Inkreto-basierte metabolische Therapien in der kardiovaskulären Medizin

Eine umfassende Übersicht über klinische Ergebnisse, pathophysiologische Mechanismen und zukünftige Grenzbereiche

Schlagwörter — Atherosklerose, Kardiometabolische Medizin, kardiorenale Protektion, kardiovaskuläre Endpunktstudien, Dipeptidyl-Peptidase-4-Inhibitoren, dualiger GIP/GLP-1-Rezeptoragonist, Glukagon-ähnlicher-Peptid-1-Rezeptoragonist, Herzinsuffizienz mit eingelegtem Auswurfleistung, Plaquestabilisierung, Semaglutid, Tirzepatid, Typ 2 Diabetes.

Abkürzungen

ApoB  Apolipoprotein B ARR  absolutes Risiko Reduzierung ASCVD  atherosklerotisch Herz-Kreislauf-Erkrankung BMI  Körpermasseindex KCTA  koronar Computertomographie Angiographie CI  Vertrauensbereich CKD  chronische Nierenerkrankung Lebenslauf  kardiovaskulär CVD  Herz-Kreislauf-Erkrankung CVOT  kardiovaskuläre Endpunktstudie DPP-4  Dipeptidyl-Peptidase-4 eGFR  geschätzt glomeruläre Filtration bewerten eNOS  endothelial Stickstoffmonoxid Synthase GIP  glukoseabhängiges insulinotropes Polypeptid GIP/GLP-1RA  duales GIP/GLP-1-Rezeptoragonist (z. B. Tirzepatid) GLP-1  Glukagon-ähnliches Peptid-1 GLP-1-Rezeptoragonist  GLP-1-Rezeptoragonist HbA1c  glykiertes Hämoglobin HDL-C  hochauflösend Lipoprotein Cholesterin HF  Herzinsuffizienz HFpEF  Herzinsuffizienz mit erhaltener Ejektionsfraktion HR  Hazard-Ratio hs-CRP  hochempfindlich C-reaktives Protein

ICAM-1  Interzelluläres Adhäsionsmolekül 1 IL-6  Interleukin-6 IVUS  Intravaskulärer Ultraschall KCCQ-CSS  Kansas City Kardiomyopathie Klinischer Summenwert des Fragebogens LDL-C  Low-Density-Lipoprotein-Cholesterin LVEF  linksventrikuläre Ejektionsfraktion MACE  schwerwiegende unerwünschte kardiovaskuläre Ereignisse MI  Myokardinfarkt NF-κB  nuklearer Faktor Kappa-B NYHA  New York Heart Association PAD  periphere arterielle Verschlusskrankheit PCSK9  Proprotein-Konvertase Subtilisin/Kexin-Typ 9 PKA  Protein Proteinkinase A RRR  relatives Risiko Reduzierung SBP  systolischer Blutdruck SC  subkutan SGLT2i  Natrium-Glukose-Cotransporter-2-Inhibitor T2D  Typ-2-Diabetes TNF-α  Tumor-Nekrose-Faktor-alpha UACR  Albumin-Kreatinin-Quotient im Urin VCAM-1  vaskuläres Zelladhäsionsmolekül 1 VSMC  vaskulär glatte Muskelfasern 6MWD  Gehstrecke in 6 Minuten

Zusammenfassung

Glucagon-like Peptide-1-Rezeptor-Agonisten (GLP-1RA) und duale GIP/GLP-1-Rezeptor-Agonisten (GIP/GLP-1RA) wurden in einem umfangreichen Rahmen untersucht kardiovaskuläre Endpunktstudie Placebo-kontrollierte Überlegenheitsstudien bei Typ-2-Diabetes (T2D) — LEADER, SUSTAIN-6, REWIND und SOUL — und bei Adipositas Die Gruppe ohne Diabetes (SELECT) wies eine statistisch signifikante Verringerung der schweren kardiovaskulären Ereignisse (MACE) um etwa 12%–26% auf [3], [4], [10]–[12PIONEER 6 wies kardiovaskuläre Sicherheit mit einem günstigen, nicht signifikanten Punktschätzer nach13]. In einem Active-Comparator-Setting war Tirzepatide bezüglich des 3-Punkte-MACE Dulaglutide nicht unterlegen in SURPASS-CVOT (HR 0,92; P = 0,09 für Überlegenheit) und reduzierte Gesamtmortalität von 16% [6]. Bei Herzinsuffizienz mit erhaltener Ejektionsfraktion (HFpEF) und Adipositas zeigte die SUMMIT-Studie eine Verringerung des kombinierten Endpunkts aus kardiovaskulärem Tod und Verschlechterung der Herzinsuffizienz um 38%, was das STEP-HFpEF-Programm ergänzt [5], [20], [21]. Die FLOW-Studie zeigte einen kardiovaskulären und renalen Nutzen bei chronischer Nierenerkrankung (CKD) mit T2D22].

Die vorherrschende klinische Frage ist, ob diese Vorteile nachgelagerte Folgen von Gewichtsverlust, einer Verbesserung des Blutzuckerspiegels und einer Senkung des Blutdrucks, oder ob sie direkte pleiotrope Wirkungen auf die Gefäßwand widerspiegeln und Myokard. Die kumulierten Daten sprechen für eine multifaktorielle Erklärung: Die kardio-metabolische Belastung ist verringert, während die rasche Trennung der MACE-Ereigniskurven in placebokontrollierten Studien – innerhalb von Monaten und vor einem nennenswerten Gewichtsverlust – zusammen mit bildgebenden Belegen für Plaque Stabilisierung und verringerte Koronardurchblutung Entzündung, plausibel zu einem Beitrag direkter vaskulär entzündungshemmender und endothelialer Mechanismen beitragen [9], [24], [25]. Diese Übersichtsarbeit fasst die zellulären und physiologischen Mechanismen zusammen, vergleicht inkretinbasierte Therapien mit lipidsenkenden Pharmakotherapien, fasst die wichtigsten randomisierten Studien zusammen und bewertet die Unterscheidung zwischen Plaquerückbildung und der Plaque-Stabilisierung, und skizziert offene Fragen sowie Überlegungen zur klinischen Umsetzung.

1. Zelluläre und physiologische Mechanismen

GLP-1-Rezeptoren werden in pankreatischen β-Zellen, den Appetitzentren des zentralen Nervensystems und – in wesentlich geringerer Dichte – in den Herzvorhöfen, Gefäßen Endothel, glatte Muskulatur, Immunzellen und das Nephron der Niere [13], [14]. Eine direkte Rezeptorexpression in menschlichen Koronarendothel- und glatten Muskelzellen ließ sich mit validierten Antikörpern nur schwer bestätigen, was die Möglichkeit aufwirft, dass einige “vaskuläre” Effekte indirekt über zirkulierende Immunzellen, hepatische Signale oder Wege des zentralen Nervensystems vermittelt werden [14]. Der duale GIP/GLP-1-Rezeptor-Agonismus nutzt komplementäre metabolische Wirkungen: Die Glukose-abhängige insulinotrope Polypeptid (GIP)-Signalübertragung verbessert den Lipidstoffwechsel und Insulinsensitivität im Fettgewebe treibt die GLP-1-Signalübertragung währenddessen Sättigung, glukoseabhängig Insulin Sekretion und der Großteil der Inkretin-vermittelten kardiovaskulären Wirkungen [2], [6]. Tabelle I ordnet Zielgewebe molekularen Kaskaden, klinischen Biomarker, und die entsprechenden kardiovaskulären Endpunkte, die sich in klinischen Studien zeigen.

Tabelle I. Zelluläre und physiologische Mechanismen der Inkretin-vermittelten Kardioprotektion.

Zielgewebe / Zielsystem	Rezeptor	Molekulare Kaskade	Biomarker / Surrogatparameter	Kardiovaskuläres Ergebnis
Vaskuläres Endothel	GLP-1R	Wiederherstellung der eNOS-Kopplung; reduzierte Superoxidbildung; erhöhte Bioverfügbarkeit von Stickstoffmonoxid.	Verbesserte flussvermittelte Dilatation; reduzierte lösliche ICAM-1 und VCAM-1.	Koronare mikrovaskuläre Vasodilatation; erhalten Endothelfunktion; reduzierte Monozytenadhäsion.
Vaskuläre und zirkulierende Immunzellen	GLP-1R	cAMP / PKA-Aktivierung; unterdrückte NF-κB-Translokation; reduziert Makrophage Aktivierung.	Senkung von hochsensitivem CRP, IL-6 und TNF-α.	Unterdrückte Monozytenrekrutierung an die Gefäßwand; verminderte Schaumzellbildung und Plaqueentzündung.
Arterielles glattes Muskelgewebe und Plaque-Matrix	GLP-1R	Verringerte VSMC-Proliferation; Modulation von Matrix-Metalloproteinase Ausdruck; erhöhte Kollagenablagerung.	Erhöhtes Volumen fibröser Plaques bei Koronare CT-Angiographie; dicker faserige Kappe zur intravaskulären Bildgebung.	Stabilisierung von vulnerable Plaque Architektur; geringerer Riss- und Erosionsschutz / Architektur; reduzierte Ruptur und Erosion.
Myokard und koronare Mikrozirkulation	GLP-1R	Erhöhtes Myokard Glucose Aufnahme unter Stress; reduzierte Kardiomyozyten-Apoptose durch Inhibierung des Caspase-3-Wegs.	Reduziert NT-proBNP und Troponin; erhaltene LVEF in ausgewählten Populationen.	Linderung von Ischämie-Reperfusions-Schäden; verbesserte diastolische Funktion; reduzierte Progression der Herzinsuffizienz.
Fettgewebe und Leber	GLP-1R und GIPR	Zentrale Appetitsuppression; reduzierte hepatische Lipogenese und ektopes Fett Ablagerung; verbesserte Insulinsensitivität.	5%–15% Gewichtsreduktion; geringer Taillenumfang; verbessert HOMA-IR.	Reduzierte kardiale Vorlast/Nachlast; Umkehrung der adipositasbedingten systemischen Entzündung.
Nierennephron und Hämodynamik	GLP-1R und GIPR	Hemmung des Natrium-Wasserstoff-Exchangers im proximalen Tubulus (NHE3); Natriurese; reduzierte glomeruläre Hyperfiltration.	2–5 mmHg Senkung des systolischen Blutdrucks Blutdruck; Erhalt der eGFR-Steigung.	Reduzierte myokardiale Wandspannung; Linderung des kardiorenalen Syndroms.

2. Vergleich von Wirkstoffklassen: Inkreto-basierte Therapien im Vergleich zu Lipidsenkern

Traditionelle lipidsenkende Therapien — Statine, Ezetimib, Proprotein-Konvertase-Subtilisin/Kexin-Typ-9-Inhibitoren (PCSK9-Inhibitoren), Inclisiran, und Bempedoinsäure — primär die Konzentration zirkulierender Apolipoprotein-B-(ApoB)-haltiger Lipoproteine senken, was sowohl die Neubildung verzögert Atherogenese und bei ausreichender Ausprägung eine angiographische Plaqueregression bewirkt15]–[17Incretin-basierte Therapien wirken über eine andere Achse: Sie haben mäßige Auswirkungen auf das Lipidprofil, aber erhebliche Auswirkungen auf systemische Entzündungen, die Gefäßbiologie, die Körperzusammensetzung, den Blutdruck und die renale Hämodynamik2], [18]. Tabelle II fasst das vergleichende Profil hinsichtlich Low-Density-Lipoprotein-Cholesterin (LDL-C), High-Density-Lipoprotein-Cholesterin (HDL-C) und MACE-Endpunkten zusammen. Die klinische Implikation ist keine Substitution, sondern eine Kombination: aggressive ApoB-Senkung zur Adressierung des Lipidtreibers der Atherogenese, gepaart mit Inkretin-Therapie zur Bekämpfung des residuellen kardiometabolischen und entzündlichen Risikos.

Tabelle II: Pharmakologische und klinische Profile: Inkretin-basierte im Vergleich zu lipidsenkenden Therapien.

Arzneimittelklasse (Beispiel)	Primäres molekulares Ziel	Lipideffekte (typisch)	Auswirkungen auf MACE und HF	Vorteile für den Sekundärstoffwechsel
GLP-1-Rezeptoragonisten (Semaglutid, Liraglutid, Dulaglutid)	GLP-1-Rezeptor	LDL-C ↓ ~2%–5%; Triglyceride ↓ ~12%–18%; HDL-C ↑ ~3%–5%; modest ApoB reduction.	MACE relative risk reduction approximately 12%–26% across positive placebo-controlled CVOTs (LEADER 13%, REWIND 12%, SOUL 14%, SELECT 20%, SUSTAIN-6 26%). PIONEER 6 was a noninferiority safety trial with a nonsignificant favorable point estimate. Favorable HF symptom and functional outcomes in HFpEF.	Weight loss 6%–15%; SBP ↓ 2–5 mmHg; significant hs-CRP reduction; eGFR preservation.
GIP/GLP-1 receptor agonist (tirzepatide)	GIP and GLP-1 receptors	LDL-C ↓ ~5%–8%; triglycerides ↓ ~20%–25%; HDL-C ↑ ~5%–8%; greater ApoB reduction than GLP-1RA monotherapy.	Noninferior to dulaglutide for 3-point MACE (HR 0.92, 95.3% CI 0.83–1.01; P = 0.09 for superiority) in SURPASS-CVOT, with 16% reduction in all-cause mortality. 38% reduction in HF-event composite and 46% reduction in worsening HF events in SUMMIT (HFpEF + obesity).	Weight loss 11%–22%; HbA1c reduction 1.5%–2.0%; SBP ↓ 3–5 mmHg; favorable eGFR slope.
Statins (HMG-CoA-Reduktase inhibitors)	Hepatic HMG-CoA reductase	LDL-C ↓ 30%–55%; triglycerides ↓ 10%–25%; HDL-C ↑ 5%–10%; ApoB ↓ 30%–50%.	Approximately 22% MACE relative risk reduction per 1.0 mmol/L (38.7 mg/dL) LDL-C reduction (CTT Meta-Analyse); neutral on HF.	Direct plaque stabilization; modest hs-CRP reduction; pleiotropic endothelial effects.
Ezetimib	NPC1L1 cholesterol transporter	LDL-C ↓ 15%–22%; triglycerides ↓ ~5%; HDL-C ↑ ~1%–3%; ApoB ↓ ~10%–15%.	~6% MACE relative risk reduction added to statin therapy (IMPROVE-IT); neutral on HF.	Localized intestinal effects; favorable safety profile.
PCSK9-Hemmer (Alirocumab, Evolocumab) and inclisiran	Circulating PCSK9 (mAb) or hepatic PCSK9 mRNA (siRNA)	LDL-C ↓ 50%–60%; ApoB ↓ 40%–50%; Lp(a) ↓ 20%–30%; modest triglyceride reduction.	~15% MACE relative risk reduction added to statin therapy (FOURIER, ODYSSEY OUTCOMES); neutral on HF.	Drives coronary plaque regression on serial IVUS (GLAGOV); rare adverse events.
Bempedoic acid	Hepatic ATP-citrate lyase	LDL-C ↓ 17%–28%; minor effect on triglycerides and HDL-C; ApoB ↓ ~15%.	13% MACE relative risk reduction in statin-intolerant patients (CLEAR Outcomes); neutral on HF.	~20% hs-CRP reduction; neutral on glycemia.

3. Evidence From Major Randomized Trials

The cardiovascular efficacy of incretin-based therapies has been established across a sequence of large prospective CVOTs. The trial program has evolved from glycemic-safety and outcomes studies in T2D (the LEADER, SUSTAIN-6, REWIND, EXSCEL, and PIONEER 6 era [10]–[13], [19]), to outcomes trials in expanded populations including obesity without diabetes (SELECT [3]), HFpEF with obesity (SUMMIT [5], with a companion semaglutide program in STEP-HFpEF [20], [21]), CKD (FLOW [22]), and an active-comparator setting (SURPASS-CVOT [6]). For navigability, the trials are summarized in two tables grouped by enrollment population: Table III covers T2D CVOTs; Table IV covers trials in obesity, HFpEF, and CKD. The next sections discuss what these trials reveal about mechanism: the time course of benefit, the imaging signature of plaque stabilization, and the limits of inference from each trial design.

Table III. Cardiovascular outcomes trials in type 2 diabetes.

Abbreviations used in this table: ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; CVD = cardiovascular disease; HR = hazard ratio; SC = subcutaneous; SGLT2i = sodium-glucose cotransporter-2 inhibitor.

Trial (publication)	Intervention vs. comparator	Population and N	Follow-up	Primary cardiovascular outcome (HR, 95% CI)	Key secondary effects and notable limitations
LEADER (Marso et al., NEJM 2016) [10]	Liraglutide 1.8 mg SC daily vs. Placebo, on standard care.	T2D with high CV risk (≥80% with established CVD). N = 9,340.	Median 3.8 years.	3-point MACE: HR 0.87 (0.78–0.97), P = 0.01 for superiority. CV death: HR 0.78 (0.66–0.93).	All-cause mortality HR 0.85; nonfatal MI and Schlaganfall numerically lower (not individually significant). GI adverse events most common discontinuation reason.
SUSTAIN-6 (Marso et al., NEJM 2016) [11]	Semaglutide 0.5 mg or 1.0 mg SC weekly vs. placebo.	T2D with high CV risk. N = 3,297.	104 weeks.	3-point MACE: HR 0.74 (0.58–0.95), P < 0.001 for noninferiority, P = 0.02 for superiority. Nonfatal stroke: HR 0.61 (0.38–0.99).	Statistically significant increase in retinopathy complications (HR 1.76, 1.11–2.78); small sample size limits stroke-subtype precision.
REWIND (Gerstein et al., Lancet 2019) [12]	Dulaglutide 1.5 mg SC weekly vs. placebo.	T2D, ~68% without established CVD (broad primary-prevention cohort). N = 9,901.	Median 5.4 years.	3-point MACE: HR 0.88 (0.79–0.99), P = 0.026 for superiority.	Benefit consistent in primary- and secondary-prevention subgroups; first GLP-1RA CVOT to show benefit in a predominantly primary-prevention population.
PIONEER 6 (Husain et al., NEJM 2019) [13]	Oral semaglutide 14 mg daily vs. placebo.	T2D ≥50 years with established CVD or CKD. N = 3,183.	Median 15.9 months.	3-point MACE: HR 0.79 (0.57–1.11); P < 0.001 for noninferiority (not powered for superiority).	CV safety trial; favorable but nonsignificant point estimate. Cardiovascular and all-cause mortality numerically lower.
SOUL (McGuire et al., NEJM 2025) [4]	Oral semaglutide titrated to 14 mg daily vs. placebo, on standard care (~27% on baseline SGLT2i).	T2D ≥50 years with established ASCVD, CKD, or both. N = 9,650.	Median 49.5 months.	3-point MACE: HR 0.86 (0.77–0.96), P = 0.006 for superiority.	Driven primarily by 26% reduction in nonfatal MI; benefit preserved regardless of baseline or in-trial SGLT2i use. GI events most common adverse-event class.
SURPASS-CVOT (Nicholls et al., NEJM 2025) [6]	Tirzepatide (max tolerated up to 15 mg) SC weekly vs. dulaglutide 1.5 mg SC weekly (active comparator).	T2D with established ASCVD. N = 13,165 (6,586 vs. 6,579).	Median 4.0 years.	3-point MACE: HR 0.92 (95.3% CI 0.83–1.01); P = 0.003 for noninferiority, P = 0.09 for superiority. Expanded 4-point MACE: HR 0.88 (0.80–0.96). All-cause mortality HR 0.84 (0.75–0.94).	Active-comparator design narrows margin for showing superiority. Tirzepatide produced ~7%–8% greater weight loss and ~0.8% greater HbA1c reduction; favorable eGFR-slope trend.

Table IV. Trials in obesity, heart failure with preserved ejection fraction, and chronic kidney disease.

Abbreviations used in this table: ARR = absolute risk reduction; BMI = body-mass index; CV = cardiovascular; HR = hazard ratio; KCCQ-CSS = Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association functional class; PAD = peripheral Arterie disease; SC = subcutaneous; UACR = urine albumin-to-creatinine ratio.

Trial (publication)	Intervention vs. comparator	Population and N	Follow-up	Primary outcome (HR or treatment difference)	Key secondary effects and notable limitations
SELECT (Lincoff et al., NEJM 2023) [3]	Semaglutide 2.4 mg SC weekly vs. placebo, all on standard CV care.	BMI ≥27 kg/m², established CVD (prior MI, stroke, or symptomatic PAD), no diabetes. N = 17,604.	Mean 39.8 months.	3-point MACE: HR 0.80 (0.72–0.90), P < 0.001 for superiority. ARR 1.5%.	Prespecified time-to-benefit analysis: nominally significant MACE reduction at 3 months (HR 0.63, 95% CI 0.41–0.95) and 6 months (HR 0.60), before substantial weight loss [25]. Cardioprotection consistent across baseline HbA1c, weight, and waist-circumference categories. GI events drove ~17% discontinuation.
SUMMIT (Packer et al., NEJM 2025) [5]	Tirzepatide titrated to maximum tolerated dose (5, 10, or 15 mg) SC weekly vs. placebo.	HFpEF (LVEF ≥50%), NYHA II–IV, BMI ≥30 kg/m², with or without diabetes. N = 731.	Median 104 weeks.	CV death or worsening HF (composite): HR 0.62 (0.41–0.95), P = 0.026. Worsening HF events: HR 0.54 (0.34–0.85).	KCCQ-CSS between-group difference +6.9 (3.3–10.6); 6-minute walk distance +18 m; weight loss treatment difference −11.6%; hs-CRP −34.9%. Modest sample size; CV death events too few to interpret individually.
STEP-HFpEF (Kosiborod et al., NEJM 2023) [20]	Semaglutide 2.4 mg SC weekly vs. placebo.	HFpEF (LVEF ≥45%), BMI ≥30 kg/m², no diabetes. N = 529.	52 weeks.	Dual primary endpoints: KCCQ-CSS change +16.6 vs. +8.7 (between-group +7.8, 95% CI 4.8–10.9, P < 0.001); body weight −13.3% vs. −2.6% (between-group −10.7%, P < 0.001).	Six-minute walk distance and CRP also improved with semaglutide. Symptom and exercise-capacity trial; not powered for hard CV endpoints.
STEP-HFpEF DM (Kosiborod et al., Lancet 2024) [21]	Semaglutide 2.4 mg SC weekly vs. placebo.	HFpEF (LVEF ≥45%), BMI ≥30 kg/m², with T2D. N = 616.	52 weeks.	Dual primary endpoints: KCCQ-CSS change +13.7 vs. +6.4 (between-group +7.3, P < 0.001); body weight −9.8% vs. −3.4% (between-group −6.4%, P < 0.001).	Six-minute walk distance and CRP improved with semaglutide; absolute weight loss smaller than non-diabetic STEP-HFpEF. Not powered for hard CV endpoints.
FLOW (Perkovic et al., NEJM 2024) [22]	Semaglutide 1.0 mg SC weekly vs. placebo (trial terminated early for efficacy).	T2D with CKD (eGFR 50–75 with elevated UACR, or eGFR 25–50). N = 3,533.	Median 3.4 years.	Composite major kidney disease events (kidney failure, sustained ≥50% eGFR reduction, kidney or CV death): HR 0.76 (0.66–0.88), P = 0.0003.	MACE: HR 0.82 (0.68–0.98). CV death: HR 0.71 (0.56–0.89). Demonstrated cardiorenal benefit in CKD with T2D.

4. Plaque Stabilization vs. Atherosclerotic Regression

A central mechanistic question is whether the MACE reduction observed with GLP-1RA therapy is mediated by physical regression of total Atherom volume or by qualitative remodeling that stabilizes the existing Plaquebelastung. Intensive lipid-lowering with hochdosierte Statine and PCSK9 inhibitors has been shown on serial intravascular ultrasound (IVUS) and coronary computed tomography angiography (CCTA) to reduce both total atheroma volume and lipid-rich plaque components [15], [17], [23]. The imaging signature of Inkretin therapy is different.

In the observational, prospective CCTA study of Hjuler Boesgaard and colleagues, 204 asymptomatic patients with T2D (55 receiving liraglutide as part of clinical care, 149 not) underwent baseline and 1-year CCTA [9]. The change in total atheroma volume did not differ between groups (38 ± 180 mm³ in the liraglutide group vs. −1 ± 160 mm³ in the comparator group, P = 0.13). However, the liraglutide group showed a significantly greater increase in fibrous-plaque volume. In the context of plaque biology, fibrous-plaque expansion is a favorable structural change: dense, collagen-rich fibrous tissue forms a thicker cap that insulates the thrombogenic lipid core from circulating coagulation factors. The shift toward fibrous composition resembles the qualitative plaque change observed with statin therapy and is the structural substrate of plaque stabilization [9], [15]. The observational design of this study limits causal inference; a randomized CCTA trial addressing this question remains an evidence gap.

Complementary in-vivo evidence for a direct anti-inflammatory vascular action comes from the LIRAFLAME positron emission tomography / computed tomography (PET/CT) substudy [24]. Thirty randomly selected participants from the parent LIRAFLAME trial underwent paired [⁶⁴Cu]Cu-DOTATATE PET/CT imaging of the Herzkranzgefäße at baseline and after 26 weeks. The tracer binds somatostatin receptor 2, which is highly expressed on activated macrophages. Coronary tracer uptake decreased significantly in the liraglutide arm (assessed as both maximum and mean-of-maximum standardized uptake values) at the participant level and the individual coronary-segment level; no such reduction was seen with placebo. The change in coronary tracer uptake correlated with the change in systemic high-sensitivity C-reactive protein (hs-CRP), linking a systemic anti-inflammatory effect to a regional reduction in macrophage activity within the coronary vessel wall [24]. Preclinical work in apolipoprotein-E–deficient and LDL-receptor–deficient mouse models, and in Watanabe heritable hyperlipidemic rabbits, has shown analogous effects: reduced macrophage accumulation, inhibited foam-cell formation, and thicker fibrous caps [14], [18]. Taken together, the human imaging and animal data are most consistent with plaque stabilization rather than gross atheroma regression, though the causal mechanism remains an inference rather than a directly proven pathway.

5. Mechanistic Basis for the Rapid Onset of Cardioprotective Benefit

The MACE event curves in SELECT diverged early. The trial’s primary result was a 20% reduction in 3-point MACE over a mean follow-up of 39.8 months (HR 0.80, 95% CI 0.72–0.90) [3]. In a prespecified time-to-benefit secondary analysis presented at the European Congress on Obesity in 2025 and subsequently published, semaglutide produced a nominally significant reduction in MACE within the first 3 months (HR 0.63, 95% CI 0.41–0.95) and the first 6 months (HR 0.60, 95% CI 0.44–0.81), with curve separation visible within approximately 3 weeks of Randomisierung [25], [26]. At 3 months, the mean placebo-adjusted body-weight difference was only approximately 3.6%, and patients were still in the protocol dose-escalation phase. The onset of clinical benefit in this secondary analysis therefore precedes substantial weight loss and predates the achievement of target maintenance dosing, although the time-to-benefit estimates carry wider confidence intervals than the primary endpoint.

Several non-weight-dependent mechanisms could plausibly explain this early cardioprotection:

Endothelial preservation. GLP-1RAs reduce reactive-oxygen-species generation and prevent endothelial nitric oxide synthase (eNOS) uncoupling, increasing local nitric-oxide bioavailability. The net effect is improved coronary microvascular vasodilation and local antithrombotic / antiplatelet tone.

Rapid suppression of plaque-local inflammation. Macrophages in vulnerable plaques produce inflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin-6 [IL-6]) and matrix metalloproteinases that degrade the fibrous cap. GLP-1R activation downregulates the nuclear factor kappa-B (NF-κB) cascade within days to weeks, preserving cap integrity and reducing the substrate for erosion and rupture.

Myocardial substrate optimization. Under ischemic and high-stress conditions, GLP-1R activation increases myocardial glucose uptake and glycolytic flux while inhibiting caspase-3–mediated cardiomyocyte apoptosis. This improves the oxygen-efficiency of energy production and reduces infarct expansion and arrhythmic substrate.

These pathways are consistent with the observation that the early MACE reduction in SELECT was driven principally by reductions in nonfatal myocardial infarction (MI) and heart-failure–related events rather than by changes that require months of weight loss to materialize [25], [27]. Direct causal demonstration in human coronary tissue remains an evidence gap.

6. The DPP-4 Inhibitor Discrepancy

A clarifying contrast comes from dipeptidyl peptidase-4 (DPP-4) inhibitors, which act by preventing degradation of endogenous active GLP-1. These agents produce modest improvements in glycated hemoglobin (HbA1c) of approximately 0.5%–0.8% and a neutral profile on weight and blood pressure [28]. Across the major CVOTs — SAVOR-TIMI 53 (saxagliptin), EXAMINE (alogliptin), TECOS (sitagliptin), CARMELINA (linagliptin), and CAROLINA (linagliptin vs. glimepiride) — DPP-4-Hemmer have demonstrated cardiovascular safety but no MACE reduction; SAVOR-TIMI 53 additionally showed an increase in heart-failure hospitalization with saxagliptin [28]–[31].

This therapeutic divergence is reconciled by drug-exposure pharmacology. Endogenous GLP-1 is secreted in small amounts from intestinal L-cells in response to nutrient stimuli and has a circulating half-life of less than two minutes due to rapid DPP-4–mediated degradation. DPP-4 inhibition extends this half-life and increases circulating active GLP-1 by approximately 2- to 3-fold, which is sufficient to engage high-density pancreatic islet receptors and produce glucose-dependent insulin secretion and glucagon suppression. Receptor density in cardiovascular and immune tissues is, however, markedly lower than in the pancreas, and the modest physiological increment in GLP-1 produced by DPP-4 inhibition does not appear sufficient to drive the downstream signaling needed for anti-inflammatory, endothelial, or plaque-modifying effects [13], [14], [28].

Engineered GLP-1RAs achieve supra-physiological active-drug exposure for extended periods. Semaglutide has a plasma half-life of approximately 155–184 hours (≈ one week), driven by albumin binding via a C18 fatty-diacid side chain [32]. Once-weekly dosing therefore produces sustained drug concentrations that are an order of magnitude or more above physiologic baseline. The implication is mechanistically important: cardiovascular benefit appears to require pharmacological-level direct receptor activation, not merely augmentation of physiologic incretin signaling.

7. Practical Clinical Implications

7.1 Population-Specific Cardiorenal Efficacy

Type 2 diabetes with established ASCVD or CKD. GLP-1RAs (subcutaneous semaglutide, liraglutide, dulaglutide) and the GIP/GLP-1RA tirzepatide are evidence-based additions to lipid-lowering and Thrombozytenaggregationshemmung. Oral semaglutide titrated to 14 mg daily reduced 3-point MACE by 14% in SOUL (HR 0.86, 95% CI 0.77–0.96), with the principal driver a 26% reduction in nonfatal MI; benefit was preserved in the prespecified subgroup receiving sodium-glucose cotransporter-2 inhibitors (SGLT2i) at baseline, which supports combined GLP-1RA + SGLT2i use as a supported option pursuing complementary pathways [4], [33].

Overweight or obesity without diabetes, with established CVD. In SELECT, semaglutide 2.4 mg subcutaneously weekly reduced MACE by 20% (HR 0.80, 95% CI 0.72–0.90) with a 1.5% absolute risk reduction over a mean follow-up of 39.8 months [3]. The cardioprotective effect was consistent across baseline HbA1c (normoglycemic and prediabetic strata) and across baseline weight and waist categories; a mediation analysis estimated that only approximately one third of the MACE benefit was attributable to waist-circumference reduction, indicating substantial weight-independent benefit [34], [35]. Therapy should therefore not be discontinued in patients with established CVD who do not achieve the weight-loss targets observed in klinische Studien.

HFpEF with obesity. In SUMMIT, tirzepatide reduced the composite of cardiovascular death or worsening heart-failure events by 38% (HR 0.62, 95% CI 0.41–0.95) and worsening HF events alone by 46% (HR 0.54, 95% CI 0.34–0.85), with a +6.9-point between-group improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), an 18-meter improvement in 6-minute walk distance (6MWD), and a placebo-adjusted weight loss of −11.6% [5]. The companion STEP-HFpEF and STEP-HFpEF DM programs demonstrated semaglutide-mediated improvements in KCCQ-CSS, body weight, and 6MWD in similar populations with and without diabetes [20], [21]. Incretin therapy is a supported, evidence-based option in obese HFpEF.

Chronic kidney disease. In SOUL, oral semaglutide reduced MACE in CKD subgroups consistent with the overall trial; in SURPASS-CVOT, tirzepatide slowed estimated glomerular filtration rate (eGFR) decline relative to dulaglutide [4], [6]. The dedicated FLOW trial of subcutaneous semaglutide in T2D-related CKD showed a 24% reduction in the composite of major kidney disease events (HR 0.76, 95% CI 0.66–0.88) and significant reductions in cardiovascular outcomes [22], supporting GLP-1RA therapy as an evidence-based addition for cardiorenal protection in this population.

7.2 Integration With Lipid Management

Statins, ezetimibe, PCSK9 inhibitors, inclisiran, and bempedoic acid remain foundational therapy for atherogenic-lipoprotein reduction. The lipid-modifying effects of GLP-1RAs are modest in comparison: the SELECT lipid analysis reported net placebo-adjusted reductions of approximately 2% in LDL-C and 15% in triglycerides [34]. The implication for practice is that incretin therapy is not a substitute for ApoB-lowering therapy in established ASCVD but is complementary: aggressive ApoB lowering addresses the lipid driver of atherogenesis, while incretin therapy addresses residual inflammatory, vascular, and metabolic risk. The combination is a supported, evidence-based approach for secondary prevention in cardiometabolically high-risk patients.

8. Open Research Questions

8.1 Direct Vascular Receptor Signaling vs. Indirect Systemic Effects

Whether the cardiovascular benefits of GLP-1RAs depend on direct receptor activation in vascular and myocardial tissue — or are mediated by indirect systemic effects on adipose-tissue inflammation, hepatic lipid handling, neurohumoral tone, and intestinal signaling — remains incompletely resolved. Validated immunohistochemistry has had difficulty confirming high-density GLP-1R expression in human coronary endothelium and smooth muscle, raising the possibility that the “vascular” effects are substantially indirect [14]. Resolving this question is more than academic: it determines whether the next generation of incretin-based molecules should be designed for receptor-selective vascular targeting or for refined systemic-metabolic activity.

8.2 The “Saturation” Hypothesis From SURPASS-CVOT

SURPASS-CVOT compared tirzepatide directly with dulaglutide and met its prespecified noninferiority margin but not formal superiority (HR 0.92, 95.3% CI 0.83–1.01; P = 0.09) [6]. Tirzepatide produced substantially greater weight loss (~7–8% additional) and superior glycemic control (~0.8% additional HbA1c reduction), yet the additional cardiovascular benefit over an already-active comparator was modest. One interpretation is a “saturation effect”: once the GLP-1 axis is fully engaged, additional metabolic improvement and GIP receptor activation may yield diminishing returns on hard macrovascular endpoints. Alternative interpretations include (a) trial design (active comparator narrows the margin to detect superiority) and (b) underlying biology that limits incremental benefit on plaque stabilization beyond a threshold. The companion finding of a significant 16% all-cause mortality reduction with tirzepatide and benefit on the expanded 4-point MACE endpoint suggests that additional risk reduction may exist but is more diffusely distributed than the 3-point MACE composite captures [6]. Adequately powered placebo-controlled trials of next-generation triple-incretin agonists will be needed to resolve this question.

8.3 Long-Term Efficacy and Combination Regimens

Prospective randomized data on multi-pathway combination regimens — GLP-1RA + SGLT2i, GLP-1RA + finerenone, GLP-1RA + intensive ApoB-lowering — remain limited. Although the SOUL prespecified analysis showed preserved MACE benefit in the SGLT2i-treated subgroup, that analysis was non-randomized for the SGLT2i exposure [33]. Dedicated factorial trials would clarify whether these complementary pathways produce additive, supra-additive, or attenuated effects on hard outcomes.

8.4 Tolerability and Real-World Adherence

Gastrointestinal adverse events drive treatment discontinuation in clinical trials. In SUMMIT, diarrhea (18.4% vs. 6.3%), nausea (17.0% vs. 6.5%), and adverse events leading to discontinuation (6.3% vs. 1.4%) were more frequent with tirzepatide than with placebo [5]. SOUL reported overall serious adverse events in 47.9% of the oral-semaglutide arm vs. 50.3% in placebo, with GI events the most common [4]. Real-world discontinuation rates are typically higher than clinical-trial rates. Long-term cardiovascular benefit depends on sustained therapy; improving titration protocols and identifying patient-level predictors of intolerance are practical research priorities.

Disclosures

The LEADER, SUSTAIN-6, REWIND, PIONEER 6, SELECT, SOUL, STEP-HFpEF (with and without diabetes), and FLOW trials were sponsored by Novo Nordisk. The SUMMIT and SURPASS-CVOT trials were sponsored by Eli Lilly. These industry sponsorships are routine for cardiovascular outcomes trials in the incretin therapeutic area; results have been published in peer-reviewed journals with adjudicated endpoints. The author declares no financial conflicts related to the manufacturers cited.

Referenzen

1. Luconi M, Cantini G, Ceriello A, Mannucci E. Perspectives on cardiovascular effects of incretin-based drugs: From bedside to bench, return trip. Int J Cardiol. 2017;241:302-310. doi:10.1016/j.ijcard.2017.02.126
2. Ibe T, Borlaug BA. Glucagon-Like Peptide 1 Receptor Agonists and Cardiovascular Disease. Annu Rev Med. 2026;77(1):1-15. doi:10.1146/annurev-med-043024-011141
3. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563
4. McGuire DK, Marx N, Mulvagh SL, et al. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. N Engl J Med. 2025;392(20):2001-2012. doi:10.1056/NEJMoa2501006
5. Packer M, Zile MR, Kramer CM, et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2025;392(5):427-437. doi:10.1056/NEJMoa2410027
6. Nicholls SJ, Pavo I, Bhatt DL, et al. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. N Engl J Med. 2025;393(24):2409-2420. doi:10.1056/NEJMoa2505928
7. Borlaug BA, Zile MR, Kramer CM, et al. Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial. Nat Med. 2025;31(2):544-551. doi:10.1038/s41591-024-03374-z
8. Borlaug BA, Zile MR, Kramer CM, et al. Impact of Body Mass Index, Central Adiposity, and Weight Loss on the Benefits of Tirzepatide in HFpEF: The SUMMIT Trial. J Am Coll Cardiol. 2025;86(4):242-255. doi:10.1016/j.jacc.2025.04.059
9. Heinsen LJ, Pararajasingam G, Andersen TR, et al. Liraglutide treatment is associated with progression of coronary artery fibrous plaque: a prospective 1-year follow-up study in asymptomatic patients with type 2 diabetes. BMC Cardiovasc Disord. 2023;23(1):214. Published 2023 Apr 28. doi:10.1186/s12872-023-03228-5
10. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827
11. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141
12. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130. doi:10.1016/S0140-6736(19)31149-3
13. Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019;381(9):841-851. doi:10.1056/NEJMoa1901118
14. Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014;155(4):1280-1290. doi:10.1210/en.2013-1934
15. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681. doi:10.1016/S0140-6736(10)61350-5
16. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387-2397. doi:10.1056/NEJMoa1410489
17. Nicholls SJ, Puri R, Anderson T, et al. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016;316(22):2373-2384. doi:10.1001/jama.2016.16951
18. Park B, Bakbak E, Teoh H, et al. GLP-1 receptor agonists and atherosclerosis protection: the vascular endothelium takes center stage. Am J Physiol Heart Circ Physiol. 2024;326(5):H1159-H1176. doi:10.1152/ajpheart.00574.2023
19. Holman RR, Bethel MA, Mentz RJ, et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2017;377(13):1228-1239. doi:10.1056/NEJMoa1612917
20. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023;389(12):1069-1084. doi:10.1056/NEJMoa2306963
21. Kosiborod MN, Deanfield J, Pratley R, et al. Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials. Lancet. 2024;404(10456):949-961. doi:10.1016/S0140-6736(24)01643-X
22. Perkovic V, Tuttle KR, Rossing P, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024;391(2):109-121. doi:10.1056/NEJMoa2403347
23. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295(13):1556-1565. doi:10.1001/jama.295.13.jpc60002
24. Jensen JK, Zobel EH, von Scholten BJ, et al. Effect of 26 Weeks of Liraglutide Treatment on Coronary Artery Inflammation in Type 2 Diabetes Quantified by [⁶⁴Cu]Cu-DOTATATE PET/CT: Results from the LIRAFLAME Trial. Front Endocrinol (Lausanne). 2021;12:790405. Published 2021 Nov 30. doi:10.3389/fendo.2021.790405
25. Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2025;393(7):635-647. doi:10.1056/NEJMoa2502081
26. Hussain M, Miras AD. Peptidhormonanaloga basierte medikamentöse Adipositastherapie ist effektiv : Was ist die Evidenz zu harten Endpunkten und zum Langzeitverlauf? [Peptide hormone analogue-based pharmacotherapy for obesity is effective : What is the evidence on hard end points and the long-term course?]. Chirurgie (Heidelb). 2026;97(1):11-20. doi:10.1007/s00104-025-02402-z
27. Deanfield J, Verma S, Scirica BM, et al. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. Lancet. 2024;404(10454):773-786. doi:10.1016/S0140-6736(24)01498-3
28. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326. doi:10.1056/NEJMoa1307684
29. Green JB, Bethel MA, Armstrong PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;373(3):232-242. doi:10.1056/NEJMoa1501352
30. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial. JAMA. 2019;321(1):69-79. doi:10.1001/jama.2018.18269
31. Rosenstock J, Kahn SE, Johansen OE, et al. Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial. JAMA. 2019;322(12):1155-1166. doi:10.1001/jama.2019.13772
32. Lau J, Bloch P, Schäffer L, et al. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem. 2015;58(18):7370-7380. doi:10.1021/acs.jmedchem.5b00726
33. Marx N, Deanfield JE, Mann JFE, et al. Oral Semaglutide and Cardiovascular Outcomes in People With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial. Circulation. 2025;151(23):1639-1650. doi:10.1161/CIRCULATIONAHA.125.074545
34. Lingvay I, Deanfield J, Kahn SE, et al. Semaglutide and Cardiovascular Outcomes by Baseline HbA1c and Change in HbA1c in People With Overweight or Obesity but Without Diabetes in SELECT. Diabetes Care. 2024;47(8):1360-1369. doi:10.2337/dc24-0764
35. Deanfield J, Lincoff AM, Kahn SE, et al. Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial. Lancet. 2025;406(10516):2257-2268. doi:10.1016/S0140-6736(25)01375-3