Dyslipidemia in diabetes

Abstract

Diabetes mellitus is a metabolic disorder that often predisposes to cardiovascular diseases (CVD). CVD is an important cause of morbidity and mortality in diabetes. The typical diabetic dyslipidaemia is characterized by low HDL cholesterol, high triglycerides with mildly increased or even normal LDL. This attenuated rise in LDL is due to the more atherogenic small dense LDL particles. Genetic factors, obesity, lack of physical activity, alcohol abuse, poorly controlled glucose levels are some of the common risk factors for dyslipidaemia. Non-pharmacological management of dyslipidaemia is important and includes modification in the diet, increase in physical activity and efforts to reduce weight. Statins remain the mainstay of pharmacotherapy for dyslipidaemia in diabetes. Due to the small dense LDL, even patients with diabetes who have normal LDL cholesterol, achieve reduction in cardiovascular risk with statin therapy. Those patients who do not achieve acceptable LDL reductions with statin alone can be treated with combination therapy of ezetimibe with statins. Many novel therapies have also emerged such as bempedoic acid and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors. The targets for LDL cholesterol depend upon the patients underlying cardiovascular risk category. The use of pharmacotherapy for lowering triglycerides in patients with mild to moderate hypertriglyceridemia and diabetes is still a matter of debate. Proper management of dyslipidaemia is critical component of treatment of diabetes mellitus.

1. Introduction

Diabetes mellitus (DM) is a metabolic disorder that frequently predisposes to cardiovascular diseases (CVD), making CVD one of the leading causes of morbidity and mortality in both type 1 and type 2 diabetes mellitus patients (T1DM and T2DM). Good glycaemic control in T1DM leads to fewer cardiovascular events. However, the presence of CVD in T2DM patients is independent of intensive glycaemic control.¹ Aside from insulin resistance and deficiency, serum lipid abnormalities, also known as dyslipidaemia, are common in T2DM patients, a condition known as metabolic syndrome.

Diabetes-related dyslipidaemia is defined by a decrease in high-density lipoprotein (HDL) cholesterol, an increase in triglyceride levels, and a mild effect on low-density lipoprotein (LDL) cholesterol.² The pathogenesis of dyslipidaemia involves the liver producing too many very low-density lipoproteins (VLDL), which contributes to an increase in serum triglyceride levels. As a result of the dysregulation of triglyceride and serum cholesterol levels, diabetic dyslipidaemia is associated with atherosclerotic cardiovascular disease (ASCVD), increasing the risk of CHD in diabetic patients.³

1.1. Risk factors for dyslipidaemia in diabetes

Dyslipidaemia is a major modifiable risk factor for type 2 diabetes, atherosclerosis, stroke, and cardiovascular disease.^4,5 However, increased urbanisation, socioeconomic development, and lifestyle changes have increased the risk of dyslipidaemia in recent years. Furthermore, the American Association of Clinical Endocrinologists (AACE) and American Diabetes Association guidelines have identified several major risk factors for dyslipidaemia and atherosclerosis in diabetes, which are categorised into four categories (Table 1).

Table 1.

Classification of risk factors in dyslipidaemia.

Parameters	Risk Factors
Personal6	■Sedentary lifestyle ■Lack of regular physical exercise ■Excessive alcohol use ■Tobacco use ■Use of illegal or illicit drugs ■Sexually transmitted infections ■Diet rich in saturated and trans fats ■Family History of dyslipidaemia
Medical7	■Elevated serum total cholesterol levels ■Elevated levels of non–high-density lipoprotein (non–HDL) levels ■Elevated low-density lipoprotein (LDL) levels ■Albuminuria ≥30 μg of albumin/mg creatinine ■eGFR <60 ml/min/1.73 m2 ■Retinopathy ■Neuropathy
Endocrine8	■Hypothyroidism ■Hyperthyroidism ■Poorly controlled diabetes ■Cushing's disease ■Pituitary diseases
Metabolic9	■Polycystic Ovarian Syndrome ■Obesity ■Hypoadiponectinemia ■Insulin Resistance

1.2. Approaches to treatment for lipid lowering in diabetes

The first-line approach in the management of dyslipidaemia in diabetes is frequently lifestyle changes emphasising weight loss, dietary changes, and regular physical aerobic exercise. Because obesity is associated with insulin resistance and increased lipid levels, weight loss can significantly improve lipid levels and reduce cardiovascular risk factors.

Pharmacological treatment approaches for diabetic dyslipidaemia include both glucose and lipid lowering drugs. Some diabetes glycaemic control agents have been shown to influence lipid levels as well as glucose metabolism.¹ The effects of some antihyperglycaemic drugs on lipoproteins are summarised in Table 2.

Table 2.

Effects of antihyperglycaemic drugs on lipoproteins.¹

Drug	Total Cholesterol	LDL cholesterol	HDL cholesterol	Triglycerides
Metformin	No effect	↓	No effect	↓
Sulfonylureas	No effect
GLP1 analogue	No effect	No effect	No effect	↓ (Fasting and Postprandial)
DPP4i	No effect	No effect	No effect	↓ (Postprandial
Acarbose	No effect	No effect	No effect	↓ (Postprandial)
Pioglitazone Rosiglitazone	No effect	↓ slightly	↑	↓
SGLT2i	No effect	↑slightly	↑slightly	No effect
Insulin	No effect

1.3. Lipid-lowering drugs

One of the key advances in cardiovascular management is the discovery of statins. The scientific community beams with evidence of lowering of serum cholesterol with statin that is eventually associated with decreased risk of CHD.

1.4. Statins

A meta-analysis of 14 randomised trials by the Cholesterol Treatment Trialists Collaboration analysed data of 18,686 subjects mostly with T2DM. It was observed that the statin treated group showed a significant reduction of 9 %, 13 % and 21 % in all-cause mortality, vascular mortality, and in major vascular events respectively, per 39 mg/dl reduction in LDL-C. There were benefits of statin therapy seen in both primary and secondary prevention patients. It was also observed that statin treatment showed similar effects in cardiovascular events for both patients with and without diabetes. Hence, this analysis indicated that statins are beneficial in reducing CVD in patients with diabetes.¹⁰ The Heart Protection Study also demonstrated a significant reduction in cardiovascular outcomes in 2912 patients with diabetes without pre-existing vascular disease when randomized to receive simvastatin.¹¹ Statins can cause a modest increase in the risk of diabetes in patients with prediabetes or normoglycaemia. This increase is due to a rise in insulin resistance associated with statin (especially, high intensity statin therapy). In patients with preexisting diabetes, the worsening of glycaemic control is usually imperceptible or mild and do not warrant discontinuation of statins which would enhance risk of CVD.¹²

1.5. Fibrates

Fibrates are another class of drugs that function by reducing triglycerides and modestly increasing HDL cholesterol. They also seem to act by multiple pathways linked to the retinoid-X receptor. Further, the results of randomized trials also suggest that fibrates also cause a reduction in cardiovascular events in patients with diabetes. One of the largest trials was the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, where 9795 patients with T2DM were treated to fenofibrate or placebo and consequently followed up for about 5 years. It was seen that there were improvements in lipid levels with fenofibrate, causing 5 % increase in HDL-C levels, 12 % decrease in LDL-C and 29 % decrease in triglycerides. There was also a reduction of 11 % in coronary events along with 24 % decrease in non-fatal MI in the fenofibrate group.¹³ Thus, the beneficial effects of fenofibrate therapy on cardiovascular disease without a previous history of cardiovascular disease was confirmed in patients of T2DM.

2. Bempedoic acid

Bempedoic acid is a new drug for dyslipidaemia which inhibits the enzyme adenosine triphosphate citrate lyase that is involved in cholesterol biosynthesis. In 2020, bempedoic acid received FDA approval for use in patients with known ASCVD who have not achieved LDL targets on a combination of lifestyle modification and statins. The randomized, placebo-controlled CLEAR Outcomes trial has shown a significant reduction in risk for a composite cardiovascular (CV) endpoint among its patients treated with bempedoic acid.¹⁴ In a recent meta-analysis, bempedoic acid has shown significant reduction in LDL cholesterol (17.5 %) and total cholesterol (10.9 %) along with reductions in non–HDL cholesterol, apolipoprotein B and hs‐CRP.¹⁵

Bempedoic acid has shown similar efficacy in patients with dysglycaemia. Unlike statins, bempedoic acid does not increase the risk of diabetes mellitus in patients with prediabetes or normoglycemic.¹⁶ A small but significant reduction in HbA_1c has been found in patients with diabetes after receiving bempedoic acid. The common adverse effects of bempedoic acid include hyperuricaemia, gout and muscle spasms. Rarely, tendon ruptures in rotator cuff and Achilles tendon can also occur. At present, bempedoic acid can be used in patients with diabetes mellitus who require further lipid lowering after maximally tolerated statin therapy and for whom other second line agents are not suitable.

2.1. Other drugs

Moreover, there are other lipid-lowering drugs that show great clinical utility as adjunct to statin therapy. Ezetimibe remains a second-line option for LDL cholesterol lowering in diabetes. Also, colesevelam, a bile acid sequestrant shows a reduction in HbA_1c along with decrease in LDL, total cholesterol, and non-HDL cholesterol levels. Many novel therapies have also emerged such as proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors that exhibit significant reductions in LDL, the hypothesis supported by several studies that demonstrate lipid-lowering effects in T2DM patients as well.17, 18, 19

The risk factor assessment in managing dyslipidaemia in diabetes is a significant process that identifies features such as nephropathy or retinopathy and other risk factors and enhances the need for treatment intensification. Table 3 summarizes the goals of lipid levels according to the risk category and duration of diabetes with their subsequent management approach. These tools and targets are a compilation of Indian and international recommendations for the management of hyperlipidaemia.

Table 3.

Dyslipidemia management in diabetes: Targets and tools.

Risk Category	Diabetes Duration	ASCVD RF Status	TOD Status	Goal		Treatment
				LDL-C	Non HDL –C	Initiation	Intensification/Addition
Very High	>20 years	Established ASCVD/≥3 RF	Present	<55	<80	LSM + Intensive Statin	Ezetimibe/PCSK9
			Nephro/Retinopathy				Fenofibrate
			Diabetic Diarrhea				Colesevelam
High	10–20 years	1–2 RF	Absent	<70	<100	LSM + Intensive Statin	Ezetimibe
Moderate	<10 years	No RF	Absent	<100	<130	LSM + Moderate Statin	Intensive Statin
Others	Newly Diagnosed	No RF	High Triglycerides	<100	<130	LSM + Good glycaemic control	Moderate Statin

RF: risk factors; LSM: lifestyle modifications.

3. Conclusion

Stringent lipid control in patients with diabetes is of key importance in reducing the risk of developing cardiovascular events. Lifestyle measures and intensive drug therapy is required to aggressively treat these risk factors of dyslipidaemia in patients with diabetes. The era of modern therapy in diabetic dyslipidaemia ensures that these group of susceptible patients with high lipid levels are adequately managed to reduce adverse cardiovascular outcomes in type 2 diabetes mellitus.

Declaration of competing interest

We declare that we have no competing interests.