Position Paper on Lipid Therapy in Patients with Diabetes Mellitus A Joint Statement by the Commission on Lipometabolism and The Heart and Diabetes Working Group of the German Diabetes Society (DDG), The Diabetology and Metabolism Section of The German Society of Endocrinology (DGE), The Heart and Diabetes Working Group of the German Cardiology Society (DGK) and The Joint Heart - Hormones – Diabetes Working Group of the DGK, DGE and DDG

Hypertension,


Introduction
Patients with diabetes mellitus generally have a significantly increased cardiovascular risk. For this reason, lipid therapy and a reduction in LDL cholesterol based on risk stratification are an integral part of diabetes therapy; the following position paper should therefore also be viewed as a topic-related supplement to the annually updated recommendation for the treatment of type 2 diabetes and should also be updated annually in future together with the DDGʼs practical recommendations.
The recently 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 recommendation for action in patients with diabetes; for in-depth explanations on lipid metabolism and the use of lipid disorders, please refer to the literature 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.

Treatment of Lipid Metabolism Disorders in Patients with Diabetes Mellitus
The primary goal of the treatment is to reduce the increased cardiovascular risk of patients with diabetes mellitus. The most important measure is the reduction of LDL 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).

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).
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 VLDL cholesterol and remnant cholesterol in addition to LDL cholesterol. The non-HDL cholesterol target value is therefore relevant in patients with hypertriglyceridemia or mixed hyperlipidaemia (typically in patients with diabetes mellitus).
In normotriglyceridemia the VLDL/remnant cholesterol concentration is < 30 mg/dl (which corresponds to a triglyceride value of approximately 150 mg/dl), which is why non-HDL cholesterol target values are each 30 mg/dl above the LDL cholesterol target value (▶Table 4). For patients who meet the LDL cholesterol target but not The lipoprotein(a) value should be determined once only. If there is no hypertriglyceridemia 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 hypercholesterolemia, if this has consequences for the indication and therapy strategy.

Lipid Phenotype
A distinction is made between hypercholesterolemia, hypertriglyceridemia and combined hyperlipidaemia. Clinically, secondary causes must be excluded or treated and important primary disorders, e. g. familial hypercholesterolemia, must be considered (▶Table 2). ▶Table 1 Further risk factors to be considered.

Risk factor Comment
Positive family history for premature atherosclerosis events Atherosclerotic events 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 dosage.

Hypertriglyceridemia
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-C especially increases CV risk; frequent with high triglycerides In addition, it should be mentioned that the American Diabetes Association (ADA) solely considers the age criteria (under/over 40 years) and presence of atherosclerosis (yes/no) [5]. All patients with atherosclerosis receive a high dose of statin (atorvastatin 40-80 mg/d or rosuvastatin 20-40 mg/d) and can also be treated with ezetimibe and PCSK9 inhibitors if the LDL cholesterol level remains above 70 mg/dl. For patients without atherosclerosis, those under 40 years of age do not generally receive a statin and those over 40 years of age receive a moderate statin dose (e. g. atorvastatin 20 mg/d or rosuvastatin 10 mg/d).
Even if, at first glance, there are clear differences between the ADA and ESC recommendations, in both cases the fact is that the vast majority of patients with diabetes mellitus should be treated with statins.
In order to achieve the ESC target values mentioned above, a gradual therapy of statins, ezetimibe and PCSK9 antibodies can be used (▶ 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, as a third step, to combine it with PCSK9 inhibitors, especially in cases of clinical progression of cardiovascular disease.
According to the decision of the Federal Joint Committee/ Gemeinsamen Bundesausschuss (G-BA), PCSK9 inhibitors must be prescribed by a doctor of internal medicine with a specialization in cardiology, nephrology, endocrinology, angiology or by a special lipid outpatient clinic and can then be prescribed by the family doctor. As a last option, regular lipoprotein apheresis therapy is also possible, however, this should only be used when all other drug approaches have been exhausted. If the clinical indication is LDL 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 [11].

Therapy Strategies for Elevated Triglycerides
Lifestyle measures and blood glucose control are the primary strategies for hypertriglyceridemia and for the reduction of triglycerides in combined hyperlipidaemia [1]. The use of fibrates and high-dose fatty acids to further reduce significantly elevated triglyceride levels must be decided individually, as endpoint studies in combination with statins have shown no clear cardiovascular benefit (▶ Table 5).

Increased lipoprotein(a) levels
Elevated Lp(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. It is important to note that approx. 20 % of the Lp(a) concentration is included in the LDL cholesterol determination, i. e. the LDL cholesterol value must be "corrected" for this. If lipoprotein(a) values are significantly elevated ( > 60 mg/dl) and there is evidence of progressive atherosclerosis over one year despite optimal control of all other risk factors, 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 statin intolerance. At least 3 different statins should be used before a statin intolerance is diagnosed (exception: rhabdomyolysis induced by a statin -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.

Severe hypertriglyceridemia
Triglyceride values above 1000 mg/dl significantly increase the risk of acute pancreatitis [12]. 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 hypertriglyceridemia, fibrates and/or high doses of omega-3 fatty acids can be used to significantly reduce triglyceride levels. If acute pancreatitis occurs at triglyceride concentrations above 1000 mg/dl, plasmapheresis is a treatment option to rapidly reduce the triglyceride concentration. Further treatment options include the administration of heparin and/or insulin (activation of lipoprotein lipase) and fasting. It is particularly worth trying a replacement of dietary fats with MCT fatty acids in cases of very high triglyceride values.

Conclusion
Cardiovascular events are a major cause of premature mortality and multimorbidity in people with diabetes. Risk stratified patientrelated LDL cholesterol reduction is an evidence-based integral part of diabetes therapy and can improve the clinical prognosis of our patients. In the case of severe hypertriglyceridemia with values above 1000 mg/dl, 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.

Measure Comment
Reaching LDL cholesterol target value Always; normally necessary to administer statins Reaching non-HDL 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 hypertriglyceridemia. Always, as this can usually significantly improve hypertriglyceridemia.
Blood glucose control Individual assessment, possibly after achieving LDL cholesterol target values in cases of very high risk and persistent hypertriglyceridemia; 1 cautious use, as no convincing endpoint studies in combination with statins have been conducted so far; note: increased risk of myopathy in combination with statins.

Fibrates
Individual assessment, possibly after achieving LDL cholesterol target values in cases of very high risk and persistent hypertriglyceridemia; cautious use, as no convincing endpoint studies in combination with statins have been conducted so far.
As a dietary fat substitute for very high triglyceride values.