrate vs. placebo, a significant reduction in non-fatal MIs and revascularization was noted in patients in the intervention arm [57]. A subsequent analysis of the diabetic population showed that fenofibrate reduced CVD events in patients with elevated triglycerides independent of the HDL level [58]. However, fibrates were less promising when given in combination with statins in patients with diabetes. In the ACCORD trial, 5518 patients on statin therapy prior to enrollment were randomized to addition of fenofibrate or placebo [59••]. While no reduction in cardiovascular events was noted overall, in the pre-specified group in the highest third of triglyceride levels and lowest third of HDL, patients experienced a reduction in clinical events that was approached significance (12.4 vs. 17.3 %, p=0.057). Furthermore, females were noted to be at risk for possible harm (interaction p=0.01) compared to men. A meta-analysis of this and other fibrate trials in persons with DM show a consistent reduction in risk in the subgroup with high triglycerides and low HDL-C [60]. Statins and Ezetimibe Ezetimibe inhibits the intestinal absorption of cholesterol and increases the catabolism of LDL and has been

Curr Cardiol Rep (2015) 17: 32 Table 1

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Summary of key trials assessing benefit of combination therapy to reduce CVD risk from dyslipidemia

Trial name, intervention

Patients and design

Main results

Comments

ARBITER 2, 2004, extended release niacin and statin vs. statin and placebo [49]

167 patients with CAD, HDL

Role for combination therapy in diabetic dyslipidemia.

Individuals with type 2 diabetes mellitus have a high residual risk of cardiovascular disease (CVD) despite maximal statin therapy and lifestyle inter...
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