This study aimed to examine the efficacy in ameliorating endothelial and arterial stiffness markers of once-weekly dulaglutide (1.5 mg) plus traditional therapy in diabetic patients with type 2 diabetes.
Our study is the first to analyse the efficacy of dulaglutide therapy on surrogate vascular endpoints such as endothelial and arterial stiffness indexes in parallel with metabolic effects.
Consistent with previous studies, we demonstrate that subjects treated with traditional therapy plus dulaglutide showed significantly lower mean fasting plasma glucose and glycated haemoglobin levels at the three- and nine-month follow-ups. Thus, our study further confirms previous findings concerning the reduction of glucose serum levels and HbA1c serum levels (33-34).
Grunberger et al (35) demonstrated a dose-dependent HbA1c reduction for dulaglutide and greater reduction than placebo. Furthermore, the multicentre, randomized, placebo-controlled REWIND study (36) that recruited participants who aged at least 50 years with type 2 diabetes, a haemoglobin A1c (HbA1c) level of 9.5% or less, and a body mass index greater than 23 kg/m2 reported that the HbA1c levels were reduced in the drug group by a mean of –0.61% compared with placebo (34).
Our study also reported that subjects treated with traditional therapy plus dulaglutide showed a significantly lower mean body weight and, BMI and significantly lower mean LDL cholesterol and total cholesterol serum levels at the nine-month follow-up.
In the REWIND study, subjects with type 2 diabetes who had a previous cardiovascular event or cardiovascular risk factors and were randomly assigned to either weekly subcutaneous injection of dulaglutide (1.5 mg) or placebo showed lower total cholesterol and lower LDL cholesterol at follow-up (36).
Atherogenic dyslipidaemia in diabetes in type 2 diabetes is characterized by the overproduction and/or delayed catabolism of triglyceride-rich particles (TRLs), including apolipoprotein apo-B-48 containing chylomicrons and apo-B100-containing VLDLs, cholesterol-rich remnant particles, small dense LDLs and a reduction in circulating HDLs (37). When the number of postprandial TRLs is reduced in response to the induction of GLP-1 signalling, GLP-2 receptor activation is involved in the promotion of lipid absorption (38). In experimental hamsters, an infusion of GLP1 and GLP2 causes an initial increase in lipid absorption and increased plasma concentrations of TRL-apo B48 in plasma and this response in terms of the increased postprandial lipid response has been reported to be enhanced under the condition of insulin resistance, such as in type 2 diabetes (39).
We also reported that subjects treated with traditional therapy plus dulaglutide showed significantly lower mean body weight, SBP, and DBP values at the nine month follow-up. Furthermore, at nine months, we observed a significant reduction in the levels of microalbuminuria, a well-known marker of vascular damage in diabetes (38,39).0
Regarding patients enrolled in the REWIND trial, their weight decreased by a mean of –1.5 kg while the systolic blood pressure and LDL cholesterol levels were slightly lower in the drug group (40).
In our trial, the metabolic effects on FPG and HbA1c were observed earlier at three months. By contrast, at nine months, we observed more delayed effects on cholesterol serum variables and vascular health indexes such as RHI and arterial stiffness indexes such as PWV and AIx, possibly indicating a more strict relationship between vascular damage markers and cholesterol serum levels.
These findings are consistent with previous studies indicating the strict relationship between cardiovascular risk factors such as systolic blood pressure, total serum cholesterol and LDL levels (41-43) and cardiovascular events and vascular health surrogate markers (44).
Furthermore, as observed in our trial, and similarly in recent studies (36,45), weekly subcutaneous injection of 1.5 mg of dulaglutide was associated with weight loss and consequently a reduction in the BMI.
A chronic inflammatory state linked to obesity leads to dysregulation of the endocrine and paracrine actions of adipocyte-derived factors, which disrupt vascular homeostasis and contribute to endothelial vasodilator dysfunction by determining, among other effects, an imbalance in the endothelin-1/nitric oxide pathway (46).
Considering these premises, the reduction of body weight and BMI observed in the dulaglutide arm at the nine-month follow-up might lead to a reduction in the systemic inflammatory state, the resumption of the correct mechanisms of vascular homeostasis and, as observed in our trial, an improvement in the vascular health indexes.
Several studies have indicated that, in addition to lowering glucose, dulaglutide affected the cardiovascular system (41-44). These investigators reported that patients with T2DM found that dulaglutide could lower systolic blood pressure by 2.8 mmHg compared with placebos. Tuttle et al., in a study of 6,005 patients with T2DM, showed that dulaglutide slightly lowered the urine protein level but did not lower the glomerular filtration rate (42).
Furthermore, Ceriello et al. showed a beneﬁcial effect of the combination of GLP-1-RA and insulin on hyperglycaemia-induced oxidative stress and endothelial function for patients with T2DM (43). The antioxidant properties of GLP-1-RA increases intracellular antioxidant defences (44). This mechanism may be due to the use of a GLP-1-RA affecting oxidative stress and vascular endothelial function characteristics. Another reason may be that glycaemic control is better in patients treated with dulaglutide plus conventional therapy and possibly related to an improvement in glucose variability, as reported by some studies (47).
Consistent with previous study finding (36, 50), our findings underlined the efficacy of dulaglutide on glycaemic control, as shown by its precocious action on lowering FPG and HbA1c not only at nine months but also at three months.
A previous study (47) demonstrated that the reduction of FPG and improvement in glycaemic variability are correlated with the reduction of oxidative stress on the vascular endothelium.
In particular, an increase in FPG and glucose variability can induce the worsening of oxidative stress through many mechanisms, including ROS overproduction mediated by many pathways, such as the increase in AGE levels, vasomotor imbalance mediated by the reduction of NO availability and increase in the oxidant peroxynitrite, increased inflammation molecules and overexpression of cellular adhesion molecules on the endothelial surface, such as ICAM, VCAM, and E-selectin, which promote inflammation by leukocyte rolling (48). These pathways may contribute to endothelial dysfunction and accelerate the process of atherosclerosis, leading to increased cardiovascular events (49).
Moreover, our study showed improvement in endothelial markers such as RHI, AIx and PWV at nine months. Thus, our findings of the precocious reduction of FPG and HbA1c at three months, owing to their possible negative action on the modulation of oxidative stress, should provide an interesting explanation for the improved endothelial function, as suggested by an increase in RHI and a decrease in PWV and AIx at nine months.
Furthermore, because the treatment and placebo curves in the REWIND were separated, starting clearly between 12 and 18 months of the trial treatment period, the beneficial vascular effect of the GLP-1 receptor agonists could be due to an anti-atherogenic effect (17,36). Our findings are consistent with these results and may offer a pathogenetic explanation for the delayed effects on cardiovascular events, indicating the amelioration of metabolic and vascular markers observed at nine months of treatment.
Our study is the first to evaluate the beneficial effects of dulaglutide on both vascular health indexes such as arterial stiffness and endothelial dysfunction markers. These novel findings may explain the interplay between the improvement in metabolic variables and reduction in cardiovascular outcomes reported by a trial on the effect of dulaglutide (45) on cardiovascular outcomes. Our findings concerning surrogate vascular markers may also represent an explanation of the cardiovascular positive effects of other glucagon-like peptide 1 receptor agonists (GLP-1-RAs), such as liraglutide and semaglutide (50-57).
Activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome plays an important role in high glucose-induced endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM). A recent study investigated whether dulaglutide possesses a protective effect against high glucose-induced activation of the NLRP3 inflammasome. These authors showed that dulaglutide treatment prevented high glucose-induced generation of reactive oxygen species (ROS) and protein carbonyls, as well as the expression of NADPH oxidase 4 (NOX-4) in human umbilical vein endothelial cells (HUVECs) (58,59).
Another recent study compared the effect of dulaglutide and liraglutide on oxidative stress and endothelial function in patients with type 2 diabetes mellitus (T2DM). No significant differences were found in d-ROMs and logarithmic-scaled RHI (L-RHI) between the two groups after 24 weeks of treatment (60).
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are emerging as an important therapy to consider for patients with type 2 diabetes (T2D) given the ability of this agent class to reduce glycated haemoglobin and associated weight loss and low risk for hypoglycaemia. Additionally, some cardiovascular outcomes trials (CVOTs) found non-inferiority for cardiovascular outcomes, with many findings of the superiority of these drugs.
A recent study of twelve-month treatment with GLP-1RA, SGLT-2i, and their combination showed greater improvement in vascular markers and effective cardiac cycles than insulin treatment in type 2 diabetes mellitus. The combined therapy as second line was superior to either insulin or GLP-1RA and SGLT-2i separately (61). Another study (62) showed that six-month treatment with liraglutide improved arterial stiffness, LV myocardial strain, LV twisting and untwisting and NT-proBNP by reducing oxidative stress in subjects with newly diagnosed T2DM.
Thus, several lines of evidence (61,62,63) have reported that newer antidiabetic drugs differentially affect endothelial function and arterial stiffness, as assessed by FMD and PWV, respectively. These findings could explain the distinct effects of these drugs on the cardiovascular risk of patients with type 2 diabetes mellitus.
However, most studies have evaluated the putative protective vascular role of liraglutide and only a few have evaluated this role for dulaglutide. No study has evaluated the role of both arterial stiffness and endothelial indexes; thus, our findings may appear original.
These findings have transformed our guidelines on the pharmacological treatment of T2D. Future prospective studies will be addressed to evaluate the relationship between the effects of GLP-1 RAs on vascular damage markers and the incidence of new cardiovascular events.
Strengths and Limitations
The strengths of our study include the broad and representative inclusion criteria and recruited participants, long follow-up, high retention, measurement of clinically relevant outcomes and of surrogate vascular endpoints.
A possible limitation is that we considered several endpoints ( metabolic and vascular ) and that we did not consider primary and secondary outcomes but some parallel aims.