Dyslipoproteinaemia: Important Concern in Type 2 Diabetes

Abstract

Dyslipoproteinaemia, also known as dyslipidaemia, occurs in more than 70% of people with diabetes and is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD) associated with obesity, hypertension, and poor glycaemic control. The prevalence of diabetes worldwide is increasing, and so is the death rate in people with diabetes. The causes of dyslipoproteinaemia are divided into primary (genetic) or secondary, which are diagnosed from history (diabetes, obesity, endocrine disorders, and chronic kidney disease). The pattern of dyslipoproteinaemia in diabetes typically consists of increased levels of fasting and post-prandial triacylglycerols (TAGs), Low Dense Lipoprotein-C (LDL-C), non-HDL-C, small LDL particles and Apo-B and lower levels of non-atherogenic HDL-C and ApoA1. Treating dyslipoproteinaemia includes patients’ risk stratification and targeting those at high risk. It consists of lifestyle modification, statins, cholesterol absorption inhibitors (ezetimibe), drugs that increase HDL and reduce LDL (niacin, fibrates), triglycerides (Omega-3) and bile acid sequestrants. Proprotein convertase subtilisin–kexin type 9 inhibitors reduce LDL by 60–80%, ApoB by 50% and Lp (a) by 25% and should be considered in all people with diabetes with other risk factors and with coexisting primary dyslipoproteinaemia before developing ASCVD as well as those with established ASCVD.

1. Introduction

Dyslipoproteinaemia, also known as dyslipidaemia, is a lipid metabolism disorder characterised by increased levels of plasma cholesterol, triacylglycerols (TAGs), or both, and a low high-dense lipoprotein cholesterol (HDL-C) level that is strongly associated with atherosclerotic vascular disease. In addition, the link between increased levels of Apo protein B or lipoprotein (A) and lower levels of Apo lipoprotein A-1 and atherosclerotic vascular disease has led to the broader use of the term dyslipoproteinaemia in preference to dyslipidaemia. Dyslipoproteinaemia in diabetes is common. It can affect up to 70% of people with type 2 diabetes mellitus. Cardiovascular disease is the leading cause of death in people with diabetes, and mortality rates are 40% higher in men and 50% higher in women with diabetes compared to those without diabetes [1]. The prevalence of diabetes continues to rise, affecting 537 million people (1 in 10) worldwide and is predicted to rise to 783.2 by 2045 [2].

Dyslipidaemia in diabetes typically consists of the following lipid abnormalities:

• Increased levels of fasting and postprandial TAGs, Low Dense Lipoprotein-C (LDL-C), non-HDL-C, small LDL particles and Apo-B

• Decreased HDL-C and ApoA1

In this chapter, the importance and scale of dysproteinaemia in diabetes as a vital risk factor for cardiovascular disease is outlined, and there is a focus on pathophysiology, current clinical management, and guidelines of dyslipoproteinaemia for primary and secondary prevention in people at high risk of cardiovascular disease.

2. Epidemiology of dyslipoproteinaemia

By 2019, over 4 million deaths were attributable to high plasma LDL-C levels, more commonly affecting men than women. Although deaths have been reduced since 1990 in middle-income compared to middle-low-income countries, ischaemic heart disease caused 8.54 million deaths, of which 44.3% were due to high plasma LDL-C levels. 2.73 million deaths were due to ischaemic stroke, of which 26.5% were attributable to high plasma LDL-C levels [3]. Estimates from the World Health Organisation in 2008 showed that the prevalence of hypercholesterolemia was 53.7% in Europe, 47.7% in the USA and lower prevalence in South East Asia and Africa [4]. Large-scale RCTs have shown that targeted dyslipidaemia treatment reduced all-cause and coronary mortality. Reducing LDL-C by one mmol/l minimises the risk of stroke, coronary revascularisation, and major cardiovascular events by about 20% [5].

3. Causes of dyslipoproteinaemia

The causes of dyslipoproteinaemia are divided into primary (genetic) or secondary, diagnosed from history and the measurement of abnormally high plasma levels of total cholesterol, TAGs, and individual lipoproteins. The treatment of dyslipoproteinaemia is primarily 2-fold, through lifestyle modifications and lipid-lowering drugs.

Primary dyslipoproteinaemia is due to genetic defects in lipid metabolism, predominantly causing impaired clearance of plasma LDL and a deficiency in LDL receptors. Levels of LDL-C in people with familial hypercholesterolemia are abnormally high at birth and are associated with the deposition of cholesterol in the arteries, skin, tendons, and corneas. Environmental factors and diseases such as diabetes, hypothyroidism, obstructive liver disease and drugs (e.g., thiazide diuretics and anabolic steroids) are often associated with secondary dyslipoproteinaemia. A thorough history and clinical examination are imperative for accurately diagnosing dyslipoproteinaemia.

4. Pathophysiology

4.1 Role of lipids

Lipoproteins are particles that transport lipids to tissues for energy utilisation, steroid hormone production and bile acid formation. Lipoproteins are made of esterified and unsterilised cholesterol, phospholipids, triglycerides, and Apo lipoproteins. Apo lipoproteins are crucial to forming cellular receptor binding, activating, and inhibiting enzyme reactions and the composition of cellular structural components. Lipoproteins are divided into seven different classes: chylomicrons, chylomicron remnants, very low dense lipoprotein (VLDL), intermediate-dense lipoprotein (IDL), intermediate-dense lipoprotein (IDL), HDL and Lp (a) depending on their size, lipid composition and Apo lipoproteins. All lipoproteins are atherogenic except anti-atherogenic HDL. Table 1 shows lipoprotein characteristics.

	Density (g/mL)	Diameter (nm)	TGs (%)	Cholesterol ester (%)	PLs (%)	Cholesterol (%)	Apolipoprotein major	Others
Chylomicrons	<0.95 1	80–100	90–95	2–4	2–6	1	ApoB-48	ApoA-I, A-II, A-IV, A-V
VLDL	0.951–1.006	30–80	50–65	8–14	12–16	4–7	ApoB8-14 1-100	ApoA-I, C-II, C-III, E, A-V
IDL	1.006–1.019	25–30	25–40	20–35	16–24	7–11	ApoB-100	ApoC-II, C-III, E
LDL	1.019–1.063	20–25	4–6	34–35	22–26	6–15	ApoB-100
HDL	1.063–1.210	8–13	7	10–20	55	5	ApoA-I	ApoA-II, C-III, E, M
Lp(a)	1.006–1.125	25–30	4–8	35–46	17–24	6–9	Apo(a)	ApoB-100

Table 1.

Lipoprotein characteristics.

Apo = apolipoprotein; HDL = high-density lipoprotein; IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; Lp (a) = lipoprotein (a); PLs = phospholipids; TGs = triglycerides; VLDL = very low-density lipoprotein.

Since the publication of the Framingham Heart Study [6], cholesterol has been identified as a critical contributory risk to coronary heart disease. A vast number of epidemiologic studies and randomised clinical trials (RCTs) have demonstrated the causal link of LDL-C to atherosclerotic cardiovascular disease (ASCVD) [7]. Managing serum cholesterol levels is now the cornerstone of primary prevention (in those individuals before developing ASCVD and secondary prevention in individuals where the ASCVD event has occurred) worldwide, focusing on lipoproteins reflected in LDL-C, non-HDL-C and TGs levels. Many studies have shown a log-linear relationship between LDL-C and the risk of ASCVD. Lowering LDL-C lowers the risk of ASCVD, providing solid support for causal and cumulative impact in the development of ASCVD dependent on exposure to high LDL-C. Equally, high levels of TAGs are associated with an increased risk of the development of ASCVD, whereas lower levels of TAGs reduce risk. The inverse association between HDL-C and the risk of ASCVD is well recognised through epidemiology studies. However, the evidence for this association needs to be more strictly and consistently compelling [8]. In a systematic review and meta-analysis of a dose response in prospective cohort studies, high TC and LDL-C serum levels were associated with increased ASCVD mortality. There is a wide ethnicity variation in the prevalence of LP (a), more common in blacks and South Asians than Chinese and whites [8]. High Lp (a) has been linked to calcific with aortic valve disease, and the oxidised phospholipids carried by Lp (a) make it more pro-atherosclerotic and proinflammatory, independently promoting ASCVD [9].

The absorption of dietary lipids occurs via enterocytes through passive diffusion or specific transporters. Within the enterocytes, TAGs, cholesteryl esters and other lipids are associated with Apo lipoprotein (ApoA-IV and ApoA-I) to form chylomicrons. Chylomicrons are then exported into the lymph and the bloodstream. Lipoprotein lipase on the luminal surface is responsible for chylomicron clearance. Lipolysis of chylomicrons produces chylomicron remnants taken up by the liver via the LDL receptor in conjunction with the LDL receptor-related protein that binds ApoE. From the liver, lipids are exported into the bloodstream as VLDLs. Like chylomicrons, TAGs from VLDLs are hydrolysed by LPL lipase in plasma, producing non-esterified fatty acids (NEFA), used as fuel in the heart and skeletal muscle or for storage within adipocytes. As the depletion of VLDLs occurs, the transfer of part of the lipoprotein surface layer closely related to phospholipids, ApoC and ApoE to HDLs occurs and is responsible for forming IDLs. Most of the formed IDLs are converted into LDL through lipolysis by hepatic enzymes, whereas the liver clears the rest through lipid receptor protein and LDL receptors. Cholesterol is transported mainly by LDL as a core of esterified cholesterol wrapped up in a shell of phospholipid, unesterified cholesterol and a single molecule of ApoB-100 bound to the LDL receptor regulated by the binding of the lysosomal enzyme Proportion Convertase Subtilizing/Kevin type 9 (PCSK9) to the LDL-receptor/LDL complex preventing the receptor to enter back to the surface and into the lysosomal catabolic pathway.

Produced by the liver and intestine, HDL is involved in reverse cholesterol transport, which protects against atherosclerosis through its anti-apoptotic, anti-thrombotic, anti-inflammatory, and anti-oxidative properties. Soon after secretion, HDLs bind Apo A-I to membrane-associated ATP-binding cassette protein-1 (ABCA-1) transporter responsible for the transport of non-esterified cholesterol and phospholipids from the cytoplasm into HDL and is followed by esterification of non-esterified cholesterol on HDL particle by lecithin–cholesterol acyltransferase which attracts more cholesterol from peripheral tissue and also recruits macrophages within artery walls through ABCA-1 and the ATP-binding cassette G1 transporters. HDL returns cholesterol to the liver through scavenger receptor B1 (SR-B1) or is taken up directly by the liver, which undergoes hydrolysis. Cholesteryl esters are transferred from HDL to VLDL, and TAGs from VLDL to HDL through cholesteryl ester transfer protein (CETP). HDL is further enriched with TAGs and phospholipids by receiving ApoC and ApoE from VLDL in circulation, later degraded by hepatic lipase to smaller HDL particles, which are removed by the liver or form part of reverse cholesterol transport. The formed lipid-poor ApoA-I is filtered from circulation by the renal proximal tubules and degraded by binding to cubilin, a protein on the apical surface of renal tubular cells.

Two hormones significantly affect lipid metabolism: adiponectin and insulin. Adiponectin promotes ApoA-I-mediated cholesterol efflux from macrophages by upregulating ABCA1 expression [10]. Adiponectin may directly reduce HDL metabolism and, therefore, is antiatherogenic. On the other hand, insulin is antilipolytic by inhibiting hormone-sensitive lipase, which then promotes the storage of TAGs in adipose tissue. In addition, insulin directly inhibits hepatic VLDL production by reducing circulating levels of NEFA, substrates for VLDL. Insulin increases LDL-receptor expression and activity, accelerating LDL clearance [11].

In high plasma concentrations, the oxidation of cholesterol promotes intercellular monocyte influx and cytokine generation of tumour necrosis factor-α, interleukin-1 and interleukin-6 (IL-6) by macrophages, lymphocytes, natural killer cells, and vascular smooth muscle cells producing a cascade for further production of cytokines causing the formation of an unstable plaque that is prone to rupture [12]. Themonocytes differentiate into macrophages, which absorb oxidised cholesterol to become foam cells and are deposited on the blood vessels’ walls, causing the formation of more atherosclerotic plaques. In parallel, LDL is transported into the extracellular matrix of the sub-endothelial space, undergoes oxidation and recruits monocytes that are transformed into macrophages to increase LDL oxidation, further causing more inflammatory reaction and damage within the vessel wall. A fibrous cap’s formation accelerates as the plaque’s damage and repair process continues. The size of the plaque can increase to a critical extent, which may become unstable and vulnerable to rupture and cause blood flow obstruction that causes unstable angina, myocardial infarction, and death in some cases. Therapies to maintain plaque stability and inhibit plaque rupture and subsequent coronary thrombosis are critical to preventing cardiovascular events [13]. Lipid-lowering therapies may reduce the increase in the size of the plaque and prevent ASCVD events [14].

The mechanism for diabetic dyslipoproteinaemia is not fully understood. Both glycaemic control and insulin resistance play a role. Insulin decreases levels of VLDL by reducing free fatty acids in circulation, which are substrates of VLDL that directly inhibit VLDL production in the liver. Insulin also inhibits the hepatic secretion of TAG-VLDL and ApoB-100. Insulin resistance in people with type 2 diabetes mellitus causes an increase in microsomal transfer protein expression and lipid bioavailability, which results in the overproduction of TAG-VLDL and VLDL-ApoB.

5. Measurement of lipids

Risk assessment of ASCVD is essential to guide therapies for primary and secondary prevention, and measurements of lipid profile form part of patient evaluation. A clear, detailed history and thorough patient examination are essential to obtain clinical features of coexisting conditions such as diabetes, obesity, thyroid, liver, and kidney disorders. More importantly, medication and other supplements may be responsible for dyslipoproteinaemia, and this can only be diagnosed from a careful history. Other essential elements include any family history of premature ASCKD events. The pattern of plasma sterols may indicate different categories of familiar hyperlipidaemias. For example, raised VLDL-C and LDL-C may indicate familial hypercholesterolemia if sterols levels are normal, familial combined hyperlipidaemia if lathosterol is high, dysbetalipoproteinemia when β-sitosterol is moderately increased, phytosterolemia if β-sitosterol is very high and cerebrotendinous xanthomatosis if very high levels of cholestanol are determined.

Assays of apo A-I provide a characterisation of HDL and its influence. It is beneficial to diagnose conditions with significant HDL deficiencies, such as apoA-I deficiency and variants, Tangier disease, and lecithin/cholesteryl acyltransferase deficiency, whereas measuring apoB may provide evidence to diagnose abetalipoproteinemia or hypobetalipoproteinaemia.

Total cholesterol is distributed among the three major lipoproteins: VDL. LDL and HDL, but some are distributed between IDL and Lp (a). Most laboratories measure total cholesterol, HDL and TAGs from which LDL-C is estimated. Direct measurement of LDL-C is possible. However, cost and inaccuracies in assays limit their availability and reproducibility.

A fasting serum sample is preferred when assessing the lipid profile due to the lower TAG levels in the fasting state, which gives more accurate LDL-C estimations. However, the changes in TAG levels in fasting and non-fasting states are small [15]. If a non-fasting sample is taken, TAG and LDL-C levels should be interpreted cautiously, especially in patients with diabetes, metabolic syndrome, and hypertriglyceridemia. Non-fasting lipid measurements can be used for population screening because of the inconvenience to patients to fast, but also the fact that systematic reviews have shown a small and non-significant difference between fasting and non-fasting lipid parameters in predicting patient prognosis when considering these levels [16].

Other laboratories also measure Lp (a) as part of a routine lipid profile, which is more informative for diagnosis and primary and secondary prevention risk stratification.

1. LDL-C is usually calculated from the Friedewald equation:

2. LDL-C 1 divided by four times TC HDL-C (TAGs/2.2) in mmol/L.

3. The formula is inaccurate when TAG levels are higher than 4.5 mmol/L.

Current guidelines recommend using one of the available risk assessment systems relevant to the patient population’s region. The SCORE (Systematic Coronary Risk Estimation) system is country specific. It is calibrated by considering population differences primarily adjusted for prevalence and mortality for ASCVD in those regions [17]. Cardiovascular risk means the likelihood of a person developing an atherosclerotic event over time. Assessing the combined effects of all identifiable risk factors of the individual is critical to estimating the risk of future cardiovascular events to determine treatment strategies for primary or secondary prevention of ASCVD events. Through total risk assessment, the cut-off points identify low, moderate, high, and very high-risk categories [18] on which lipid-lowering treatment is based. Clinicians and their multidisciplinary teams must agree on which guidelines apply to their patient populations and healthcare systems.

Examples of categories from low to high risks:

• Patients at low risk have a calculated SCORE of less than 1% over ten years to develop fatal ASCVD.

• Those at moderate risk are young people with T2DM younger than 50 years old and T1DM less than 35 years old with diabetes duration of less than ten years, without other risk factors have a calculated SCORE of 1% - 5% risk for ten years to develop fatal ASCVD.

• Those at high risk have TC more than eight mmol/L, LDL-C more than 4.9 mmol/L, or BP higher than 180/110 mmHg, people with FH without other major risk factors or with diabetes without target organ damage, with diabetes duration of more than ten years or another additional risk factor or those with moderate CKD (eGFR 30–59 mL/min/1.73 m²) have a calculated SCORE of at least 5% - 10% risk over ten years to develop fatal ASCVD.

• Those at very high risk are people with any of the following: documented ASCVD or have diabetes with target organ damage, or at least three major risk factors, or early onset of T1DM duration of at least 20 years or CKD stage 4 (eGFR <30 mL/min/1.73 m²) have a calculated SCORE of at least 10% over a 10-year to develop of fatal ASCVD.

The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology and European Atherosclerosis Society for lipid profile assessment [17] recommends the following:

• TC should be measured routinely to estimate total ASCVD risk using the SCORE system.

• HDL-C analysis should be measured to refine risk estimation using the online SCORE system.

• LDL-C analysis should be used for screening, diagnosis, and management.

• Non-HDL-C is recommended for risk assessment, particularly in people with high TAG levels, obesity, or very low LDL-C.

• ApoB analysis is recommended for risk assessment in people with high TAG levels, diabetes, obesity, metabolic syndrome, or very low LDL-C levels. ApoB can be used as an alternative to LDL-C as the primary measurement for very low LDL-C levels.

• Consider Lp (a) measurement at least once in each adult person’s lifetime to identify those with very high risk.

6. Dyslipoproteinaemia in special groups

6.1 Diabetes

Substantial evidence supports the targeting of LDL-C lowering to reduce the risk and mortality of ASCVD. Still, the benefit of treating hypertriglyceridemia in people with has been questioned. However, more recently, a meta-analysis of studies of fibrates in primary prevention of ASCVD in people with type 2 diabetes reported that fibrates significantly reduced the risk of non-fatal MI by 21% but had no effect on the overall mortality risk [18]. All people with diabetes at high risk should be considered for statin therapy and lifestyle modification. Those that do not reach target levels should be offered non-statin therapy. Targeting dyslipoproteinaemia in individuals at risk of developing diabetes is one aspect of managing risk factors before they develop diabetic complications and ASCVD. Specific clinical characteristics may indicate a risk of progressing to diabetes, e.g., metabolic syndrome, obesity, hypertension, fasting glucose >6.0 mmol/l and raised TAGs. More recently, the hypertriglyceridemia waist phenotype (waist circumference over 85 cm in women and over 90 cm in men and raised TGs) has been proposed as a more robust marker of ASCVD risk than metabolic syndrome [19].

6.2 Familial dyslipidaemias

Familial dyslipidaemias can be monogenic when one major gene is responsible for the condition or heterogenic when more than one gene variant affects lipid metabolism. The association of familial dyslipidaemia with ASCVD and premature deaths is well recognised, and early diagnosis is critical for primary and secondary prevention of ASCVD. The treatment requires a combination of statin and non-statin therapies, and in severe cases, lipid apheresis may be necessary.

6.3 Familial hypercholesteraemic (FH)

FH is a monogenic dyslipidaemia with autosomal dominance inheritance occurring in 1/200–250 population, predominantly causing a lifelong increase in LDL-C and premature death if left untreated. This condition is due to the mutation of the gene that encodes for the LDL receptor or Apo gene and can be diagnosed by the presence of characteristic clinical physical findings (tendon xanthomata, arcus senilis and xanthelasma) and the demonstration of the gene mutations. More than 1000 gene mutations for the LDL receptor have been identified. When a single gene mutation is inherited from both parents, the condition is called homozygous FH and heterozygous when inheritance is from one single parent only. Typically, in FH, the TC is higher than 8 mmol/l in patients <40 years old or there is a history of premature CVD under 60 years old and characteristic clinical findings on examination. Both the Dutch Lipid Clinic Network (DLCN) criteria and the Simon Broome Register (SBR) have been adopted worldwide to diagnose FH [20]. These criteria are based on a score generated from a personal and family medical history, clinical characteristics, LDL-C concentration, and DNA testing. The higher the score, the higher the chances of the person having FH.

6.4 Familial dysbetalipoproteinemia (FD)

FD is rare and is inherited as an autosomal recessive disorder with variable penetrance. The characteristics of FD are increased levels of both TC and TGs, tuberoeruptive xanthomas over the elbows and knees, and palmar xanthomata of the hands and wrists. The risk of CVD is very high and includes atherosclerosis of the femoral and tibial arteries; most cases are homozygous for the E2 isoform of ApoE. ApoE promotes the clearance of chylomicron remnants and IDL.

6.5 Familial combined hyperlipidaemia (FCH)

FCH is more common than previously recognised, occurring at a frequency of 1:100–200 in the population, and typically presents with increased levels of LDL-C, TAGs, or both. The diagnosis is frequently missed. High levels of ApoB improve the detection of this condition [20].

6.6 Familial hypertriglyceridemia (FHTG)

FHTG is polygenic due to the involvement of multiple gene mutation defects in the catabolism pathway for chylomicrons and VLDL, causing elevated levels and a high risk for CVD and pancreatitis [21].

7. Management of dyslipoproteinaemia

7.1 Lifestyle modification

European Cardiology and European Atherosclerotic Societies recommended lifestyle modification for primary and secondary prevention of ASCVD based on sufficient evidence from observational studies and RCTs, which have shown a positive effect of cholesterol and other biomarkers on reducing cardiovascular risk. In the INTERHEART study in 52 countries, nearly 50% of risk factors for myocardial infarction were modifiable lifestyle parameters: physical activity and intake of fruit and vegetables reduced risk, whereas alcohol use and smoking increased risk. The cumulative risk of myocardial infarction increased as the number of risk factors (smoking, diabetes, obesity, raised ApoB/ApoA1 ratio, hypertension, lack of fruit and vegetable consumption and exercise) increased too [22].

Other epidemiological studies have also shown that high fruit consumption and non-starchy vegetables, nuts, legumes, fish, vegetable oils, yoghurt, and whole grains, in addition to lower intake of red and processed foods, salt and switching from animal fats to vegetable sources of fats lowered risk of ASCVD. Saturated fatty acids increase LDL-C, whereas unsaturated fat-rich oils from sunflower, flaxseed, corn, olives, or soybeans reduce LDL-C levels. Although weight loss has a negligible impact on LDL-C reduction, its effects on lowering TAGs and increasing HDL-C are significant.

The ACC–AHA Risk Calculator is recommended for adults 40 to 75 years of age who do not have diabetes and whose LDL cholesterol level is 70 mg per decilitre or higher to estimate the risk of ASCVD. Those with low to moderate risk can be managed through lifestyle modification alone, but those with high risk require pharmacological interventions. The presence of multiple risk factors such as a strong family history or premature ASCVD, preeclampsia, South Asian ancestry, hypertension, early menopause, chronic kidney disease, HIV, persistently elevated triglyceride levels, and elevated levels of high-sensitivity C-reactive protein and Lp(a) requires pharmacological interventions for primary prevention of ASCVD. The same principle applies to individuals without multiple risk factors who have severe primary hyperlipidaemia when their LDL cholesterol level is≥190 mg per decilitre. People with diabetes and LDL cholesterol levels>70 decilitres do not require risk calculation as they are at high risk of ASCVD anyway and require pharmacological treatment [23].

8. Drug therapy in dyslipoproteinaemia

8.1 Statins

8.1.1 Evolution of statins

3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase is the rate-limiting enzyme in the cholesterol biosynthetic pathway (Figure 1), which is inhibited by statins resulting in the lowering of LDL-C serum levels. The first statin in the world was mevastatin, a naturally derived statin from fungal species Aspergillum and Penicillium in the 1970s, but it was never marketed. Lovastatin, also a naturally occurring statin, was granted FDA approval for commercial production in 1987 and was later modified semi-synthetically to form simvastatin. Later, pravastatin was modified from mevastatin. Synthetic statins soon followed on the market (Table 2). Extensive studies have shown that statins stabilise atherosclerotic plaques to prevent rupture and the development of ASCVD events. Statins are among the most widely used drugs, with atorvastatin as the best-selling statin worldwide. Estimates showed that more than 145 million people were taking statins by 2018 [24] (Figure 2).

Figure 1.

Cholesterol metabolism.

Characteristic	Atorvastatin	Rosuvastatin	Simvastatin	Pravastatin	Lovastatin
High intensity (Lowers TC by ≥50%)	40–80	20–40
Moderate intensity (Lowers TC by 30–50%)	10–20	5–10	20–24	40–80	40
Low intensity (Lowers TC by <30%			10	10–20	20
HDL % increase	7–8	11–14	8–12	3–8	6–9
TGs % increase	28–47	29–38	19–32	20	10–23

Table 2.

Common statin drug characteristic.

Figure 2.

Evolution of statins.

8.1.2 Adverse effects of statin

• Myopathy is the most common adverse reaction with statin therapy, whereas rhabdomyolysis can be one of the most severe, occurring on average at 13 cases/100,000 patient-years. Rhabdomyolysis typically presents with severe muscular pain, muscle necrosis and myoglobinuria and may progress to severe acute kidney injury, and creatine kinase may rise 10 to >40 fold before death occurs.

• Statins are contraindicated in acute liver failure or decompensated liver disease.

• The association of statins and cancer has been the subject of exciting debates concerning those studies that involved individuals with LDL-C below two mmo/l. However, many meta-analyses of randomised trials that recruited large numbers of cancers showed that current standard statin regimens do not increase the relative risk of any cancer over five years [25].

• Other important adverse reactions include liver failure, alopecia, memory loss, pancreatitis, paraesthesia, sexual dysfunction, new-onset diabetes, and haemorrhagic stroke.

Follow-up and monitoring of statin therapy:

• Statins are indicated for both primary and secondary prevention.

• Monitor liver function tests at baseline and within three months of starting treatment.

• Avoid statins if transaminase (alanine aminotransferase or aspartate aminotransferase) levels three or more times the upper limit of normal and in pregnancy.

8.1.3 Bile acid sequestrants

• Synthesised in the liver from cholesterol bile sequestrants work by binding bile and depleting bile salts from enterohepatic circulation, forcing the liver to synthesise more, thereby increasing LDLR expression and reducing LDL-C.

• Bile acid sequestrants are polymeric compounds that serve as ion exchange resins.

• Bile acid sequestrants are indicated for hypercholesterolemia without hypertriglyceridemia for individuals intolerant to statins or as an add-on therapy when the statin is insufficient.

• Bile acid sequestrants reduce LDL-C by 15–30% at total doses.

• In addition to a bad taste in the mouth, bile sequestrants may cause constipation, diarrhoea, bloating, and flatulence.

Three commonly used bile acid sequestrants are:

• Cholestyramine – taken at 4 g 1–2 times a day, and the maximum dose is 24 g/day.

• Colestipol – is taken at 2 g 1–2 times a day, and the maximum dose is 20 g, which reduces LDL-C by 20% with very few adverse effects.

• Colesevelam – available at a maximum dose of 3.75 g/day.

8.2 Cholesterol absorption inhibitors

Cholesterol absorption inhibitors prevent intestinal cholesterol absorption but do not affect TGs and bile acid absorption.

8.2.1 Ezetimibe

• Reduces the cholesterol content of triglyceride-rich lipoproteins and the concentrations of atherogenic remnant particles and can be combined with other lipid-lowering medications.

• It inhibits the sterol transporter Neimann-Pick C1 located on the border cells in the small intestine.

• Due to the long half-life, Ezetimibe is administered once daily at 10 mg.

• It lowers LDL-C by 10–15% and has a good safety profile.

• Adverse reactions include asthenia, gastrointestinal symptoms, muscle aches, thrombocytopenia, and hypertension.

8.2.2 Fibrates

Fibrates act on peroxisome proliferator-activated receptor alpha (PPAR-a) to regulate various steps in lipid lipoprotein metabolism, reduce TAGs and TAG lipoprotein-rich remnant particles, and increase HDL-C levels. Outcome studies in lowering ASCVD have been disappointing. However, a subgroup analysis from the ACCORD trial showed that fibrates, in addition to statins, decreased the risk of nonfatal MI, nonfatal stroke, or death from cardiovascular (CV). In this study, despite lowering fasting triglyceride levels by 26% with pemafibrate, there was no significant impact on major cardiovascular events compared to the placebo [26]. Overall, the role of fibrates as monotherapy is limited.

8.2.3 Nicotinic acid

Nicotinic acid inhibits diacylglycerol acyltransferase-2 and decreases VLDL, Lp (a) and LDL particles and increases HDL-C and ApoA1 in the liver, however in a systematic Cochrane Review [27] of 23 RCTs nicotinic acid had no significant positive impact on cardiovascular and non-cardiovascular mortality. At the recommended dose of 500 mg daily, Nicotinic acid-induced flushing is a significant adverse reaction that may contribute to poor patient compliance with this treatment.

8.2.4 Proprotein convertase subtilizing/kevin type 9 inhibitors

PCSK9 down-regulates LDL receptors on hepatocytes. On binding to the LDL receptor, it causes the degradation of the receptor, leading to increased levels of LDL-C. The monoclonal antibodies alirocumab and evolocumab do the opposite and inhibit PCSK9 binding to LDL receptors and upregulate the recycling of LDL receptors, increasing LDL-C uptake and indirectly lowering circulating LDL-C levels. Both alirocumab and evolocumab are injected subcutaneously once every two weeks. In the ODYSSEY OUTCOMES trial, alirocumab reduced circulating LDL-C and prevented CV events [28].

Similarly, in the FOURIER trial, evolocumab decreased CV events by 15% compared to placebo [29]. The trials mentioned above provided important information on the PCSK9 inhibitor safety profile. Apart from reactions at the injection sites and flulike symptoms, both agents have an excellent safety profile. Together with statins, they can reduce LDL-C by 40–73%, depending on dose regimens. In addition, both agents lower TAGs and Lp (a).

Both alirocumab and evolocumab are indicated in primary prevention in high-risk groups or secondary prevention. Despite maximal conventional lipid-lowering therapies, target LDL goals are not achieved, and stain intolerance is an issue. Evolocumab is administered into the thigh, abdomen, or upper arm at 140 mg every two weeks or 42 mg monthly for primary or mixed hyperlipidaemia or atherosclerotic disease. Alirocumab is administered starting at 75 mg every two weeks and increasing to 150 mg every four weeks or 300 mg every four weeks.

8.2.5 Small interfering ribonucleic acid (siRNA) inhibitors

Inclisiran, a siRNA, inhibits the translation of PCSK9 by cleaving messenger RNA, decreasing PCSK9 production and upregulating LDL receptors, lowering LDL-C levels in circulation. The inclisiran administration regime is simple at days 1, day 90, day 180, followed by six monthly. Inclisiran-related adverse effects commonly reported are headache, cough, back pain, acute nasopharyngitis, hiccups, and local reactions. In the ORION trials [30], Inclisiran reduced LDL-C by 52%, and adverse reactions occurred in 11% in the treatment arm compared to 8% in the placebo. Inclisiran is an alternative therapy to PCSK9 inhibitors.

8.2.6 Omega-3 fatty acids (OM3-FA)

Eicosapentaenoic acid and Docosahexaenoic acid can lower TAGs and VLDL levels, but the mechanism for this indication has yet to be well studied. In a meta-analysis of 32 studies involving 15,903 subjects [31], OM3-FA used as monotherapy or in combination confirmed significant reductions in levels of TAGs, VLDL-C, non-HDL-C, Apo-B, and Apo-AI while increasing the levels of HDL-C. OM3-FA compounds can be considered for treating endogenous hypertriglyceridemia when dietary measures are insufficient to produce an adequate response. The dose is one capsule per day.

8.2.7 Bempedoic acid

Bempedoic acid is an ATP citrate lipase inhibitor that reduces LDL-C. Several studies have shown a reduction of LDL-C by 17–28% [32]. The main advantage of Bempedoic acid was the lack of muscular adverse effects compared to statins. A double-blind, randomised, placebo-controlled trial involving patients intolerant to statin treatment Bempedoic acid reduced significant adverse cardiovascular by 13% compared to placebo [32]. Bempedoic acid should be considered in statin intolerance in combination with ezetimibe. The recommended dose is 180 mg orally per day. Adverse effects include anaemia, gout, diarrhoea, and muscle spasms.

9. Case study

• Referred to lipid clinic Jan 2021

• 54-year-old female

• Smoker

• No family history of premature ASCVD

• On atorvastatin on the first visit to a lipid clinic

• Myocardial infarction 2013 4 stents aged 48 and non-STEMI 2021

• BMI 43 BP 156/47 Corneal arcus nil else

• Genetics: PCSK9:c:1120 GOF variant elevated SNP score

• Diagnosis: Heterozygous FH

• Treatment: In combination, she responded to maximum doses of statin, Ezetimibe, Evolocumab, and Inclisiran. No adverse reaction was observed (Table 3).

Date	TC (mmol/l)	TG (mmol/l)	HDL C (mmol/l	Non-HDL (mmol/l)	Chol: HDL ratio	LDL-C	Other
May 2019	13.9	5.3	1.2	12.7	11.6	—	Atorvastatin 80 mg
Sep 2019	12.5	5.0	1.1	11.4	11.4	—	Atorvastatin 80 mg
Dec 2019	12.8	5.6	1.0	11.8	12.8	—	Atorvastatin 80 mg
Feb 2020	18.7	6.6	0.7	18.0	26.7	15 (estimated)	—
Jan 2021	12.3	4.i	1.1	11.2	11.2	9.3	Atorvastatin 40 mg
March 2021	8.7	5.5	1.2	5.9	5.9	4.1	Atorvastatin 40 mg; Evolocumab 140 mg fortnightly; Ezetimibe 10 mg
Nov 2022	3.7	2.8	1.7	2.0	2.2	0.7	As above and added Inclisiran 284 mg
March 2023	3.9	2.8	1.7	3.0	2.8	1.7	As above; Inclisiran 284 mg 6monthly

Table 3.

Lipid profile – May 2019 to March 2023.

10. Conclusion

Dyslipoproteinaemia is a common lipid disorder affecting a very high proportion of people with diabetes at a very high risk of developing cardiovascular disease. Early diagnosis through routine screening and treatment to target as recommended by national and international guidelines is vital in the primary and secondary prevention of ASCVD. Substantial evidence supports the targeting of LDL-C lowering to reduce the risk and mortality of ASCVD. The benefit of hypertriglyceridemia treatment in people with diabetes has been questioned. However, more recently, a meta-analysis of studies of fibrates in the primary prevention of ASCVD in people with diabetes reported that fibrates significantly reduced the risk of non-fatal MI by 21% but had no effect on the overall mortality risk [33]. All people with diabetes at high risk should be considered for statin therapy and lifestyle modification. Those who do not reach target levels should be offered non-statin therapy.

There are five stages to incorporate in the management of dyslipoproteinaemia routinely:

1. Clinical history and examination

   • Family history

   • ASCVD risk factors: poor diet, excess alcohol, smoking, diabetes, thyroid disorder, liver and CKD, obesity, premature or any past CVD events and autoimmune disorders

   • Pancreatitis – high levels of TAGs

   • Xanthoma/xanthelasma/corneal arcus

2. Laboratory tests

   • TC

   • LDL-C

   • TAGs

   • HDL-C

   • ApoB

   • Lp(a)

3. Genetic testing

   • Monogenic or polygenic

4. Management

   • Risk charts

   • Address secondary causes

   • Lifestyle modification

   • Treat risk factors to targets.

   • Treat LDL-C to targets

   • Treat TAGs >10 mmol/l to prevent pancreatitis.

5. Lipid Lowering Agents (guidance according to availability)

   • Statins

   • Ezetimibe

   • Fibrates

   • Bempedoic acid

   • Bile acid sequestrants

   • OM3-FA

   • siRNA

   • PCSK9 inhibitors