Hypertension (HTN) and Type 2 Diabetes Mellitus (T2DM) represent two of the most prevalent chronic non-communicable diseases globally, acting as primary drivers of cardiovascular morbidity and mortality [1]. While each condition independently promotes the development and progression of atherosclerosis, their frequent coexistence creates a clinical scenario of substantially elevated cardiovascular risk [2]. The pathophysiological link between HTN and T2DM is complex and bidirectional, involving shared mechanisms such as insulin resistance, activation of the renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system overactivity, and chronic low-grade inflammation [3].

The vascular wall is the principal target of the damage inflicted by both HTN and T2DM. Two key subclinical indicators of this damage are increased arterial stiffness and endothelial dysfunction. Arterial stiffness, a measure of the reduced distensibility of large arteries, is an independent predictor of cardiovascular events and all-cause mortality [4]. It is commonly quantified non-invasively by measuring carotid-femoral pulse wave velocity (cfPWV), with higher values indicating stiffer arteries. Endothelial dysfunction, characterized by impaired endothelium-dependent vasodilation, is considered one of the earliest events in the atherosclerotic cascade [5]. It is typically assessed by measuring the brachial artery's flow-mediated dilation (FMD), where a reduced response signals impaired nitric oxide (NO) bioavailability and endothelial damage.

Hypertension promotes arterial stiffness through sustained mechanical stress, leading to medial hypertrophy, elastin fatigue, and collagen deposition [6]. Concurrently, T2DM accelerates vascular stiffening through mechanisms like the formation of advanced glycation end-products (AGEs), which cross-link collagen, and through oxidative stress and inflammation [7]. Similarly, both conditions impair endothelial function; HTN via shear stress and RAAS activation, and T2DM via hyperglycemia-induced oxidative stress, which reduces NO bioavailability [8].

While numerous studies have established the individual impact of HTN and T2DM on vascular health, the additive or potentially synergistic effect of their combination requires further clarification. Recent evidence suggests that the combined presence of these pathologies may lead to a degree of vascular damage that is greater than the sum of their individual effects [9]. Quantifying this difference is essential for identifying high-risk individuals who may benefit from more intensive therapeutic interventions. However, there is a relative paucity of studies that directly compare well-matched cohorts of patients with hypertension alone to those with both hypertension and T2DM using gold-standard measures of cfPWV and FMD in the same study population.

Therefore, the aim of the present study was to conduct a direct comparative evaluation of arterial stiffness and endothelial dysfunction in patients with essential hypertension alone versus patients with concomitant hypertension and T2DM, hypothesizing that the dual-diagnosis group would exhibit significantly worse vascular health markers.

A total of 200 participants aged 40 to 70 years were recruited from outpatient clinics. A power calculation based on detecting a 1.5 m/s difference in cfPWV with a standard deviation of 2.0 m/s, an alpha of 0.05, and a power of 90% indicated a required sample size of approximately 95 participants per group. To account for potential dropouts, we recruited 100 participants for each group. Participants were allocated into two groups:

• Group 1 (HTN-only): 100 patients with a confirmed diagnosis of essential hypertension.
• Group 2 (HTN+T2DM): 100 patients with confirmed diagnoses of both essential hypertension and T2DM.

Inclusion Criteria

1. Age between 40 and 70 years.
2. Confirmed diagnosis of essential hypertension (office blood pressure ≥140/90 mmHg or on stable antihypertensive medication for at least 6 months).
3. For Group 2, a confirmed diagnosis of T2DM according to American Diabetes Association criteria (e.g., HbA1c ≥6.5% or fasting plasma glucose ≥126 mg/dL) for at least one year.

Exclusion Criteria

1. History of established cardiovascular disease (myocardial infarction, stroke, peripheral artery disease, or revascularization).
2. Chronic kidney disease (eGFR < 60 mL/min/1.73m²).
3. Type 1 diabetes mellitus.
4. Atrial fibrillation or other significant arrhythmias.
5. Active inflammatory or autoimmune disease.
6. Current smokers or smoking cessation within the last year.
7. Malignancy.
8. Pregnancy.

Procedures
All assessments were performed in a quiet, temperature-controlled room (22–24°C) after a 15-minute rest period in the supine position. Participants were instructed to fast for at least 10 hours and to abstain from caffeine and alcohol for 24 hours prior to the visit.

• Clinical and Anthropometric Assessment: A detailed medical history was obtained. Body weight and height were measured to calculate the Body Mass Index (BMI). Blood pressure was measured three times in the seated position using a validated automated oscillometric device (Omron HEM-907), and the average of the last two readings was recorded.
• Biochemical Analysis: Venous blood samples were drawn after an overnight fast. Samples were analyzed for fasting plasma glucose, HbA1c, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) using standard enzymatic assays on an automated analyzer. High-sensitivity C-reactive protein (hs-CRP) was measured by immunoturbidimetry. Nitric oxide metabolites (NOx; nitrate/nitrite) were measured using the Griess reaction colorimetric assay.
• Arterial Stiffness Assessment: Carotid-femoral pulse wave velocity (cfPWV) was measured non-invasively using applanation tonometry (SphygmoCor XCEL, AtCor Medical, Australia). Pulse waveforms were recorded sequentially at the right common carotid and right femoral arteries. The transit time (Δt) was determined from the foot-to-foot delay of the pressure waves, referenced to a simultaneously recorded ECG. The distance between the two recording sites was measured over the body surface. cfPWV was calculated as Distance (m) / Δt (s). The average of two technically acceptable measurements was used.
• Endothelial Function Assessment: Brachial artery flow-mediated dilation (FMD) was assessed using high-resolution ultrasound (Vivid E9, GE Healthcare) with a 12-MHz linear-array transducer. The right brachial artery was imaged in the longitudinal plane, 2–5 cm above the antecubital fossa. Baseline artery diameter and flow velocity were recorded. A blood pressure cuff on the forearm was inflated to 50 mmHg above systolic pressure for 5 minutes to induce reactive hyperemia. The cuff was then rapidly deflated, and the post-deflation brachial artery diameter was recorded continuously for 3 minutes. FMD was calculated as the maximum percentage increase in diameter from the baseline: FMD (%) = [(Peak Diameter – Baseline Diameter) / Baseline Diameter] × 100.

Statistical Analysis Data were analyzed using SPSS software, version 26.0 (IBM Corp., Armonk, NY). The normality of data distribution was assessed using the Shapiro-Wilk test. Continuous variables are presented as mean ± standard deviation (SD) and were compared between groups using the independent samples t-test. Categorical variables are presented as numbers (%) and were compared using the Chi-square test. A two-sided p-value of < 0.05 was considered statistically significant.

Baseline Characteristics

A total of 200 participants completed the study. The baseline demographic and clinical characteristics of the two study groups are presented in Table 1. The groups were well-matched for age, sex, and BMI. As expected, the HTN+T2DM group had significantly higher fasting plasma glucose and HbA1c levels. While both groups had controlled systolic and diastolic blood pressure on medication, the HTN+T2DM group had a slightly, but significantly, higher systolic blood pressure. The lipid profile also differed, with the HTN+T2DM group exhibiting higher triglycerides and lower HDL-C.

Table 1. Baseline Demographic and Clinical Characteristics

Arterial Stiffness and Endothelial Function

The primary outcomes related to vascular function are detailed in Table 2. The HTN+T2DM group demonstrated significantly higher arterial stiffness, as evidenced by a mean cfPWV that was 1.7 m/s higher than in the HTN-only group (p < 0.001). Endothelial function was profoundly impaired in the dual-diagnosis group. The mean FMD percentage in the HTN+T2DM group was approximately 37% lower than that observed in the HTN-only group (4.3% vs. 6.8%, p < 0.001).

Table 2. Comparison of Arterial Stiffness and Endothelial Function Parameters

Inflammatory and Vasoactive Biomarkers

The analysis of biomarkers supported the findings from the vascular function tests (Table 3). The HTN+T2DM group exhibited a state of heightened systemic inflammation, with significantly higher levels of hs-CRP. Furthermore, this group showed significantly lower levels of nitric oxide metabolites (Nox), consistent with the observed endothelial dysfunction and reduced NO bioavailability.

Table 3. Comparison of Inflammatory and Vasoactive Biomarkers

The principal finding of this study is that the concomitant presence of T2DM in patients with hypertension is associated with a significantly greater degree of arterial stiffening and more severe endothelial dysfunction compared to hypertension alone. These results provide direct quantitative evidence for the synergistic adverse impact of these two highly prevalent conditions on the structural and functional integrity of the vasculature.

Our observation of a markedly higher cfPWV in the HTN+T2DM group aligns with and extends previous research. Both HTN and T2DM are well-established contributors to arterial stiffening [10]. The chronic mechanical load of hypertension induces hypertrophic remodeling and fatigue of elastic fibers in the arterial media. T2DM exacerbates this process through metabolic pathways, primarily via the non-enzymatic glycation of long-lived proteins like collagen, forming advanced glycation end-products (AGEs). The accumulation of AGEs cross-links collagen fibers, reducing their elasticity and making the arterial wall stiffer [11]. The substantial 1.7 m/s difference in cfPWV observed in our study suggests that these mechanisms are not merely additive but may interact synergistically, leading to accelerated vascular aging in patients with this dual diagnosis. This finding is consistent with results from larger cohort studies, such as the Maastricht Study, which demonstrated that diabetes and hypertension have interactive effects on arterial stiffness [12].

The profound impairment in FMD in the HTN+T2DM group highlights a severe state of endothelial dysfunction. Endothelial cells play a critical role in vascular homeostasis, primarily through the release of nitric oxide (NO), a potent vasodilator. In our study, the HTN-only group already exhibited reduced FMD, consistent with the known effects of hypertension on endothelial function through mechanisms like increased oxidative stress and RAAS activation [13]. However, the addition of T2DM led to a further, dramatic reduction in FMD. This is likely attributable to hyperglycemia-induced overproduction of reactive oxygen species (ROS), which scavenge NO and uncouple endothelial nitric oxide synthase (eNOS), shifting it towards a superoxide-producing enzyme [8]. The significantly lower levels of nitric oxide metabolites (NOx) in our HTN+T2DM group provide direct biochemical evidence for this reduced NO bioavailability.

The biomarker data further illuminates the underlying pathophysiology. The elevated hs-CRP in the HTN+T2DM group points to a greater systemic inflammatory burden. Chronic low-grade inflammation is a key feature of both conditions and is known to promote endothelial dysfunction and arterial stiffening by activating pro-inflammatory signaling pathways within the vessel wall [14]. The combination of HTN and T2DM appears to amplify this inflammatory state, creating a vicious cycle of vascular damage.

The clinical implications of our findings are significant. cfPWV and FMD are not merely markers of subclinical disease; they are powerful, independent predictors of future cardiovascular events [4, 5]. The values observed in our HTN+T2DM group (mean cfPWV of 11.4 m/s) place these individuals in a high-risk category for cardiovascular mortality. This underscores the necessity for aggressive risk factor management in this patient population, going beyond standard blood pressure and glycemic targets. Therapeutic strategies should perhaps also focus on agents with pleiotropic vascular benefits, such as ACE inhibitors, ARBs, or SGLT2 inhibitors, which have been shown to improve endothelial function and, in some cases, reduce arterial stiffness, independent of their primary hemodynamic or glucose-lowering effects [15].

This study has several strengths, including the use of gold-standard, non-invasive techniques to assess vascular function and the recruitment of well-characterized, age- and sex-matched patient groups. However, some limitations must be acknowledged. First, the cross-sectional design precludes any inference of causality; we can only report associations. A longitudinal study is needed to determine if the observed differences in vascular health translate to a differential rate of cardiovascular events over time. Second, while we controlled for major confounders, the influence of unmeasured variables, such as diet, physical activity, or specific medication regimens, cannot be entirely ruled out. Finally, this was a single-center study, which may limit the generalizability of our findings to other populations.

In conclusion, this study demonstrates that patients with coexistent hypertension and type 2 diabetes mellitus exhibit a significantly greater burden of both arterial stiffness and endothelial dysfunction compared to patients with hypertension alone. The findings highlight a synergistic negative interaction between these two conditions on vascular health, which is supported by evidence of increased inflammation and reduced nitric oxide bioavailability. This pronounced vascular impairment likely contributes to the exceptionally high cardiovascular risk observed in this patient population and emphasizes the critical need for early, aggressive, and comprehensive management strategies targeting both hemodynamic and metabolic abnormalities.

1. World Health Organization. Noncommunicable diseases. [Internet]. Geneva: WHO; 2022. Available from: https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases.
2. Glovaci D, Fan W, Wong ND. Epidemiology of Diabetes Mellitus and Cardiovascular Disease. Curr Cardiol Rep. 2019;21(4):21. doi: 10.1007/s11886-019-1107-y. PMID: 30838491.
3. Petrie JR, Guzik TJ, Touyz RM. The physiological basis and clinical application of SGLT2 inhibitors in heart failure. Br J Pharmacol. 2022;179(13):3183-3200. doi: 10.1111/bph.15781. PMID: 35038101.
4. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;55(13):1318-27. doi: 10.1016/j.jacc.2009.11.063. PMID: 20338492.
5. Inaba Y, Chen JA, Bergmann SR. Prediction of future cardiovascular outcomes by flow-mediated vasodilation of brachial artery: a meta-analysis. Int J Cardiovasc Imaging. 2010;26(6):631-40. doi: 10.1007/s10554-010-9616-1. PMID: 20437053.
6. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25(5):932-43. doi: 10.1161/01.ATV.0000160548.78317.29. PMID: 15731494.
7. Bucala R, Vlassara H. Advanced glycation end products. In: Leroith D, Taylor SI, Olefsky JM, editors. Diabetes Mellitus: A Fundamental and Clinical Text. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 1109-1121.
8. Forstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33(7):829-37, 837a-837d. doi: 10.1093/eurheartj/ehr304. PMID: 21890489.
9. Lastra G, Syed S, Kurukulasuriya LR, Manrique C, Sowers JR. Type 2 diabetes mellitus and hypertension: an update. Endocrinol Metab Clin North Am. 2014;43(1):103-22. doi: 10.1016/j.ecl.2013.09.005. PMID: 24582103.
10. Stehouwer CD, Henry RM, Ferreira I. Arterial stiffness in diabetes and the metabolic syndrome: a pathway to cardiovascular disease. Diabetologia. 2008;51(4):527-39. doi: 10.1007/s00125-007-0918-3. PMID: 18259747.
11. Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol. 2014;18(1):1-14. doi: 10.4196/kjpp.2014.18.1.1. PMID: 24623989.
12. Sörensen BM, Houben AJ, Berendschot TT, Schouten JS, van der Kallen CJ, Koster A, et al. The Interplay Between Type 2 Diabetes and Hypertension and Vascular Function: The Maastricht Study. J Hypertens. 2016;34(6):1156-64. doi: 10.1097/HJH.0000000000000913. PMID: 26998811.
13. Landmesser U, Hornig B, Drexler H. Endothelial function: a critical determinant in atherosclerosis? Circulation. 2004;109(21 Suppl 1):II27-33. doi: 10.1161/01.CIR.0000129501.88485.1f. PMID: 15173062.
14. Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54(23):2129-38. doi: 10.1016/j.jacc.2009.09.009. PMID: 19942084.
15. Chilton R, Tikkanen I, Narkiewicz K. The effect of selected antihypertensive agents on insulin sensitivity and endothelial function. Cardiovasc Diabetol. 2016;15:1. doi: 10.1186/s12933-015-0322-x. PMID: 26732976.