Management of dyslipidaemia in patients with comorbidities: facing the challenge: type 2 diabetes mellitus

Abstract

Type 2 diabetes mellitus typically has the lipid features of elevated trigycerides, reduced HDL-cholesterol (both parts of the metabolic syndrome) and average or slightly elevated LDL-cholesterol. In consequence of hypertriglyceridemia, LDL particles are small and dense and therefore highly atherogenic. Outcome studies reveal that LDL-C lowering drugs have an above-average efficacy in type 2 diabetes as compared with non-diabetic patients. A minor increase of glycaemia in statin trials does not impair the beneficial cardiovascular results. Non-statin lipid lowering drugs do not impair glycaemia. Type 2 diabetes mellitus is now considered a major indication for lipid lowering drugs, thus there is a high value of and no major limitation for those compounds.

Graphical Abstract

Graphical Abstract.

Central illustration: the central illustration depicts the major site of action as well as the level of evidence for cardiovascular risk reduction.

Preface and background

The aspect of comorbidities and the value and limitations of lipid lowering drugs have been previously reported from three review articles in this journal^1-3 and we now focus on type 2 diabetes mellitus (T2DM).

Pathophysiologically, T2DM has two characteristic features: insulin resistance mainly due to obesity, and deficient insulin secretion due to impaired pancreatic beta cell function. The former reduces the activity of lipoprotein lipase leading among other effects to impaired clearance of triglycerides (TGs) from the blood. The latter primarily reduces the first spike of the post-prandial insulin response by the beta cells and prolongs the duration of post-prandial hyperinsulinemia.

Epidemiology of cardiovascular disease in type 2 diabetes

Due to the obesity epidemic and other factors the prevalence of T2DM is steadily increasing. It is estimated that currently 589 million people are affected globally, that is 1 in 9 of the adult population.⁴

T2DM increases the likelihood of atherosclerotic cardiovascular disease (ASCVD) two- to three-fold. In fully adjusted models, individuals with diabetes using insulin exhibited a five-fold higher risk among women (RR: 5.44; 95% CI: 4.90–6.05) and a three-fold higher risk among men (RR: 3.13; 95% CI: 2.84–3.45) for incident ASCVD events compared with those without diabetes⁵ Life expectancy of individuals with T2DM is reduced by 6 years when compared with non-diabetic controls and by 12 years, if T2DM and ASCVD coexist.⁶ T2DM increases the risk for progression of ASCVD by a comparable amount irrespective of the pre-existing degree of atherosclerosis.⁷ The duration of diabetes and/or glycaemic control have not been tested as modifiers of lipid lowering efficacy, e.g. in the ‘Improved Reduction of Outcomes: Vytorin Efficacy International Trial’ IMPROVE-IT.⁸

Pathophysiology of cardiovascular disease in T2DM

The pathophysiology of ASCVD in T2DM is multi-factorial, including obesity, hyperglycaemia, insulin resistance, elevated blood pressure, low-grade/chronic inflammation, and diabetic dyslipidaemia.⁹ Overnutrition and obesity are the most common causes of insulin resistance and are often associated with low-grade inflammation.¹⁰

Lipoprotein metabolism in type 2 diabetes

Excess release of free fatty acids from the adipose tissue promotes ectopic lipid accumulation especially in the liver, but also in the heart and the skeletal muscle, in states of overnutrition and obesity, which then induce tissue-specific insulin resistance. As a consequence of hepatic insulin resistance, de novo lipogenesis and gluconeogenesis are activated, fatty acid metabolism is impaired and VLDL secretion increased.^11,12

In terms of lipoproteins, the TG-rich lipoproteins are elevated and therefore the plasma level of TG is elevated to various degrees, typically between 150 and 300 mg/dL (1.69 and 3.39 mmol/L). As typical for hypertriglyceridemic states, HDL-cholesterol is reduced both in men and in women with T2DM. The total level of LDL-cholesterol is average or slightly elevated. However, evidence from genetic, observational, and interventional studies has firmly established a dose-dependent relationship between low-density lipoprotein cholesterol (LDL-C) and the development of ASCVD. In essence, higher levels of LDL-C are directly associated with an increased risk of ASCVD.^13,14

Fundamental changes are observed in the composition of lipoproteins due to the action of the cholesterol ester transfer protein (CETP). Increased activation of CETP¹⁵ causes TG enrichment of LDL and HDL particles and cholesteryl ester enrichment of TG-rich lipoproteins, resulting in small dense (sd) LDL particles and a shift from larger HDL2 towards smaller HDL3 particles. sdLDL particles are more prone to oxidation and enter the sub-endothelial space more easily and rapidly, and thus are considered highly atherogenic.¹⁶ LDL enriched in TG ultimately become a target for lipoprotein and hepatic lipase. Small dense LDL have been shown to be more atherogenic than typical LDL.¹⁷

Besides elevated TG and preponderance of sdLDL particles, diabetic dyslipidaemia is also characterized by low HDL-C and apolipoprotein AI levels, reduced size and dysfunctional HDL particles.^18-20 The latter is related to the formation of advanced glycation end products (AGEs), which activate a molecular cascade inducing the expression of caveolin-1, the key protein in LDL internalization.²¹ As a consequence, cholesterol efflux capacity and antioxidant capacity of HDL particles are impaired, thereby further increasing vascular vulnerability.^22-26 Together this dysfunctional lipid pattern commonly is termed ‘diabetic dyslipidaemia’.

Other pathophysiological aspects

T2DM is recognized not only as a metabolic disorder but also as a chronic low-grade inflammatory condition, which plays a key role in the pathogenesis of insulin resistance and β-cell dysfunction, while diabetes can, in turn, exacerbate inflammation. Pro-inflammatory cytokines, which are usually elevated as a consequence of macrophage infiltration in the adipose tissue in metabolically unhealthy obese patients, deteriorate tissue-specific insulin signalling, especially in the heart. This further diminishes whole body insulin sensitivity.^27,28 Additionally, elevated neutrophil extracellular trap activation might also contribute to atherogenesis in patients with T2DM, thus linking inflammation with cardiovascular disease.²⁹

Insulin resistance is also associated with reduced endothelial nitric oxide (NO) synthase and NO production and increased expression of adhesion molecules on endothelial cells inducing endothelial dysfunction and enhanced vascular permeability for inflammatory cells.³⁰ Elevated inflammatory markers in T2DM include C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), increased white blood cell counts and other innate immune cell activity and adipose tissue macrophage infiltration and secretion of pro-inflammatory cytokines. Obesity, especially visceral fat, leads to immune cell recruitment (e.g. M1 macrophages).³¹

Despite advancements in controlling traditional risk factors like dyslipidaemia and hypertension, a considerable residual cardiovascular risk persists, highlighting the need for innovative therapeutic approaches. Advances in multi-omics and systems biology are deepening our understanding of the molecular drivers of atherosclerosis.³² In epidemiological terms however, clinical trials targeting inflammation in T2D never showed any benefit. Moreover, whether the side effect profile of lipid lowering drugs changes in light of the underlying low-grade inflammation in T2D is not known.

The role of hyperglycaemia in atherogenesis is less clear. AGE as a consequence of chronic hyperglycaemia enhances adhesion molecule expression and activation of endothelial cells thus promoting the initial steps of atherogenesis. Additionally, AGE not only modify HDL particles leading to reduced cholesterol efflux capacity but also further augment atherogenicity of LDL particles.^33-35 Increased intra-cellular glucose levels or metabolites induce reactive oxygen species (ROS) and pro-inflammatory responses which further promotes atherosclerosis in T2DM.^36,37

Current guidelines for lipid-lowering treatment in type 2 diabetes

Epidemiological studies have shown that high levels of LDL-C and non-HDL-C and low levels of HDL-C are associated with an increased risk of CV events and mortality in patients with and without T2DM.¹³ Conversely, RCTs with lipid-lowering agents in patients at risk of CV events (including patients with T2DM) have demonstrated a log-linear proportional reduction of CV events and mortality for each 1 mmol reduction of LDL-C (38.7 mg).³⁸ LDL-C is the primary target of lipid-lowering therapies, non-HDL-C the secondary target particularly in T2DM. Non-HDL-C should therefore be considered in patients with T2DM and combined dyslipidaemias, although there are limited data from interventional trials. Treatment goals among patients with T2DM are based on their cardiovascular risk.

Due to the lack of evidence, no clear recommendations can be given for patients with T2DM at low CV risk.⁶

Lipid-lowering agents

For the drug classes discussed below, the main site of action and the level of evidence for cardiovascular risk reduction are summarized in the central illustration.

Statins

Table 1 summarizes the key aspects of statin trials that included patients with T2DM.

Table 1.

Placebo-controlled outcome studies with statins ^39-54

Study	Active drug	Comparator	Number of participants (n)	People with Diabetes (%)	Duration (Median, years)	Endpoint	Outcome	References
4S (1994)	Simvastatin 20 mg	Placebo	4444	5	5.4	The primary endpoint: total mortality. Secondary endpoint: analysed by time of first event, ‘major coronary events’, (coronary deaths, definite or probable hospital-verified non-fatal acute MI, resuscitated cardiac arrest, and definite silent MI verified by electrocardiogram).	Not specific for diabetes; long-term treatment with simvastatin improved survival in CHD patients.	39
WOSCOPS (1995)	Pravastatin 40 mg	Placebo	6595	1	4.9	Primary endpoint: occurrence of non-fatal myocardial infarction or death from coronary heart disease as a first event. Other principal endpoints were the occurrence of death from coronary heart disease and non-fatal myocardial infarction.	Not specific for diabetes; pravastatin significantly reduced incidence of MI and death from cv causes.	40
AFCAPS/TexCAPS (2000)	Lovastatin 20–40 mg	Placebo	6605	3	5.0 (at least)	First acute major coronary event defined as fatal or non-fatal myocardial infarction, unstable angina, or sudden cardiac death.	History of diabetes not a significant predictor of outcome; lovastatin reduces risk for first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C.	41
CARDS (2004)	Atorvastatin 10 mg	Placebo	2838	100	3.9	Primary endpoint: time to first occurrence of acute coronary heart disease events, coronary revascularization, or stroke.	Atorvastatin is efficacious in reducing the risk of first cv disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol.	42
CARE (1996)	Pravastatin 40 mg	Placebo	4159	15	5.0	Primary endpoint: a fatal coronary event or a non-fatal myocardial infarction.	The benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels.	43
LIPID (1998)	Pravastatin 40 mg	Placebo	9014	6	6.0	Primary endpoint: death from CHD or non-fatal myocardial infarction (combined).	Patients with diabetes or IFG; Cholesterol-lowering treatment with pravastatin therapy prevents cardiovascular events, including stroke, in patients with diabetes or IFG and established CHD.	44
JUPITER (2008)	Rosuvastatin 20 mg	Placebo	17 802	0	1.9	Primary outcome: the occurrence of a first major cardiovascular event, defined as non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from cardiovascular causes. Secondary endpoints: the components of the primary endpoint considered individually—arterial revascularization or hospitalization for unstable angina, myocardial infarction, stroke, or death from cardiovascular causes—and death from any cause.	Rosuvastatin significantly reduced the incidence of major cardiovascular events of apparently healthy persons without hyperlipidaemia but with elevated high-sensitivity C-reactive protein levels.	45
ASPEN (2006)	Atorvastatin 10 mg	Placebo	2410	100	4.0	Composite primary endpoint: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, recanalization, coronary artery bypass surgery, resuscitated cardiac arrest, and worsening or unstable angina requiring hospitalization.	Composite endpoint reductions were not statistically significant.	46
HPS (2002, 2003) (Prim. + Sec.Prev.)	Simvastatin 40 mg	Placebo (Prim.Prev.) or Usual care (Sec.Prev.)	20 536 (5963 with diabetes) 2912 of those in Prim.Prev., 3051 in Sec.Prev.	15.0	5.0	Prim.prev. Primary outcomes: mortality (for overall analyses) and fatal or non-fatal vascular events (for sub-category analyses), with subsidiary assessments of cancer and of other major morbidity. Sec.prev. First major coronary event (i.e. non-fatal myocardial infarction or coronary death) and of first major vascular event (i.e. major coronary event, stroke or revascularization).	Significant reduction (33%) in defined endpoint for sub-categories. 24–27% reduction in major vascular events; in diabetics, coronary events fell from 11.8% to 8.7% (HR 0.73, P < 0.0001).	47,48
ALLHAT-LLT (2002)	Pravastatin 40 mg	Usual care	10 355	35	4.8	Primary outcome: all-cause mortality.	No significant reduction in primary endpoint.	49
ASCOT-LLA (2003, 2005)	Atorvastatin 10 mg	Placebo	10 305 2532 with diabetes	25	3.3	Primary endpoint: non-fatal myocardial infarction and fatal CHD.	Significant reduction (36%) in primary endpoint. Diabetes patients (23% reduction in cardiovascular and coronary endpoints). 36% reduction in MI/CAD death overall; diabetic sub-group saw a 23% decrease in CV events (P = 0.036).	50,51
MEGA (2006)	Pravastatin 10–20 mg	Usual care	7832	21	5.3	Primary endpoint: the first occurrence of coronary heart disease.	Significant reduction (33%) in coronary heart disease events.	52
4D (2005)	Atorvastatin 20 mg	Placebo	1255	100	4.0	Primary endpoint: composite of death from cardiac causes, non-fatal myocardial infarction, and stroke. Secondary endpoints: death from all causes and all cardiac and cerebrovascular events combined.	No statistically significant effect on the composite primary endpoint.	53
SPARCL (2018)	Atorvastatin 80 mg	Placebo	4731	17	4.9	Primary endpoint: first non-fatal or fatal stroke.	No significant reduction in strokes, significant reduction in incidence of strokes and of cardiovascular events.	54

Among the earlier randomized clinical trials, T2DM patients represented a variable proportion in the whole trial cohorts, since no trial focused specifically on T2DM patients. The breakthrough trial—the Scandinavian Simvastatin Survival Study (4S)—did not specifically look at T2DM, e.g. only 201 diabetes patients were among the 4444 of the 4S cohort).³⁹

Sub-group analyses have the major methodological limitation that there is no randomization according to presence of T2DM and that the diabetes sub-groups are not large enough to fulfil the requirements of a sample size calculation and adequate statistical power.⁵⁵ Specifically, 4S was event-driven. It appeared that the T2DM sub-group responded similarly to the non-diabetic one to statin intervention. Further, placebo-controlled trials as the West of Scotland Coronary Prevention Study (WOSCOPS)⁴⁰ and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)⁴¹ in primary prevention settings as well as, e.g. CARE, LIPID^43,44 in the secondary prevention setting, did not specify on event rates in T2DM vs. non-T2DM.

It was therefore very important to conduct a separate trial specifically on patients with T2DM. Here, the Collaborative Atorvastatin Diabetes Study (CARDS) represents a milestone.⁴² In 2838 patients, atorvastatin 10 mg was tested against placebo. The intervention was so effective, that the trial had to be stopped pre-maturely for efficacy,⁵⁶ i.e. 37% reduction in first major CV events (HR not stated), 48% fewer strokes, with a 27% lower overall mortality (P = 0.059).⁴²

As early as in 2008 the highly respected Cholesterol Treatment Trialist’s (CTT) Collaborators from Oxford³⁸ published data on the efficacy on cholesterol-lowering therapy in 18 686 people with diabetes. They undertook a prospective meta-analysis in the diabetic individuals (1466 with type 1 and 17 220 with T2DM) and compared their outcomes with those of 71 370 without diabetes, by collecting data from 14 randomized trials of statins. During a mean follow-up of 4.3 years, 3247 major vascular events were observed in the diabetes group. The proportional reductions in diabetic vs. non-diabetic patients are depicted in Figure 1.^38,57 In synopsis, diabetic and non-diabetic patients had similar proportional reduction of endpoints per 1 mmol/L (38.7 mg/dL) reduction in LDL-cholesterol. Furthermore, in diabetic participants there were reductions of these endpoints irrespective of whether there was a prior history of vascular disease or other baseline characteristics. After 5 years, 42 fewer persons with diabetes had major vascular events per 1000 allocated to statin therapy. Importantly, the similar reduction of major vascular events and myocardial infarction were significantly higher in absolute terms in diabetic patients. As mentioned above, it is important to remember that the absolute risk of the diabetic patients is at least two- to three-fold higher than in non-diabetic ones.^5,58 Consequently, the number needed to prevent one event is much lower in diabetes.

Figure 1.

Statins in patients with diabetes. Relative risk reduction per 1 mmol/L LDL-C (38.7 mg/dL) reduction with and without diabetes.^37,56

Statins can increase glycaemia to a minor degree, a fact that does not reduce their positive effect on ASCVD. Thus, the minor increase of glycaemia in statin trials does not impair the beneficial cardiovascular results. Any theoretical adverse effects of statins on cardiovascular risk that might arise from these small increases in glycaemia (or, indeed, from any other mechanism) are already accounted for in the overall reduction in cardiovascular risk that is seen with statin therapy in these trials.⁵⁹ Details are given in the previous article on T1DM.³

Ezetimibe

Lowering of LDL-C can be further intensified by adding ezetimibe to a statin. Ezetimibe affects cholesterol absorption by inhibiting intestinal uptake of dietary and biliary cholesterol. The site of ezetimibe`s action is the brush border of the intestinal enterocytes (mainly jejunum), where it blocks the Nieman–Pick C1-like protein responsible for cholesterol uptake into enterocytes, without affecting the absorption of fat-soluble nutrients. By doing so, less cholesterol is packaged into chylomicrons and ezetimibe reduces the amount of cholesterol delivered to the liver. This, in turn, leads to an up-regulation of the LDL-receptor, which leads to an increased clearance of LDL particles from the bloodstream.^13,60 Because lowering LDL-C by statins may also lead to a compensatory increase in intestinal cholesterol absorption⁶¹ and ezetimibe, in turn, may induce HMG-CoA reductase expression,⁶² a combination of statins and ezetimibe is considered particularly useful.^63,64

Clinical studies have shown that ezetimibe monotherapy at the standard daily dose of 10 mg reduces LDL-cholesterol levels by 15–22% in various populations with hypercholesterolemia. A meta-analysis of RCTs including over 2700 people showed an 18.5% reduction in LDL-cholesterol vs. placebo.⁶⁵ Several trials have evaluated the use of ezetimibe in patients with diabetes. In the VYTAL trial (Vytorin vs. Atorvastatin in patients with T2DM and hypercholesterolaemia), 1229 patients with T2DM were randomized to receive ezetimibe in combination with varying doses of a moderate-intensity (simvastatin) or a high-intensity (atorvastatin) statin. After 6 weeks of treatment, ezetimibe plus simvastatin had greater LDL-C reductions as compared with atorvastatin, irrespective of its dose.⁶⁶ In general, given the mode of action of ezetimibe, combination studies adding ezetimibe to statins, bile acid sequestrates, bempedoic acid or pro-protein convertase subtilisin/kexin type-9 (PCSK9) inhibitors showed consistent and clinically meaningful lipid-lowering effects. Accordingly, in a recent study in patients with T2DM comparing the combination of a low-dose of high-intensity statin with ezetimibe to a high-dose of a high-intensity statin monotherapy, favourable biomarker outcomes (such as LDL-C and HOMA-B) for the former over the latter were seen,⁶⁷ which is supported by another report.⁶⁸

Several studies have used carotid intima-media thickness (C-IMT) as surrogate endpoint for vascular disease. The ENHANCE trial, a study in patients with familial hypercholesterolemia (FH), included only 1.8% patients with diabetes.⁶⁹ The SANDS trial enrolled 427 patients with diabetes investigating a combination of statin and ezetimibe, showing that aggressive lipid-lowering (with or without the inclusion of ezetimibe), can positively affect C-IMT.⁷⁰ However, an ezetimibe-specific effect, beyond aggressive lipid-lowering, could not be demonstrated, hence primarily confirming a ‘the lower the better’ approach, irrespective of the drug being used for lipid-lowering.

The SEAS study⁷¹ had T2DM as an exclusion criterion. Therefore, the first RCT to yield information about clinical endpoints when using ezetimibe in patients with diabetes was the SHARP trial.⁷² This was a placebo-controlled study in patients with chronic kidney disease, 23% of whom had diabetes. The study showed that reduction of LDL-cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease. No difference in outcome in any of the studied sub-groups was shown, including in patients with diabetes.

Finally, the IMPROVE-IT trial showed significantly reduced MACE (composite of CV death, non-fatal MI, unstable angina requiring re-hospitalization, coronary revascularization ≥30 days after randomization, or non-fatal stroke; HR 0.94; 95% CI, 0.89–0.99) in patients post-ACS receiving simvastatin plus ezetimibe vs. simvastatin alone.⁸ In the sub-group of patients with diabetes, the effect was more pronounced, indicating an even greater benefit in T2DM (HR 0.85; 95% CI, 0.78–0.94; P < 0.001).⁷³ The largest relative reductions in patients with T2DM were in myocardial infarction (24%) and ischaemic stroke (39%). No differences in safety outcomes by treatment were observed regardless of diabetes. When stratified further by age, patients ≥75 years of age had a 20% relative reduction in the primary endpoint regardless of diabetes (Pint = 0.91), whereas patients <75 years of age with diabetes had greater benefit than those without (Pint = 0.011).⁷³

Studies comparing high intensity statin vs. low-to-moderate intensity statin plus ezetimibe in patients at high-risk of ASCVD, including diabetes, have been performed more recently. In a pre-specified sub-group analysis of the diabetes cohort in the RACING trial,⁷⁴ similar efficacy results were seen with respect to the primary endpoint, a 3-year composite of CV death, major CV events, or non-fatal stroke, with more favourable results in terms of LDL reduction and overall tolerability of the moderate-intensity statin with ezetimibe combination therapy (vs. high-intensity statin alone). Based on these and similar findings,⁷⁵ alternative LDL-lowering strategies (vs. a high-intensity statin strategy), involving ezetimibe in combination with low-dose statin have gained interest, indicating similar clinical efficacy and favourable reductions in LDL levels, along with better drug tolerability and lower risk of new-onset diabetes.⁷⁶

Ezetimibe is a valuable adjunct to statin therapy in minimizing CV risk in various populations, including patients with diabetes, which are in the higher risk categories for ASCVD.⁶ Ezetimibe can be used as monotherapy (in case of statin intolerance), and in combination with statins, with bempedoic acid (in case of statin intolerance), in triple combination (with a statin and bempedoic acid) and in combination with drugs targeting the PCSK9 pathway. The combination of ezetimibe with a statin is recommended in patients with diabetes and a recent ACS, especially when an LDL-C target <55 mg/dL (1.42 mmol/L) is required and not achieved with a statin alone.⁶ Accordingly, a statin-ezetimibe combination as first choice treatment in very high-risk patients with high LDL levels is recommended.^64,77

PCSK9 inhibitors

PCSK9 is a molecule that binds to LDL particles in the circulation. The PCSK9/LDL complex then binds to the LDL-receptor and enters the cell. Due to the degradation of the LDL and its receptor it prevents the recycling of the LDL-receptor to the cell membrane. The reduced number of LDL-receptors ensues in reduced cellular uptake of LDL particles and therefore increases the level of circulating LDL. Around 2012, gain-of-function and lack-of-function mutations were discovered, which showed that the PCSK9 molecule is very strongly associated with LDL-C levels.

The first approach to inhibit PCSK9 was to trap it in the circulation by humanized monoclonal antibodies. Two antibodies were tested in outcome trials: Evolocumab in ‘Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk’ (FOURIER),⁷⁸ and Alirocumab in the trial ‘Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab’ (ODYSSEY OUTCOMES).⁷⁹ A third trial, Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE), was stopped because of inhibiting secondary antibodies and ensuing loss of efficacy.⁸⁰

The proportion of diabetic patients was 37% in FOURIER which included 27 564 patients with ASCVD and 29% of patients out of 18 924 participants in ODYSSEY OUTCOMES with recent ACS.

The efficacy of PCSK9 inhibitors in patients with diabetes has been summarized by Imbalzano et al.⁸¹ In FOURIER, evolocumab reduced LDL-cholesterol levels by 59%⁷⁸ and the relative risk reduction for major adverse cardiovascular events (primary composite endpoint) was slightly greater in diabetic patients than in non-diabetic counterparts (17% vs. 13%, P < 0.0001).⁸² Incidence of serious adverse events, muscle-related events, new-onset diabetes, haemorrhagic stroke, and neurocognitive events with long-term evolocumab were similar to the placebo arm during the study and afterwards.⁸³

In ODYSSEY OUTCOMES, LDL-cholesterol was reduced by ∼60%⁷⁹ and in patients with diabetes alirocumab showed a greater absolute risk reduction that was attributable to their higher baseline risk (2.3%).⁸⁴

Notably, in both trials there was no signal of worsening glycaemia. Moreover, a ODYSSEY OUTCOMES sub-study definitely showed that LDL-cholesterol lowering does not increase the likelihood of haemorrhagic stroke.⁸⁵ Finally, the safety of alirocumab was reportedly favourable in an analysis of 47 296 patient-years.⁸⁶

In summary, the two studies revealed high efficacy and safety. As a limitation, neither all-cause nor cardiovascular mortality incidence in FOURIER was significantly reduced, only MACE were reduced. Therefore, the FOURIER trialists decided to make an open label extension that showed that cardiovascular mortality was significantly reduced (23%).⁸³ By comparison, in ODYSSEY OUTCOMES all-cause mortality was reduced significantly by 15% but based on hierarchical testing this finding was not over-emphasized.⁷⁹

The broad use of PCSK9 antibodies in clinical practice is limited by their high cost. Thus, in most European countries restrictive reimbursement regulations exist due to problems in affordability. Thus, these antibodies are not yet used as first-line therapy. The Guideline recommend use of PCSK9 inhibitors in patients with established ASCVD who do not reach LDL-cholesterol goals despite maximally tolerated statins and ezetimibe as well as familial hypercholesterolemia patients, or statin intolerant individuals.¹³ Generally, clinical observations show that these antibodies are very well tolerated.⁸² Statins remain the first-line therapy also in diabetic patients.

Inclisiran

Inclisiran offers a different approach to reduce PCSK9, since it is a small interfering RNA (siRNA) that decreases the intra-cellular production of PCSK9 through a different mechanism: a reduced production rather than neutralization by antibodies. The efficacy of this drug is well documented.⁸⁷ LDL-cholesterol lowering is slightly less than with the antibodies, around 50%.⁸⁸ The efficacy is higher in diabetic patients than in those with normoglycaemia or pre-diabetes and in those with a higher vs. lower BMI.⁸⁹ The drug is well tolerated and has the enormous advantage that it is administered sub-cutaneously only twice a year (with antibodies the interval of injections is 2–4 weeks). The safety record of inclisiran is extremely good.^87,90-92 No results of outcome studies are available at the moment, data from the ‘Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease’ (ORION-4) (cardiovascular outcome trial) is expected in 2026.⁸⁸

Bempedoic acid

The cholesterol lowering via bempedoic acid [ECT1002], an ACL-inhibiting regimen trial (CLEAR OUTCOME) was conducted in 13 970 statin-intolerant patients and compared with placebo.⁹³ This is an important difference to the PCSK9 inhibitor trials that used the antibodies on top of statins. The reason is that one inclusion criterion in CLEAR OUTCOME was statin intolerance.

The main observation was that LDL-cholesterol was reduced by around 16%⁹³ and in combination with ezetimibe by about 36%,⁹⁴ comparable to a moderate intensity statin, e.g. simvastatin 40 mg/d. The outcome was very positive with a 13% reduction of the primary efficacy endpoint (four component MACE—death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, or coronary revascularization).⁹³ A systematic review of cardiovascular events has been published earlier in this journal by Mutschlechner et al.⁹⁵

Additional interesting published results from CLEAR OUTCOME were that patients in primary prevention benefited equally or even slightly better than patients in secondary prevention. Here it should be noted, that the percentage of diabetes patients was 46% in the whole trial and 65% in the primary prevention sub-group.⁹⁶ In other words, this was not a usual primary prevention population for two reasons: a high proportion of diabetic patients and the inclusion criterion of statin intolerance.

A further remarkable positive finding in the CLEAR OUTCOME trial was that glycaemic levels were not deteriorated, nor was the incidence of newly diagnosed diabetes increased.^93,97

A summary of the lipid-lowering and antihyperglycaemic drugs that have just arrived at the market or that are expected to arrive soon has been recently published.^98,99 Among the future topics Lp(a) will become very important, however, at the time of this writing no outcome data are available.¹⁰⁰

Effects of glucose-lowering medication on lipoprotein profile

Improvement of glycaemic control and/or weight loss in T2DM is usually associated with a significant amelioration of the lipoprotein profile characterized by reductions in total cholesterol, TGs and increases in HDL-cholesterol. Despite these general effects, some antidiabetic drugs additionally exert direct effects on lipoprotein metabolism. The following paragraph focuses on specific effects of antidiabetic medications on lipid metabolism.

Metformin

Little is known about specific effects of metformin therapy on lipoprotein metabolism. In a meta-analysis investigating studies in non-diabetic patients, metformin therapy was associated with a slight but significant decrease in LDL-C and total cholesterol levels (LDL-C: −4.69 mg/dL (0.12 mmol/L) [95% CI, −7,39−2)], total cholesterol: −6.57 mg/dL (0.17 mmol/L) [95% CI, −9,66−3,47]) while HDL-C and TG levels remained unchanged. Also, TG levels were significantly reduced in metformin-treated patients with polycystic ovarian syndrome suggesting indirect effects by improving insulin sensitivity.¹⁰¹

Sodium–glucose transport protein 2 inhibitors

While Sodium–glucose transport protein 2 (SGLT-2) inhibitor treatment is consistently associated with increases in HDL-C levels by about 2 mg/dL (0.05 mmol/L),¹⁰² their effect on LDL-C levels is inconsistent showing decreasing, neutral, or increasing effects.^102-107 Mechanistically, increased LDL-C levels might result from reduced clearance resulting from greater lipolysis of TG-rich lipoproteins.¹⁰⁸ In HepG2 cells, dapaglifozin exposure resulted in a down-regulation of PCSK9 and up-regulation of the LDL-receptor was reported.¹⁰⁹ In contrast to human studies, dapagliflozin treatment was associated with reduced LDL-C levels in high-fat diet fed mice while no effect was observed in the chow-fed control mice. Additionally, dapagliflozin therapy was associated with a decrease of harmful sdLDL particles and an increase in less atherogenic large buoyant LDL particles.¹⁰⁷

Taken together these studies suggest that anti-atherogenic effects of SGLT-2 inhibitors might partly be driven by improving lipoprotein profile in patients with diabetic dyslipidaemia. However, further studies are required to validate the effects of SGLT-2 inhibitors on blood lipid profiles and to demonstrate the underlying mechanisms of action. From a Scandinavian cohort study positive cardiovascular and renal effectiveness was reported for empagliflozin and dapagliflozin.¹¹⁰

Thiazolidindione

Improved insulin sensitivity upon pioglitazon treatment is associated with a marked decrease in fasting and post-prandial TG levels and an increase in HDL-C levels.^111-114 In a study comparing pioglitazon and metformin treatment in patients with T2DM, TG levels decreased by 19% in the pioglitazon group and by 10% in the metformin group. Accordingly, HDL-C levels increased by 14% in the piogltiazon and 7% in the metformin group.¹¹³

While pioglitazon treatment is associated with a slight increase in LDL-C concentration, LDL-particle number and size are reduced. In contrast, rosiglitazon is associated with moderate increases in LDL-C concentrations, TG concentrations and LDL particle concentrations.¹¹⁵ Mechanistically, increases in total VLDL particle concentration is more pronounced by rosiglitazone than by pioglitazon. On the other hand, pioglitazon has stronger decreasing effects on VLDL particle size than rosigltiazon. Both, pioglitazon and rosiglitazon lead to an increase in LDL particle size with stronger effects with pioglitazon than with rosiglitazon. Finally, pioglitazon but not rosiglitazon therapy is associated with increased HDL-C levels.¹¹⁶

Incretin mimetics

Incretin mimetics have been widely investigated in patients with obesity, T2DM, but metabolic dysfunction-associated fatty liver disease and heart failure, respectively.^117-129

Dependent on the inclusion criteria and the study design, effects on body weight, insulin sensitivity and glycaemic control vary widely and observed alterations in lipid profile might often reflect metabolic improvements rather than direct effects.

In a network meta-analysis by Yao et al.¹³⁰ semaglutide was reported to be the only glucagon-like peptide-1 (GLP-1) receptor agonist, which reduced LDL-C by 6.19 mg/dL (0.16 mmol/L) 95% CI (−0.3–0.02) while exenatide and tirzepatide displayed TG lowering effects when compared with placebo (exenatide: −140.72 mg/dL (−1.59 mmol/L) [95%CI, −2.86 −0.32]; tirzepatide: −78.77 mg/dL (−0.89 mmol/L) [95%CI, −1.64 −0.13]). Polyethylene glycol-loxenatide was associated with a slight increase in HDL-C. Decreased chylomicron secretion via reductions in apoB48 secretion and intestinal microsomal TG transfer protein (MTP) activity might explain beneficial effects on TG metabolism.^131-133 Additionally, in vitro and animal models suggest that GLP-1 receptor agonists lower VLDL secretion by modulating hepatic lipid metabolism.^134,135

Dipeptidyl peptidase-IV (DPP-IV) inhibitors

Several clinical studies and meta-analysis reported reduced total cholesterol and TG levels in DPP IV inhibitor treated patients as reviewed elsewhere in detail.^136,137 However, in a recent meta-analysis, DPP-IV inhibitor treatment was associated only with a slight but significant increase of HDL-C while no effect was found on TG or LDL-C levels.¹³⁸  In vitro and in vivo studies revealed various beneficial effects of DPP-IV inhibitors on hepatic lipid metabolism and intestinal cholesterol reabsorption.^139-142

Sulfonylureas

Data on effects of sulfonylurea on lipid profile are limited, reaching from lacking or inconclusive effects^143-146 to small reductions in TG, total cholesterol^147,148 or LDL-C levels.¹⁴⁹ It should be noted however, that clinical trials with sulfonylureas were performed ‘in the old times’ when RCTs had not the standards we would expect today, this partly also applies to metformin studies.

Insulin

Insulin initiation in hyperglycaemic patients with T2DM is usually associated with dose-dependent reductions in free fatty acids, total cholesterol and triglyzeride levels. In parallel HDL-C levels increase and reverse cholesterol transport improves explaining an increase in LDL particle size.^150,151 In a mechanistic study, reductions in HbA1c levels were directly correlated with increases in HDL-C. TG reductions were not associated with falling HbA1c levels suggesting that neither insulin treatment nor improvement or normalization of glycaemia were capable to normalize reverse cholesterol transport and fatty acid metabolism in patients with T2DM.¹⁵²

Insulin effects independent of glycaemia were reported from euglycaemic clamp studies in non-diabetic subjects. In this study, insulin infusion was associated with a marked decrease in TG levels, reductions in total cholesterol and LDL-C and a slight increase in HDL-C levels.¹⁵³ Acute insulin infusion reduces VLDL-1, apolipoprotein B100 and also intestinal apolipoprotein B48 secretion suggesting suppressive effects on TG secretion by insulin in the liver and the intestine.^154,155 The effects of insulin on lipoprotein lipase are tissue-specific with stimulating effects in the adipose tissue and suppressing effects in skeletal muscle.^156-162

Additionally, acute insulin therapy reduces cholesterol synthesis and cholesterol absorption by reducing 12 α hydroxylated bile acids thus in an animal model further suggesting direct effects on cholesterol metabolism.¹⁶³

Overall conclusion

Many experts now consider type 1 diabetes as a sugar disease and type 2 diabetes as a fat disease.

Data availability

No new data were generated or analysed in support of this research.