Blood Pressure Effects of SGLT2 Inhibitors and GLP-1 Receptor Agonists in People with High Blood Pressure and Type 2 Diabetes in Saudi Arabia

Type 2 diabetes (T2D) is one of the fastest growing non-communicable diseases, affecting 529 million adults in 2021 and projected to reach 1.31 billion by 2050 [1]. Its growing prevalence has been consistently associated with increased cardiovascular morbidity and mortality, largely through coexisting risk factors such as obesity, dyslipidemia, and, most importantly, hypertension [2,3,4]. Globally, hypertension affects nearly one billion people, with two-thirds residing in developing countries, and its prevalence is nearly double among individuals with T2D relative to non-diabetic populations [5,6,7]. Hypertension is not only the most common comorbidity in patients with T2D but also the most devastating if left unmanaged, as its coexistence with diabetes exacerbates the risk of cardiovascular events and mortality by 41% and 44%, respectively—much higher than the 7% and 9% increases seen with diabetes alone [8,9,10,11].

T2D management has shifted from a glucocentric to a cardiometabolic approach [12]. As a result, selecting antihyperglycemic treatments with established cardiovascular and renal benefits is now an essential component of T2D management [13]. Sodium–glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) stand out among diabetes medications for their cardiovascular benefits and improved renal outcomes, as evidenced by multiple cardiovascular outcome trials [14]. Evidence indicates that both GLP-1RA and SGLT2i effectively reduce systolic blood pressure (SBP), with variable effects on diastolic blood pressure (DBP), which reduces the incidence of cardiovascular events among this patient population [15,16,17,18,19,20]. Moreover, recent findings indicate that SGLT2i reduce SBP more effectively than GLP-1RA in T2D patients and have shown a notable distinction in their respective impacts on heart failure and stroke risks, which indicates varied cardiovascular profiles [21]. Despite the growing recognition of the cardiovascular benefits associated with SGLT2i and GLP-1RA in previous studies, few have made direct comparisons between these two classes in terms of blood pressure (BP) effects [14,15,16,17,18,19,20,21].

This gap in knowledge is especially crucial in the context of the Saudi Arabian population, which has witnessed a significant increase in T2D prevalence over a 30-year period, soaring from 8.5% in 1992 to 39.5% in 2022 [22]. At the same time, hypertension also constitutes a major public health issue in Saudi Arabia, affecting approximately one-fourth of the Saudi population aged 14 years and above [23]. While recent studies conducted in Saudi Arabia have explored the effects of SGLT2i and GLP-1RA on BP, there is a noticeable lack of research that focuses specifically on the direct impact these drugs have on BP or on direct comparisons between their respective effects [24,25,26,27]. The primary objectives of the study were to evaluate changes in SBP and DBP over time within each class and to determine which class is more effective, while the secondary objectives were to assess modifications in the antihypertensive regimen and the incidence of adverse events following initiation of the two agents. This retrospective cohort study ultimately aimed to address this gap by directly comparing the impact of these medication classes on BP in Saudi patients with T2D and hypertension.

This retrospective cohort study compared the BP-lowering effects of SGLT2i and GLP-1RA in Saudi patients with hypertension and T2D, with a focus on changes in SBP, DBP, antihypertensive regimen modifications, and adverse events. Both drug classes significantly reduced SBP; however, only the SGLT2i group achieved a significant reduction in DBP. Notably, most patients maintained BP control without altering their antihypertensive regimens, and adverse event rates were comparable between the groups.

The findings of this study align with previous literature demonstrating the BP-lowering effects of SGLT2i and GLP-1RA in patients with T2D. A systematic review and meta-analysis by Diallo et al. reported an overall reduction in SBP of 2.9 mmHg with SGLT2i and 1.4 mmHg with GLP-1RA [21], reinforcing the greater hypotensive effect of SGLT2i. Similarly, our study observed reductions in SBP in both treatment groups. In the SGLT2i group, SBP decreased from 137.4 mmHg at baseline to 121.8 mmHg at the fifth visit, while the GLP-1RA group showed a decline from 135.4 ± 17.3 mmHg to 133.0 ± 15.4 mmHg over the same period. The observed reductions are clinically relevant, as studies have shown that a 5 mmHg SBP decrease is associated with a 10% reduction in major cardiovascular events [21,30].

Both SGLT2i and GLP-1RA demonstrated a more pronounced effect on SBP in the early treatment phases, with significant reductions observed between the baseline and the first and second visits. However, for DBP, only SGLT2i showed a significant early reduction, whereas GLP-1RA did not exhibit a statistically significant change over the same period. Recent evidence indicates that even modest reductions in DBP are clinically relevant, as they are associated with a decreased risk of stroke and heart disease [31]. This result suggests that SGLT2i has both statistically significant and potentially clinically meaningful benefits.

In an exploratory subgroup analysis of patients who completed all five visits, both SGLT2i and GLP-1RA showed reductions in SBP. However, between-group observations appeared similar for DBP, which differs from the main analysis, where only SGLT2i demonstrated a significant reduction; this discrepancy, based on a small sample size, may reflect limited statistical power rather than true equivalence and should be interpreted with caution. Larger studies with extended follow-up are needed to confirm whether GLP-1RA can achieve comparable effects.

The SBP reduction observed in the SGLT2i group was likely due to natriuresis, osmotic diuresis, and renin–angiotensin–aldosterone system modulation, which leads to early plasma volume reduction and confers long-term vascular benefits [32]. In contrast, GLP-1RA lower SBP through vasodilation and transient natriuresis but have a minimal impact on vascular resistance, which primarily influences DBP [33]. Meanwhile, SGLT2i enhances arterial compliance and provides sustained natriuresis, both of which contribute to DBP reduction [32].

Following treatment initiation with SGLT2i or GLP-1RA, most patients remained on the same antihypertensive regimen, while a smaller subset either had their doses reduced or discontinued one or more antihypertensive agents. The higher rate of antihypertensive medication discontinuation observed in the SGLT2i group occurred alongside significant BP reductions, which might suggest that BP control was maintained even with fewer antihypertensive agents. This finding is consistent with real-world data, as demonstrated by An et al. [34], who observed that initiation of SGLT2i in hypertensive patients led to both significant blood pressure reduction and a reduced requirement for concomitant antihypertensive medications. Taken together, these findings could suggest a potential role for SGLT2i in reducing polypharmacy, a common challenge in patients with T2D and hypertension [35,36]. However, the reasons for antihypertensive medication discontinuation were not explored in this study and may have been influenced by clinician judgment, comorbidities, or perceived patient risk rather than a direct pharmacologic effect. Further research is needed to determine whether this effect could support antihypertensive medication de-escalation in clinical practice, especially among populations at risk of experiencing a medication burden.

Adverse event rates in the two groups were comparable and aligned with findings from the cohort study by Baviera et al. [37]. Therapy discontinuation was significantly higher in the GLP-1RA group (12.6%) than in the SGLT2i group (2.4%), primarily due to gastrointestinal side effects, which accounted for the majority of discontinuations. This finding aligns with the study by Almohaileb et al. [38], which reported that gastrointestinal-related adverse events were among the most common reasons for GLP-1RA discontinuation. In contrast, SGLT2i discontinuation was less frequent and was mainly attributed to dehydration and hypotension. This difference in discontinuation rates suggests that tolerability may play a role in therapy persistence, potentially favoring persistence with SGLT2i.

Our study findings have important clinical considerations. By highlighting the potential role of SGLT2i and GLP-1RA in BP control, our results support their consideration in patients with T2D and hypertension. In clinical practice, these agents are increasingly selected for patients with multiple comorbidities, as they can target several conditions simultaneously. For instance, SGLT2i are widely used in patients with diabetes, heart failure, and chronic kidney disease because of their demonstrated cardiovascular and renal benefits [15,16,19,39], while GLP-1RA are frequently chosen in patients with diabetes and obesity due to their favorable effects on body weight, and metabolic parameters [40].

From a patient-centered perspective, both classes may also contribute to improved quality of life and treatment satisfaction. Semaglutide has been shown to enhance patient-reported quality of life alongside metabolic improvements [40], while dapagliflozin has been associated with greater treatment satisfaction in overweight patients [41]. While these outcomes were not within the scope of this study, evidence from the literature provides complementary insights into the broader therapeutic value of these agents.

Taken together, these considerations suggest that the integration of SGLT2i or GLP-1RA into management decisions for patients with T2D and hypertension reflects a broader clinical approach—prioritizing not only BP reduction but also cardiovascular and renal protection, weight management, and patient-reported outcomes.

The study provides the first direct comparison of the BP-lowering effects of SGLT2i and GLP-1RA in a real-world Saudi cohort with both hypertension and T2D. The multicenter design and the use of strict inclusion and exclusion criteria strengthen the internal validity of the findings. Moreover, the study is highly relevant to Saudi patients, a population with a particularly high prevalence of both conditions [22,23].

However, several limitations should be acknowledged. The retrospective, non-randomized design restricts the ability to establish a causal relationship between SGLT2i or GLP-1RA use and BP reduction. In addition, potential confounding by indication may have influenced treatment choices, as prescribing decisions could have been shaped by disease severity, comorbidities, or physician preference. This makes it challenging to determine whether the observed BP effects were attributable to the medications themselves or to underlying patient differences. The relatively small sample size in the subgroup analysis further reduced statistical power and limited the generalizability of the results, highlighting the need for larger, prospective studies. Moreover, although outpatient visits were scheduled at 3–6-month intervals, actual visit timing varied across patients, potentially introducing heterogeneity in treatment exposure duration and influencing the magnitude of observed BP changes. Another limitation arises from the retrospective data collection, which precluded detailed information on BP measurement methods and may have introduced variability due to visit-to-visit fluctuations or the white-coat effect. Additionally, data on adherence to the study medications, lifestyle factors (e.g., diet and physical activity), and socioeconomic status were not explored. These areas could be considered for future investigation to provide a more comprehensive understanding of BP control. Future studies should also further investigate the severity and management of clinical consequences to ensure the safe use of these drugs. Finally, as the study was conducted in a specific Saudi population, the generalizability of the findings to other populations may be limited. Future investigations in diverse cohorts with longer follow-up periods are warranted to confirm these results and better evaluate the safety and clinical outcomes of SGLT2i and GLP-1RA in broader clinical contexts.

In this multicenter, real-world cohort of Saudi adults with T2D and hypertension, both SGLT2i and GLP-1RA were associated with significant SBP reductions, while a significant DBP reduction was observed only with SGLT2i. Most patients remained on the same antihypertensive regimen; de-escalation occurred more often with SGLT2i. Adverse events were comparable between the drug classes, while treatment discontinuation was higher with GLP-1RA. These findings support considering either class for patients with both conditions, with SGLT2i potentially offering added benefit for DBP lowering and regimen simplification. Further prospective studies and randomized trials are warranted to confirm these observations and to define their long-term impact on patient outcomes.