Position Paper on Lipid Therapy in Patients with Diabetes Mellitus

Key words

diabetic dyslipidemia, diabetic dyslipoproteinemia, hypertriglyceridaemia

Introduction

Patients with diabetes mellitus generally have a significantly increased cardiovascular risk. For this reason, lipid therapy and a reduction in low-density lipoprotein (LDL) cholesterol or non-high-density lipoprotein (HDL) cholesterol based on risk stratification are an integral part of diabetes therapy. This following position paper should therefore also be viewed as a topic-related supplement to the annually updated guideline for the treatment of type 2 diabetes and is also to be updated annually in future together with the DDGʼs clinical practice guidelines.

The published guidelines and recommendations of the European Society of Cardiology (ESC), the European Atherosclerosis Society (EAS), the American Association of Clinical Endocrinologists (AACE), the American Diabetes Association (ADA) and the American National Lipid Society (NLA) [1] [2] [3] [4] [5] form the basis for the information contained below.

This position paper is therefore to be understood as a short, current, clinically-oriented action guideline for patients with diabetes; for in-depth explanations on lipid disorders in diabetes, please refer to the references provided.

Stratification of cardiovascular risk

Patients with diabetes mellitus usually have a significantly increased cardiovascular risk [6]. It is nonetheless recommended to break this risk down further. The same risk factors apply as for patients without diabetes ([Table 1]). It should be noted that the presence of several risk factors has a cumulative effect on the overall risk [7]. The estimated overall risk is an essential determinant of whether and, if so, how intensively a lipid-lowering therapy should be carried out. It should be noted that, in addition to lipids, the consistent and individual adjustment of all other traditional and non-traditional risk factors should be strived for, including addressing the residual inflammatory and/or thrombotic risk with the implementation of personalized risk stratification and therapy.

Table 1 Further risk factors to be considered.

Risk factor	Comment
Positive family history for premature atherosclerosis events	Only in atherosclerosis before the age of 55 or 65 in men and women respectively; this age limit is currently not evidence-based and should possibly be shifted upwards in the future in view of increasing life expectancy.
Nicotine abuse	Number of “pack years” is relevant.
Impaired renal function	The impairment of kidney function leads to an increase in the risk of atherosclerosis depending on the stage.
Hypertriglyceridaemia	Independent risk factor; probably also as an indicator for elevated non-HDL cholesterol with atherogenic remnant particles
HDL cholesterol reduction	Inverse risk factor in population studies; low HDL-cholesterol especially increases CV risk; frequent with high triglycerides
Lipoprotein(a) increase	Independent risk factor for cardiovascular disease and aortic valve stenosis
Elevated blood pressure values	>130/85 mmHg or with antihypertensives

Lipid diagnostics

The basis is made up of the determination of total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides as well as the calculation of the of the non-HDL cholesterol level. If not yet determined, the lipoprotein(a) value should be determined once. If there is no hypertriglyceridaemia and the LDL cholesterol is determined directly, the determination can be carried out in a non-fasting state [8]. If the LDL cholesterol is calculated using the Friedewald formula, the patient should be fasting as the triglyceride level is included in the calculation. Genetic diagnosis is clinically justified in cases of high suspicion of familial hypercholesterolaemia or severe monogenic hypertriglyceridaemia (familial chylomicronaemia syndrome) if this has consequences for the indication and therapy strategy.

Lipid phenotype

A distinction is made between hypercholesterolaemia, hypertriglyceridaemia and combined hyperlipidaemia. Clinically, secondary causes must be excluded or treated and important primary disorders, e. g. familial hypercholesterolaemia or familial chylomicronaemia syndrome, must be considered ([Table 2]).

Table 2 Classification of lipid metabolic disorders.

Lipid metabolism	Cholesterol	Triglyceride	LDL chol	HDL chol	non-HDL chol
LDL hypercholesterolaemia	↑	n	↑	n	↑
Hypertriglyceridaemia	↑	↑	n	↓	↑
Combined hyperlipoproteinemia	↑	↑	↑	↓	↑
Isolated HDL cholesterol reduction	n	n	n	↓	n or ↑
Lipoprotein(a) increase	Can occur in isolation or in combination with any lipid metabolism disorder.

LDL: low-density lipoprotein; chol: cholesterol; HDL: high-density lipoprotein; n: not changed.

Treatment of lipid metabolism disorders in patients with diabetes mellitus

The goal is to reduce the increased cardiovascular risk of patients with diabetes mellitus. The most important measure is the reduction of LDL cholesterol or non-HDL cholesterol. Furthermore, the risk of acute pancreatitis can be reduced by lowering excessively elevated triglyceride levels. Normalization of elevated triglyceride levels can also improve blood glucose control ([Table 3]).

Table 3 Treatment targets for lipid metabolism disorders.

Treatment	Clinical effect	Evidence
LDL cholesterol reduction	Reduction of atherosclerosis events	Proven
Reduction of non-HDL cholesterol	Reduction of atherosclerosis events	Proven
Reduction of lipoprotein(a)	Reduction of atherosclerosis events	Presumed
Reduction of triglycerides	Reduction of atherosclerosis events	Presumed
Reduction of highly elevated triglycerides	Reduction of the incidence of acute pancreatitis	Proven

LDL: low-density lipoprotein; chol: cholesterol; HDL: high-density lipoprotein.

Therapy strategies aimed at lowering LDL cholesterol levels

In accordance with the recommendations of the European specialist societies, the reduction of LDL cholesterol levels is “target value-oriented”, taking into account the cardiovascular risk [1]. A distinction is made between 3 categories that apply equally to patients with type 1 and type 2 diabetes mellitus ([Table 4]):

Table 4 Lipid target values in patients with diabetes mellitus.

		Primary target	Secondary targets
Risk group	Definition	LDL chol	non-HDL chol	ApoB
Very high risk	Proven atherosclerosis and/or additional serious risk factors1 and/or end organ damage2 or early manifested type 1 diabetes with long diabetes duration (>20 years)	≥50% reduction and target<55 mg/dL (1.4 mmol/L)* “ideal” target and clinically “good” at<70 mg/dL (1.8 mmol/L)3	<85 mg/dl (2.2 mmol/l)	<65 mg/dl
High risk	Without proven atherosclerosis, without terminal organ damage2 with diabetes duration>10 years or other risk factors1	<70 mg/dl (1.8 mmol/l) and≥50%reduction of initial value	<100 mg/dl	<80 mg/dl
Moderately increased risk	Young patients with type 1 diabetes (<35 years) and type 2 diabetes (<50 years) with diabetes duration<10 years and no other risk factors	<100 mg/dl (2.6 mmol/l)	<130 mg/dl (3.4 mmol/l)	undefined

For patients at the age of ≤ 30 years and without indications for vascular damage or microalbuminuria, it seems reasonable to wait until the age of 30 years before beginning a statin therapy. ¹ Hypertension, nicotine abuse, severe dyslipoproteinemia ² E.g., microalbuminuria, retinopathy or neuropathy ³ For patients with confirmed atherosclerotic disease who experience a recurrence within 2 years despite maximal statin therapy, an LDL cholesterol target of<40 mg/dl (<1.0 mmol/l) may be considered. ^*This addition to a clinical evaluation by the author group of this clinical practice guideline is based on the fact that the evidence for a further effective absolute risk reduction when comparing LDL-C values in treatment between<70 mg/dl and<55 mg/dl is still low and depends very much on the individual patient risk. LDL chol: low density lipoprotein cholesterol; non-HDL chol: high density lipoprotein cholesterol; ApoB: apolipoprotein B.

• Proven atherosclerosis and/or additional serious risk factors and/or end organ damage or early manifested type 1 diabetes with long diabetes duration (>20 years)

• Without proven atherosclerotic disease, end-organ damage with diabetes duration>10 years, or additional risk factors

• Young patients with type 1 diabetes (<35 years) and type 2 diabetes (<50 years) with diabetes duration<10 years and no other risk factors.

Secondary target values are the concentrations of non-HDL cholesterol and apolipoprotein B. This reflects the fact that probably all lipoproteins containing apolipoprotein B are atherogenic [9]. The non-HDL cholesterol value (= total cholesterol minus HDL cholesterol) also approximately reflects this and includes very low density lipoprotein (VLDL) cholesterol and remnant cholesterol in addition to LDL cholesterol. The non-HDL cholesterol target value is therefore relevant in patients with hypertriglyceridaemia or mixed hyperlipidaemia (typically in patients with diabetes mellitus). In normotriglyceridemia, the VLDL/remnant cholesterol concentration is<30 mg/dl (0.8 mmol/l) (which corresponds to a triglyceride value of approximately 150 mg/dl; 1.7 mmol/l), which is why non-HDL cholesterol target values are each 30 mg/dl (0.8 mmol/l) above the LDL cholesterol target value ([Table 4]). For patients who meet the LDL cholesterol target but not the non-HDL cholesterol target, the non-HDL cholesterol level can be achieved by either lowering the triglyceride level (reduction of VLDL/remnant cholesterol) or further reducing the LDL cholesterol.

In addition, it should be mentioned that the ADA now recommends a similar approach [5]. For example, all patients with atherosclerosis should receive a high dose of a statin (atorvastatin 40–80 mg/day or rosuvastatin 20–40 mg/day) and may also be treated with ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to induce LDL cholesterol reduction of>50% and achieve the target value of<55 mg/dl. Patients without atherosclerosis are recommended to receive high- or moderate-dose statin therapy, depending on the presence of additional risk factors, with a reduction of>50% from baseline and a target level of<70 mg/dl.

The implementation of both ADA and ESC recommendations means that the vast majority of patients with diabetes mellitus should be treated with statins.

Statins, ezetimibe, bempedoic acid and PCSK9 inhibitors are available to achieve the ESC targets listed above ([Fig. 1]) [10]. After excluding or treating secondary causes of hyperlipidaemia, statins are used as the therapy of choice. If, despite a sufficient dose, this is not sufficient to achieve the individual target value, the next step is to combine it with ezetimibe and, if necessary, bempedoic acid. Another treatment option, especially in the case of clinical progression of atherosclerosis, is in combination with PCSK9 inhibitors.

Fig. 1 Therapy algorithm to achieve LDL cholesterol target levels. Bempedoic acid and inclisiran have been available since 11/2020, and 2/2021, respectively. Bempedoic acid can be used alone or in combination with other lipid-lowering agents; inclisiran is an alternative to PCSK9 antibodies. LDL-C: low density lipoprotein cholesterol; LSM: lifestyle modification; PCSK9: proprotein convertase subtilisin/kexin type 9.

Since this ladder therapy is not consistently implemented in many patients, it is discussed whether a combination therapy (statin with ezetimibe) should be used primarily in patients with very high risk.

Bempedoic acid has been available since November 2020 and inclisiran since February 2021 as further lipid-lowering drugs. Bempedoic acid is mainly used in patients with statin intolerance (in combination with ezetimibe and/or statins) but can also be used in addition to high-dose statins and ezetimibe. In the meantime, an endpoint study has shown that therapy with bempedoic acid translates into a cardiovascular risk reduction in statin-intolerant patients [11]. Inclisiran is an alternative to PCSK9 antibodies, although endpoint studies are still lacking. According to the decision of the Federal Joint Committee/Gemeinsamen Bundesausschuss (G-BA), PCSK9 inhibitors and inclisiran must be prescribed by a specialist in cardiology, nephrology, endocrinology, angiology or by a specialized lipid outpatient clinic and can then be further prescribed by the family doctor. Regular lipoprotein apheresis can be used as a last resort therapy. This is only used after all dietary and drug approaches have been exhausted and requires a separate application procedure. If the clinical indication is for lipoprotein apheresis, the G-BA decision is that the administration of a PCSK9 inhibitor is considered an alternative and economical option. In patients who are already on lipoprotein apheresis therapy primarily to lower LDL cholesterol, the administration of a PCSK9 antibody should reduce the apheresis frequency and even aim to terminate this therapeutic concept [12].

Therapy strategies for elevated triglycerides

Lifestyle measures and blood glucose control are in the foreground for hypertriglyceridaemia and for the reduction of triglycerides in combined hyperlipidaemia [1]. The use of fibrates to further lower markedly elevated triglyceride levels must be decided on an individual basis, as endpoint studies in combination with statins have not shown a cardiovascular benefit ([Table 5]) [14].

Table 5 Therapeutic strategies for elevated triglycerides. Data according to [13]

Measure	Comment
Reaching LDL cholesterol target value	Always; administration of statins is normally necessary.
Reaching non-HDL cholesterol target value	If possible, either further LDL cholesterol reduction or reduction of VLDL/remnant cholesterol (and thus triglyceride reduction).
Lifestyle measures	Always, as this can usually significantly improve hypertriglyceridaemia.
Blood glucose control	Always, as this can usually significantly improve hypertriglyceridaemia.
Fibrates	Individual assessment, possibly after achieving LDL cholesterol target values in cases of very high risk and persistent hypertriglyceridaemia; 1 cautious use, as there are no positive endpoint studies in combination with statins; caveat: increased risk of myopathy in combination with statins. This particularly affects combinations with gemfibrozil, whereas no increased myopathy incidence is observed in combinations with fenofibrate.
High-dose eicosapentaenoic acid	Not available in Germany. Individual assessment, after achieving LDL cholesterol target values in cases of very high risk and persistent hypertriglyceridaemia. In one study, a risk reduction was shown regardless of the baseline triglyceride level and regardless of the triglyceride level achieved with EPA therapy.
MCT fatty acids	As a dietary fat substitute for very high triglyceride levels.

¹ Repeated fasting triglyceride levels>500 mg/dl (5.7 mmol/l) a therapy attempt should be made with fibrates and/or high-dose omega-3 fatty acids to reduce the risk of acute pancreatitis. EPA: eicosapentaenoic acid; MCT: medium-chain triglycerides.

LDL: low-density lipoprotein

, HDL: high-density lipoprotein

, VLDL: very low-density lipoprotein.

With regard to the administration of omega-3 fatty acids, a distinction must be made between a low-dose administration (1 g/day) of omega-3 fatty acids (no risk reduction), a higher dose (2–4 g/day) of eicosapentaenoic acid (EPA) in combination with docosahexaenoic acid (DHA) (reduction of triglycerides, but no risk reduction) and a high-dose administration of EPA (risk reduction) [15]. The administration of high-dose EPA reduced the risk of cardiovascular events regardless of the level of initial triglycerides and regardless of the triglyceride level achieved during therapy. However, the drug used in the study is currently not available in Germany.

Therapy strategies for special situations

Increased lipoprotein(a) levels

Elevated lipoprotein (a) values (or also low HDL cholesterol levels) cannot currently be specifically influenced by medication, therefore in these cases the remaining risk profile must be optimized and thus, e. g., an optimal adjustment of the LDL cholesterol should be sought. If lipoprotein (a) values are significantly higher (>60 mg/dl/ca 150 nmol/l) and there is evidence of progressive atherosclerosis despite optimal control of all other risk factors over one year, regular lipoprotein apheresis therapy can be started to lower elevated lipoprotein (a) values.

Statin intolerance

Patients with diabetes mellitus and statin intolerance should be treated similarly to patients without diabetes and with statin intolerance. At least 2 different statins should be used before a statin intolerance is diagnosed (exception: rhabdomyolysis – then a second statin should only be used very cautiously). In many patients, it is possible to use a low statin dose in combination with ezetimibe to significantly reduce LDL cholesterol levels. Bempedoic acid is now available as a further treatment option, which, similar to statins, inhibits cholesterol biosynthesis, but only works in the liver, which is why myopathies are much rarer. PCSK9 inhibitors are well-tolerated by a high number of patients with statin intolerance and can be used in patients with very high risk and significant distance to the target value. Data from Germany show that PCSK9 inhibitors are used in 70–80%of patients with statin intolerance.

Severe hypertriglyceridaemia

Triglyceride values above 1000 mg/dl (approx. 11 mmol/l) significantly increase the risk of acute pancreatitis [13]. By consistently implementing lifestyle measures (alcohol abstinence, largely abstaining from refined carbohydrates) and a strict blood glucose control it is usually possible to lower the values significantly. In order to minimize the risk of pancreatitis in severe hypertriglyceridaemia, fibrates and/or high doses of omega-3 fatty acids can be used to significantly reduce triglyceride levels. Statins in high doses can lower triglyceride concentrations somewhat, but this is usually not sufficient to treat severe hypertriglyceridaemia. If acute pancreatitis occurs at triglyceride concentrations above 1000 mg/dl (approx. 11 mmol/l), plasmapheresis is a treatment option to rapidly reduce the triglyceride concentration [16]. Further treatment options include the administration of heparin and/or insulin (activation of lipoprotein lipase) and fasting. In intervals, it is particularly worth trying a replacement of dietary fats with medium-chain triglyceride (MCT) fatty acids in cases of very high triglyceride values. In very severe hypertriglyceridaemia in the setting of familial chylomicronemia syndrome (genetic evidence required), the antisense oligonucleotide volanesorsen, which inhibits the synthesis of apolipoprotein C-III, can be used.

Conclusion

Cardiovascular events are a major cause of premature mortality and multimorbidity in people with diabetes. Risk stratified patient-related LDL cholesterol reduction is an evidence-based integral part of diabetes therapy and can improve the clinical prognosis of our patients. High-dose statin therapy, if necessary, in combination with ezetimibe, is the most important drug therapy. In moderate hypertriglyceridaemia, lifestyle measures and blood glucose control are in the foreground, as fibrates and the available omega-3 fatty acid supplements did not show any risk reduction for cardiovascular events. As a secondary goal, attention should be paid to non-HDL cholesterol levels. In the case of severe hypertriglyceridaemia with values above 1000 mg/dl (approx. 11 mmol/l), the following measures reduce triglyceride concentrations and therefore significantly reduce the risk of pancreatitis: lifestyle measures (alcohol abstinence, largely abstaining from refined carbohydrates), good blood glucose control, possible administration of fibrates and/or omega-3 fatty acids.

Company representatives

K.G. Parhofer and D. Müller-Wieland represent the German Diabetes Society (DDG).

A.L. Birkenfeld represents the Heart and Diabetes Working Group (AG Diabetes und Herz).

W. Krone and M. Merkel represent the German Society of Endocrinology (DGE).

M. Lehrke, N. Marx, K.S. Schütt and A. Zirlik represent the Heart and Diabetes Working Group of the German Cardiology Society (AG Herz und Diabetes der DGK).

N. Marx, W. Krone, D. Müller-Wieland represent The Joint Heart – Hormones – Diabetes Working Group of the DGK, DGE and DDG (AG Herz-Hormone-Diabetes der DGK-DGE-DDG).

German Diabetes Association: Clinical Practice Guidelines This is a translation of the DDG clinical practice guidelinepublished in Diabetol Stoffwechs 2023; 18 (Suppl 2): S330–S336DOI 10.1055/a-2076-0160

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