Treatment of Diabetic Dyslipidaemia

Dyslipidaemia is a common and powerful predictor of cardiovascular disease (CVD) in patients with type 2 diabetes (T2D). Diabetic dyslipidaemia refers to a cluster of lipid and lipoprotein abnormalities that cause macrovascular diseaese. Elevated plasma concentrations of triglyceride (typically > 2.2 mmol/L) and reduced high-density lipoprotein cholesterol (HDL-cholesterol, typically <1.0 mmol/L), in both the fasting and postprandial states, are core abnormalities. Accumulation of both small dense low-density lipoprotein (sdLDL) particles, reflected by elevated plasma apolipoprotein B-100 (apoB) concentration(>1.0 g/L), and triglyceride-rich lipoproteins (TRLs), including chylomicron remnants and very-low density lipoprotein (VLDL) remnants, are characteristic of diabetic dyslipidaemia (or dyslipoproteinaemia).

Aetiology

Figure 1.  Plasma lipoprotein profile of a normal individual (A) and an individual with diabetic dyslipidaemia (B). In type 2 diabetes the lipoprotein profile is typically atherogenic. This includes increased plasma levels of large triglyceride-rich very-low-density lipoprotein (VLDL) and small dense low-density lipoprotein (LDL), with decreased levels of large high-density lipoprotein (HDL) and a shift in distribution to smaller HDL particles.
Figure 1. Plasma lipoprotein profile of a normal individual (A) and an individual with diabetic dyslipidaemia (B). In type 2 diabetes the lipoprotein profile is typically atherogenic. This includes increased plasma levels of large triglyceride-rich very-low-density lipoprotein (VLDL) and small dense low-density lipoprotein (LDL), with decreased levels of large high-density lipoprotein (HDL) and a shift in distribution to smaller HDL particles.
Diabetic dyslipidaemia is caused by several factors, including hyperglycaemia, insulin resistance, hyperinsulinaemia, visceral adiposity, hepatic steatosis, and dysregulated fatty acid metabolism [1][2]. The complexity of the mechanisms involved is depicted in Figure 1. Genetic variants controlling lipid and lipoprotein metabolism and other non-genetic factors (proteinuria; hypothyroidism; high fructose intake; alcohol; drugs e.g. corticosteroids, antipsychotics and thiazides) can exacerbate diabetic dyslipidaemia [3].

Insulin resistance increases fatty acid flux from adipose tissue to the liver, inducing hepatic steatosis and over secretion of larger triglyceride-rich VLDL1 particles [2]. Insulin resistance also impairs the inhibitory effect of insulin on hepatic apoB secretion. Further, hyperglycaemia per se drives overproduction of VLDL1 triglyceride.

Impaired chylomicron clearance in T2D results from the reduced activity of lipoprotein lipase, an endothelial bound enzyme, and decreased receptor-mediated endocytosis in the liver. Insulin resistance also increases the hepatic secretion of apolipoprotein C-III, which when attached to VLDL contributes to delayed clearance of TRLs by inhibiting both LPL and binding of remnant TRLs to hepatic receptors. These mechanisms collectively account for postprandial lipaemia [4].

Compositional and atherogenic changes in seen in all plasma lipoproteins in T2D [1][2][3][4].The expanded VLDL triglyceride pool leads to cholesterol depletion and triglyceride enrichment of LDL and HDL, mediated via cholesteryl ester transfer protein (CETP). Increased phospholipid transfer protein activity contributes to hypertriglyceridaemia and lipid compositional changes in HDL. Overactivity of hepatic lipase, due to insulin resistance, increases the lipolysis of triglyceride enriched LDL and HDL particles. This produces smaller and denser lipoprotein particles that induce and perpetuate atherosclerosis. Small dense (sd) LDL particles induce endothelial dysfunction and more easily penetrate the arterial wall, where they have a high binding affinity to intimal proteoglycans. In the intima, retained LDL particles are modified when exposed to oxidative stress, with sdLDL being more sensitive to oxidation, particularly when glycated. Diabetic dyslipidaemia is also characterised by low HDL-cholesterol concentrations with greater reductions in HDL2 than HDL3; there is also a global reduction in the total concentration HDL lipoproteins containing both Apo A-I and Apo A-II. These compositional changes in HDL particles are associated with reductions in both reverse cholesterol transport and the direct anti-atherogenic properties of HDL, including antioxidant, anti-inflammatory and anti-thrombotic effects.

Management

Treatment of diabetic dyslipidaemia targets the foregoing compositional and kinetic changes in lipoprotein particles. The aim is to reduce hepatic secretion of VLDL-apoB and –triglyceride and the transfer of neutral lipids from VLDL to LDL and HDL, as well as to accelerate the clearance of all apoB-containing lipoproteins [2][3][4]. Secondary causes of dyslipidaemia beyond diabetes and obesity must first be corrected. Improved glycaemic control is essential.

Dietary and lifestyle modifications

Lifestyle modifications are central for controlling hyperglycaemia, hypertriglyceridaemia and obesity in patients with T2D [3][5]. These interventions include weight reduction, altered dietary composition, exercise and regulation of alcohol consumption. In T2D, modest weight loss can lower plasma triglyceride levels by up to 25% and normalise postprandial triglyceride concentration [3][4]. Physical activity aid maintenance of weight loss achieved through caloric restrictions. An intensive lifestyle intervention may not, however, reduce the rate of cardiovascular events in T2D [6]. Whether alterations in dietary composition, such as with the Mediterranean diet, improves clinical outcome in diabetes warrants investigation [7]. A Mediterranean and low-carbohydrate diet can achieve greater reduction in triglyceride levels than standard low energy diets. Smoking cessation is imperative.

Pharmacotherapies

Statin monotherapy

As supported by large clinical trials, statins are the cornerstone of treatment for diabetic dyslipidaemia [8]. Whilst LDL cholesterol targets can be achieved in most patients, the effects on triglycerides and HDL are generally modest. More potent statins (atorvastatin and rosuvastatin) can lower plasma triglyceride levels by increasing lipolysis and the clearance of TRLs [3]. Plasma aminotransferase, creatine kinase, creatinine and glucose should be monitored before and after initiating statins, but there is no evidence these agents aggravate glycaemic control. Statin myopathy may be more common in diabetic patients, especially Asians. Statins do not adequately correct dyslipidaemia and residual CVD risk, so that drug combination therapies are often indicated [9]. Cardiovascular outcome data supporting the use of combination therapy is, however, sparse, the supporting evidence coming from changes in lipid endpoints.

Fibrates and statin-fibrate combination

Fibrates (gemfibrozil, fenofibrate) act on peroxisome proliferator-activated receptor alpha (PPAR-α) [2][10]. Fibrates decreases hepatic VLDL secretion and can lower triglyceride, TRL remnants and apoB by up to 30% , and increase the turnover of HDL apoA-I [2]. Meta-analyses suggest that fibrates are most effective in diabetes when triglycerides are elevated (> 2.2 mmol/L) and HDL-cholesterol low (< 1.0 mmol/L). Every 0.10 mmol/l reduction in triglyceride with fibrates confers a 5% reduction in CVD events. Fenofibrate alone or when added to a statin can decreased progression of diabetic retinopathy, but this appears to be unrelated changes in plasma lipids [9].

Niacin and statin-niacin combination

Niacin can decrease plasma triglyceride by 30% via the inhibition of hepatic diacylglycerol acyltransferase-2 , a rate-limiting enzyme of triglyceride synthesis. It also raises HDL-cholesterol and uniquely lowers lipoprotein(a). In spite of the positive outcomes of earlier studies, the current use of niacin against a background of statin therapy has been challenged by two recent clinical trials which, despite favourable changes in plasma lipids and lipoproteins, failed to show significant benefits on CVD events [3]. The safety of niacin use in type 2 diabetes is also questionable owing potential deterioration in glycaemic control. However, the effect of niacin on glycaemic control is minimal when used in lower doses (1g/day).

Ezetimibe and statin-ezetimibe combination

Ezetimibe can lower plasma LDL-cholesterol incremental to statins by inhibiting intestinal cholesterol absorption via Niemann-Pick C1-Like 1 protein [2]. While its effects of fasting triglyceride and HDL are minimal, it can significantly improve postprandial plasma triglyceride in diabetic patients . The combination of a statin and ezetimibe can decrease progression of carotid atherosclerosis in T2D and CVD events in patients with chronic kidney disease [9].

n-3 fatty acid and statin-n-3 fatty acid combination

Supplemental n-3 polyunsaturated fatty acids , mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid, dose-dependently lower plasma triglyceride levels [11]. However, recent clinical outcome trials using lower doses of n-3 PUFAs (1g/day) have failed to show significant CVD benefits against a background of optimal therapy, including statins, in high risk subjects including diabetics . However, patients were not selected for elevated plasma triglyceride levels [3]. The effect of pure EPA (4g/day) on CVD events in high-risk patients with elevated plasma triglyceride who are at LDL cholesterol target on statin therapy is currently under investigation [3].

Incretin-based therapy

Glucagon-like peptide-1 (GLP-1) receptor analogs, such as liraglutide and exenatide, delay gastric emptying and thereby delay postprandial hypertriglyceridaemia. By increasing plasma concentrations of GLP-1, Dipeptidyl peptidase-4 inhibitors, such as sitagliptin, saxagliptin and alogliptin, improve insulin sensitivity, β-cell function and postprandial glycaemia and lipaemia [3][4]. Their role in management of diabetic dyslipidaemia is not established, noting the futile results reported to date in CVD outcome trials.

Safety aspects of combination drug therapy

Plasma levels of aminotransferases, creatinine kinase, creatinine and glucose should be measured prior to initiating a second agent [3][9]. Musculoskeletal symptoms may be more common in diabetic patients on a statin and fibrate. Musculoskeletal symptoms should trigger the measurement of plasma creatinine kinase; if this exceeds 5 times the upper limit of normal and /or symptoms are severe the second agent should be discontinued. Alanine and aspartate aminotransferases should be measured 3 months after adding a fibrate and yearly thereafter, or more frequently when increasing the dose of the statin; hepatoxicity is a potentially serious side-effect when a statin is combined with a fibrate or niacin. Plasma creatinine should be periodically checked in patients receiving statins plus fenofibrate, although it should be noted that the increases in creatinine reported with fenofibrate in recent trials is reversible and not associated with adverse events. Should niacin be used, plasma glucose, glycated haemoglobin and urate levels should be monitored closely.

Pipeline therapies

These include selective peroxisome proliferator-activated receptor (PPAR)-α modulators; PPAR-α/δ agonists; inhibitors of diacylglycerol O-acyltransferase, proprotein convertase subtilisin/kexin type 9, CETP and microsomal triglyceride transfer protein; antisense oligonucleotides against apoB-100 and apoC-III; reconstituted and recombinant HDL [3]. Their efficacy and long-term safety in humans need to be established.

Treatment Guidelines and Targets

Figure 2.  Pathogenesis of diabetic dyslipidaemia. Hypertriglyceridaemia reflects accumulation in plasma of triglyceride-rich lipoproteins (TRLs), the pivotal defect in lipoprotein metabolism. Oversecretion of VLDL and chylomicrons by the liver and intestine, coupled with decreased catabolism, increases the plasma pool of TRLs, including remnant lipoproteins; increased heteroexchange of neutral lipids between TRLs and LDLs and HDLs via CETP results in remodelling of LDLs and HDLs to form correspondingly smaller, denser particles. LPL activity is decreased in skeletal muscle and adipose tissue owing to the inhibitory effects of insulin resistance and apoC-III;  Abbreviations: ApoAI, apolipoprotein AI; ApoB, apolipoprotein B; CE, cholesteryl ester; CETP,cholesteryl ester transfer protein; FFA, free fatty acids; HDL, high-density lipoprotein; HTGL, hepatic triglyceride lipase; IR, insulin ressitance; LDL, low-density lipoprotein; LPL, lipoprotein lipase; TRL, triglyceride-rich lipoproteins; VLDL, very-low-density lipoprotein.
Figure 2. Pathogenesis of diabetic dyslipidaemia. Hypertriglyceridaemia reflects accumulation in plasma of triglyceride-rich lipoproteins (TRLs), the pivotal defect in lipoprotein metabolism. Oversecretion of VLDL and chylomicrons by the liver and intestine, coupled with decreased catabolism, increases the plasma pool of TRLs, including remnant lipoproteins; increased heteroexchange of neutral lipids between TRLs and LDLs and HDLs via CETP results in remodelling of LDLs and HDLs to form correspondingly smaller, denser particles. LPL activity is decreased in skeletal muscle and adipose tissue owing to the inhibitory effects of insulin resistance and apoC-III; Abbreviations: ApoAI, apolipoprotein AI; ApoB, apolipoprotein B; CE, cholesteryl ester; CETP,cholesteryl ester transfer protein; FFA, free fatty acids; HDL, high-density lipoprotein; HTGL, hepatic triglyceride lipase; IR, insulin ressitance; LDL, low-density lipoprotein; LPL, lipoprotein lipase; TRL, triglyceride-rich lipoproteins; VLDL, very-low-density lipoprotein.
Guidelines for managing diabetic dyslipidaemia suggest statins plus lifestyle changes as first-line therapy, with use of fibrates, n-3 fatty acids or niacin as second line agents [5] [12][13][14][15][16][17][18][19]. There could also be a role for ezetemibe [9]. A simple scheme is suggested in Figure 2, in which plasma LDL-cholesterol is the primary treatment target. With elevated TG ( > 2.0 mmol/L), non-HDL-cholesterol and apoB are also recommended as targets for treatment. The therapeutic targets in diabetes are: LDL-cholesterol < 1.8 mmol/L ( with CVD), < 2.6 ( no CVD + at least one other major CVD risk factor); non-HDL-cholesterol < 2.6 mmol/L (with CVD), < 3.4 ( no CVD + at least one other major CVD risk factor); apoB < 0.8 g/L ( with CVD), < 1.0 g/L ( no CVD+ at least one other major CVD risk factor) [3][9][14]. Ideally all targets for LDL-cholesterol, non-HDL- cholesterol and apolipoprotein B should be attained, especially in diabetic patients with established CVD.

 Figure 3.  Algorithm for managing atherogenic dyslipidaemia in patients with type 2 diabetes.
Figure 3. Algorithm for managing atherogenic dyslipidaemia in patients with type 2 diabetes.
The recent AHA/ACC guidelines have singularly recommended, on the basis of statin trials alone, that for patients with T2D aged 40 to 75 years the following statin regimens should be used: moderate-intensity ( no CVD, 10-yr CVD risk < 7.5% using Pooled Cohort Equations), moderate-to-high intensity ( no CVD, 10-yr CVD risk > or = 7.5%), high intensity ( with CVD); no treatment targets are given for any plasma lipids or lipoproteins and no drug therapy is recommended for residual hypertriglyceridaemia [19]. This approach to lipid management is a significant departure from standard recommendations and its value remains to be demonstrated in clinical practice.

None of the available guidelines provide treatment targets for plasma HDL-cholesterol.

References

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  3. ^ Watts GF, Ooi EE, Chan DC. Demystifying the management of hypertriglyceridaemia. Nature Review Cardiology 2013; 10: 648-61.

  4. ^ Pang J, Chan DC, Barrett PH, Watts GF. Postprandial dyslipidaemia and diabetes: mechanistic and therapeutic aspects. Current Opinion in Lipidology 2012; 23: 303-309

  5. ^ American Diabetes Association. Standards of Medical Care in Diabetes-2013. Diabetes Care 2013; 36: S11-66.

  6. ^ The Look AHEAD Research Group: Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. New England Journal of Medicine 2013;369:145-154

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  9. ^ Watts GF, Karpe F. Triglycerides and atherogenic dyslipidaemia: extending treatment beyond statins in the high-risk cardiovascular patient. Heart 2011; 97: 350–356

  10. ^ Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. European Heart Journal 2011; 32: 1345–1361.

  11. ^ Mozaffarian D, Wu JHY. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. Journal of American College of Cardiology 2011; 58: 2047-2067.

  12. ^ Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143–3421.

  13. ^ Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Stone NJ. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Journal of American College of Cardiology 2004. 44(3): 720-732

  14. ^ Brunzell J D, Davidson M, Furberg CD et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care 2008; 31: 811–822.

  15. ^ Miller M, Stone NJ, Ballantyne C et al Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011; 123: 2292–2333

  16. ^ Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. European Heart Journal 2011; 32: 1345–1361.

  17. ^ Reiner Ž, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P: ESC/EAS Guidelines for the management of dyslipidaemias. European Heart Journal 2011;32:1769-1818

  18. ^ Anderson TJ, Grégoire J, Hegele RA, Couture P, Mancini GB, McPherson R, et al. 2012 Update of the Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Canadian Journal of Cardiology. 2013;29:151-67.

  19. ^ Stone NJ, Robinson J, Lichtenstein AH, Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Nov 12. [Epub ahead of print]

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