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Effect of sotagliflozin as an adjunct to insulin therapy on blood pressure and arterial stiffness in adults with type 1 diabetes: A post hoc pooled analysis of inTandem1 and inTandem2.
Rodbard, HW, Giaccari, A, Cariou, B, Garg, S, Davies, MJ, Seth, K, Sawhney, S
Diabetes & vascular disease research. 2021;(1):1479164121995928
Abstract
OBJECTIVE Evaluate the effect of sotagliflozin, a dual inhibitor of sodium glucose cotransporter (SGLT) 1 and 2, on arterial stiffness in patients with type 1 diabetes (T1D) treated with sotagliflozin as adjunct to optimized insulin therapy. METHODS In this post hoc analysis, indirect markers of arterial stiffness, including pulse pressure, mean arterial pressure (MAP), and double product, were calculated using observed systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse rate at 24 weeks using data from a pooled patient population from the inTandem1 and inTandem2 randomized controlled trials (n = 1575). RESULTS Baseline characteristics were similar among groups. Relative to placebo at Week 24, sotagliflozin 200 mg and 400 mg reduced SBP by 2.03 mm Hg (95% CI -3.30 to -0.75; p = 0.0019) and 2.85 mm Hg (-4.12 to -1.57; p < 0.0001), respectively. DBP decreased by 1.1 and 0.9 mm Hg, MAP by 1.4 and 1.6 mm Hg, and double product by 202.5 and 221.1 bpm × mm Hg, respectively (p < 0.05 for all). No increases in heart rate were observed. CONCLUSION In adults with T1D, adding sotagliflozin to insulin significantly reduced blood pressure and other markers of arterial stiffness and vascular resistance.
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Effect of tofogliflozin on arterial stiffness in patients with type 2 diabetes: prespecified sub-analysis of the prospective, randomized, open-label, parallel-group comparative UTOPIA trial.
Katakami, N, Mita, T, Yoshii, H, Shiraiwa, T, Yasuda, T, Okada, Y, Torimoto, K, Umayahara, Y, Kaneto, H, Osonoi, T, et al
Cardiovascular diabetology. 2021;(1):4
Abstract
BACKGROUND Tofogliflozin, an SGLT2 inhibitor, is associated with favorable metabolic effects, including improved glycemic control and serum lipid profile and decreased body weight, visceral adipose tissue, and blood pressure (BP). This study evaluated the effects of tofogliflozin on the brachial-ankle pulse wave velocity (baPWV) in patients with type 2 diabetes (T2DM) without a history of apparent cardiovascular disease. METHODS The using tofogliflozin for possible better intervention against atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. As one of the prespecified secondary outcomes, changes in baPWV over 104 weeks were evaluated in 154 individuals (80 in the tofogliflozin group and 74 in the conventional treatment group) who completed baPWV measurement at baseline. RESULTS In a mixed-effects model, the progression in the right, left, and mean baPWV over 104 weeks was significantly attenuated with tofogliflozin compared to that with conventional treatment (- 109.3 [- 184.3, - 34.3] (mean change [95% CI] cm/s, p = 0.005; - 98.3 [- 172.6, - 24.1] cm/s, p = 0.010; - 104.7 [- 177.0, - 32.4] cm/s, p = 0.005, respectively). Similar findings were obtained even after adjusting the mixed-effects models for traditional cardiovascular risk factors, including body mass index (BMI), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, systolic blood pressure (SBP), hypertension, smoking, and/or administration of drugs, including hypoglycemic agents, antihypertensive agents, statins, and anti-platelets, at baseline. The findings of the analysis of covariance (ANCOVA) models, which included the treatment group, baseline baPWV, and traditional cardiovascular risk factors, resembled those generated by the mixed-effects models. CONCLUSIONS Tofogliflozin significantly inhibited the increased baPWV in patients with T2DM without a history of apparent cardiovascular disease, suggesting that tofogliflozin suppressed the progression of arterial stiffness. Trial Registration UMIN000017607. Registered 18 May 2015. ( https://www.umin.ac.jp/icdr/index.html ).
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Aortic Calcification and Arterial Stiffness Burden in a Chronic Kidney Disease Cohort with High Cardiovascular Risk: Baseline Characteristics of the Impact of Phosphate Reduction On Vascular End-Points in Chronic Kidney Disease Trial.
Lioufas, NM, Pedagogos, E, Hawley, CM, Pascoe, EM, Elder, GJ, Badve, SV, Valks, A, Toussaint, ND, ,
American journal of nephrology. 2020;(3):201-215
Abstract
Chronic kidney disease (CKD) is associated with excess cardiovascular morbidity and mortality compared to the general population. Hyperphosphataemia, associated with vascular calcification and arterial stiffness, may play a key role in the pathogenesis of cardiovascular disease (CVD) associated with CKD, although phosphate reduction strategies have not consistently proven to beneficially affect clinically relevant outcomes. The IMpact of Phosphate Reduction On Vascular End-points in CKD (IMPROVE-CKD) study is an international, multi-centre, randomized, placebo-controlled trial investigating the effect of the phosphate binder lanthanum carbonate on intermediate cardiovascular markers in patients with stage 3b-4 CKD. The primary end-point is change in carotid-femoral pulse wave velocity (PWV, SphygmoCor) after 96 weeks. Secondary outcomes include change in abdominal aortic calcification (AAC, computed tomography), serum phosphate and fibroblast growth factor 23 (FGF-23). In total, 278 participants were recruited and randomized, mean age 63 ± 13 years, 69% male, 45% diabetes, 32% CVD, 33% stage 3b CKD and 67% stage 4 CKD. Mean estimated glomerular filtration rate and serum phosphate were 26.6 ± 8.3 mL/min/1.72 m2 and 1.25 ± 0.20 mmol/L, respectively. Median (interquartile range) intact and c-terminal FGF-23 levels were 133.0 (89.1-202) pg/mL and 221.1 (154.3-334.1) RU/mL, respectively. Mean PWV was 10.8 ± 3.6 m/s and 81% had AAC (median Agatston score 1,535 [63-5,744] Hounsfield units). PWV ≥10 m/s was associated with older age, diabetes, CVD, presence of AAC, higher systolic blood pressure (BP), larger waist circumference and higher alkaline phosphatase. AAC was associated with older age, male sex, diabetes, CVD, higher diastolic BP, dyslipidaemia (and use of statins), smoking, larger waist circumference and increased PWV. In conclusion, IMPROVE-CKD participants had high baseline risk for cardiovascular events, as suggested by high baseline PWV and AAC values.
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Switching from Warfarin to rivaroxaban induces sufficiency of vitamin K and reduction of arterial stiffness in patients with atrial fibrillation.
Ikari, Y, Saito, F, Kiyooka, T, Nagaoka, M, Kimura, M, Furuki, T, Tanaka, S
Heart and vessels. 2020;(12):1727-1733
Abstract
Use of chronic vitamin K antagonist (VKA) induces a long-term deficiency of vitamin K, which may cause arterial stiffness and bone-related disease. Switching from VKA to rivaroxaban could induce rapid sufficiency of vitamin K and improvement of arterial stiffness. The K2 SUMMIT-3 study is a multicenter, open-label, prospective, and randomized design. Patients with atrial fibrillation who have been taking VKA for more than 6 months but less than 10 years were randomly assigned to two groups; those switching from VKA to rivaroxaban and those continuing with VKA medication. The primary endpoint was the percentage difference of brachial-ankle pulse wave velocity (baPWV) in 3 months. A total of 77 patients were randomly assigned to receive rivaroxaban (n = 38) or VKA (n = 39). The average age was 74 ± 9 years. The duration for which VKA was prescribed prior to randomization was 90 ± 87 months.Abnormally high levels of Des-gamma carboxyprothrombin (PIVKA-II) or uncarboxylated osteocalcin (ucOC) indicating vitamin K insufficiency were observed in 100% or 82% of the patients at baseline but it reduced to 2% (p < 0.0001) or 55% (p = 0.01) at 3 months in the rivaroxaban group. To the contrary, theses data had no changes in the VKA group. The percentage difference in baPWV was - 1.4 ± 10.0% vs. 3.5 ± 14.7% in the rivaroxaban and the VKA groups, respectively. (p = 0.02). Switching from VKA to rivaroxaban resulted in rapid sufficiency of vitamin K and reduction of arterial stiffness in 3 months.
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Mediterranean-Style Diet Improves Systolic Blood Pressure and Arterial Stiffness in Older Adults.
Jennings, A, Berendsen, AM, de Groot, LCPGM, Feskens, EJM, Brzozowska, A, Sicinska, E, Pietruszka, B, Meunier, N, Caumon, E, Malpuech-Brugère, C, et al
Hypertension (Dallas, Tex. : 1979). 2019;(3):578-586
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Abstract
We aimed to determine the effect of a Mediterranean-style diet, tailored to meet dietary recommendations for older adults, on blood pressure and arterial stiffness. In 12 months, randomized controlled trial (NU-AGE [New Dietary Strategies Addressing the Specific Needs of Elderly Population for Healthy Aging in Europe]), blood pressure was measured in 1294 healthy participants, aged 65 to 79 years, recruited from 5 European centers, and arterial stiffness in a subset of 225 participants. The intervention group received individually tailored standardized dietary advice and commercially available foods to increase adherence to a Mediterranean diet. The control group continued on their habitual diet and was provided with current national dietary guidance. In the 1142 participants who completed the trial (88.2%), after 1 year the intervention resulted in a significant reduction in systolic blood pressure (-5.5 mm Hg; 95% CI, -10.7 to -0.4; P=0.03), which was evident in males (-9.2 mm Hg, P=0.02) but not females (-3.1 mm Hg, P=0.37). The -1.7 mm Hg (95% CI, -4.3 to 0.9) decrease in diastolic pressure after intervention did not reach statistical significance. In a subset (n=225), augmentation index, a measure of arterial stiffness, was improved following intervention (-12.4; 95% CI, -24.4 to -0.5; P=0.04) with no change in pulse wave velocity. The intervention also resulted in an increase in 24-hour urinary potassium (8.8 mmol/L; 95% CI, 0.7-16.9; P=0.03) and in male participants (52%) a reduction in pulse pressure (-6.1 mm Hg; 95% CI, -12.0 to -0.2; P=0.04) and 24-hour urinary sodium (-27.1 mmol/L; 95% CI, -53.3 to -1.0; P=0.04). In conclusion, a Mediterranean-style diet is effective in improving cardiovascular health with clinically relevant reductions in blood pressure and arterial stiffness. Clinical Trial Registration- URL: http://www.clinicialtrials.gov . Unique identifier: NCT01754012.
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Measurement of arterial stiffness and vascular aging in community pharmacies-The ASINPHAR@2action project.
Pereira, T, Paulino, E, Maximiano, S, Rosa, M, Pinto, AL, Mendes, MJ, Brito, J, Soares, P, Risse, J, Gose, S
Journal of clinical hypertension (Greenwich, Conn.). 2019;(6):813-821
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The ASINPHAR@2action project aims at raising awareness to arterial stiffness (AS) and early vascular aging (EVA) through a community pharmacy-based intervention. This preliminary analysis is focused on the analysis of the proportion of participants with increased AS and the identification of its main determinants. We performed an observational cross-sectional study of participants enrolled in 11 community pharmacies in Portugal, between April and November 2017. Blood pressure (BP) and arterial function parameters were measured with a validated device. Clinical and demographic information was gathered, as well as the estimation of global cardiovascular risk, health-related quality of life, and dietary profile. Cholesterol and glycaemia were taken from a recent laboratory bulletin. The cohort includes 658 participants with a mean age of 57.3 ± 16.3 years, 66% women. Brachial BP was 126.6 ± 16.4 mm Hg and 79.9 ± 11.5 mm Hg, and central BP was 115.8 ± 15.4 mm Hg and 81.2 ± 11.6 mm Hg, respectively, for systolic and diastolic BP. Mean pulse wave velocity (PWV) was 8.5 ± 2.3 m/s, and the augmentation index was 23.6 ± 15.6%. The proportion of participants with increased AS was 19.8%. The overall best-fitting model for AS included age, gender, aortic PP, visceral fat, HDL cholesterol, AIx@75, total vascular resistance, hypertension, and diabetes, corresponding to an AUC of 0.910 (CI: 0.883, 0.937; P < 0.001) in the ROC curve analysis. The preliminary results of this pioneering large-scale study measuring arterial function in community pharmacies provide the grounds for the operationalization of subclinical target organ damage screening in pharmacies, as a strategy to improve cardiovascular risk monitoring and to promote adherence to treatment.
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Switching Dipeptidyl Peptidase-4 Inhibitors to Tofogliflozin, a Selective Inhibitor of Sodium-Glucose Cotransporter 2 Improve Arterial Stiffness Evaluated by Cardio-Ankle Vascular Index in Patients with Type 2 Diabetes: A Pilot Study.
Bekki, M, Tahara, N, Tahara, A, Igata, S, Honda, A, Sugiyama, Y, Nakamura, T, Sun, J, Kumashiro, Y, Matsui, T, et al
Current vascular pharmacology. 2019;(4):411-420
Abstract
BACKGROUND We have found that anagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4) significantly ameliorates arterial stiffness in Type 2 Diabetes Mellitus (T2DM) patients compared with an equivalent hypoglycaemic agent, glimepiride. However, it remains unclear whether switching DPP-4 inhibitors to tofogliflozin, a selective inhibitor of Sodium-Glucose Cotransporter 2 (SGLT2) improves arterial stiffness in T2DM patients. METHODS Nineteen T2DM patients who had received DPP-4 inhibitors for at least 1 year were enrolled in this study. Clinical parameters and arterial stiffness evaluated by cardio-ankle vascular index (CAVI) were measured at baseline and after 6-months treatment with tofogliflozin. RESULTS At 6 months after switching to tofogliflozin, CAVI, waist circumference, body weight, body mass index, subcutaneous and visceral fat volume, white blood cell number, fasting plasma insulin, uric acid, aspartate transaminase (AST), γ-glutamyl transferase (GTP), and advanced glycation end products (AGEs) were significantly reduced, while red blood cell number, haemoglobin, and HbA1c values were increased. When stratified by median values of change in CAVI after switching to tofogliflozin (ΔCAVI), baseline serum levels of AGEs were significantly higher in the low ΔCAVI group (high responder) than in the high one (low responder). ΔAST and ΔGTP were positively correlated with ΔCAVI. CONCLUSION The present study suggests that switching DPP-4 inhibitors to tofogliflozin ameliorates arterial stiffness in T2DM patients partly via improvement of liver function. Baseline serum levels of AGEs may identify patients who improve arterial stiffness more after treatment with tofogliflozin.
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The modifying effect of the MTHFR genotype on the association between folic acid supplementation and pulse wave velocity: Findings from the CSPPT.
Yang, X, Zhang, M, Song, R, Liu, C, Huo, Y, Qian, G
Cardiovascular therapeutics. 2018;(6):e12473
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OBJECTIVE In a subgroup analysis of the China Stroke Primary Prevention Trial, we aimed to explore the impact of folic acid supplementation on arterial stiffness and assess the modifying effect of the methylenetetrahydrofolate reductase (MTHFR) gene in Chinese patients with hypertension. METHODS This prospective study enrolled 2529 hypertensive Chinese patients. Participants were randomized to receive treatment with either a combination of enalapril and folic acid or enalapril. Brachial-ankle pulse wave velocity (PWV) was measured by trained medical staff using PWV instruments at both baseline and exit visits, approximately 5 years after enrollment. This trial was registered with clinicaltrials.gov (NCT00794885). RESULTS During the follow-up, change in folate was significantly and independently correlated with change in ba-PWV in study patients (β = -1.31, P < 0.001). Individuals with CC genotype had a significantly greater PWV response to folic acid supplementation than did carriers of the T allele (β = -2.79, P < 0.001 for CC homozygotes compared with β = -0.56, P = 0.464 for TT homozygotes). The positive effect of folic acid on improved PWV was modified by the MTHFR genotype (P for interaction = 0.034). CONCLUSION In a subgroup of Chinese hypertensive patients who had received 5-year antihypertensive therapy, increases in folate status were associated with higher reductions in PWV, and individuals with the CC genotype showed greatest PWV response to folic acid supplementation.
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The matrix proteins aggrecan and fibulin-1 play a key role in determining aortic stiffness.
Yasmin, , Maskari, RA, McEniery, CM, Cleary, SE, Li, Y, Siew, K, Figg, NL, Khir, AW, Cockcroft, JR, Wilkinson, IB, et al
Scientific reports. 2018;(1):8550
Abstract
Stiffening of the aorta is an important independent risk factor for myocardial infarction and stroke. Yet its genetics is complex and little is known about its molecular drivers. We have identified for the first time, tagSNPs in the genes for extracellular matrix proteins, aggrecan and fibulin-1, that modulate stiffness in young healthy adults. We confirmed SNP associations with ex vivo stiffness measurements and expression studies in human donor aortic tissues. Both aggrecan and fibulin-1 were found in the aortic wall, but with marked differences in the distribution and glycosylation of aggrecan reflecting loss of chondroitin-sulphate binding domains. These differences were age-dependent but the striking finding was the acceleration of this process in stiff versus elastic young aortas. These findings suggest that aggrecan and fibulin-1 have critical roles in determining the biomechanics of the aorta and their modification with age could underpin age-related aortic stiffening.
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The effect of sacubitril/valsartan compared to olmesartan on cardiovascular remodelling in subjects with essential hypertension: the results of a randomized, double-blind, active-controlled study.
Schmieder, RE, Wagner, F, Mayr, M, Delles, C, Ott, C, Keicher, C, Hrabak-Paar, M, Heye, T, Aichner, S, Khder, Y, et al
European heart journal. 2017;(44):3308-3317
Abstract
AIMS: Progressive aortic stiffening eventually leads to left ventricular (LV) hypertrophy and heart failure if left untreated. Anti-hypertensive agents have been shown to reverse this to some extent. The effects of sacubitril/valsartan (LCZ696), a dual-action angiotensin receptor blocker (ARB), and neprilysin inhibitor, on arterial stiffness and LV remodelling have not been investigated. METHODS AND RESULTS This was a randomized, multi-centre, double-blind, double-dummy, active-controlled, parallel group, study to compare the effects on cardiovascular remodelling of sacubitril/valsartan with those of olmesartan in patients with hypertension and elevated pulse pressure. Magnetic resonance imaging scans were used to assess LV mass and local aortic distensibility, at baseline and at 12 and 52 weeks after initiation of treatment. Central pulse and systolic pressure were determined using a SphymoCor® XCEL device at each time point. A total of 114 patients were included, with 57 in each treatment group. The mean age was 59.8 years, and 67.5% were male. Demographic characteristics did not vary between the two sets of patients. Left ventricular mass index decreased to a greater extent in the sacubitril/valsartan group compared to the olmesartan group from baseline to 12 weeks (-6.36 vs. -2.32 g/m2; P = 0.039) and from baseline to 52 weeks (-6.83 vs. -3.55 g/m2; P = 0.029). These differences remained significant after adjustment for systolic blood pressure (SBP) at follow-up (P = 0.036 and 0.019 at 12 and 52 weeks, respectively) and similar signals (though formally non-significant) were observed after adjusting for changes in SBP (P = 0.0612 and P = 0.0529, respectively). There were no significant differences in local distensibility changes from baseline to 12 or 52 weeks between the two groups; however, there was a larger reduction in central pulse pressure for the sacubitril/valsartan group compared to the olmesartan group (P = 0.010). CONCLUSION Since LV mass change correlates with cardiovascular prognosis, the greater reductions in LV mass indicate valuable advantages of sacubitril/valsartan compared to olmesartan. The finding that LV mass index decrease might be to some extent independent of SBP suggests that the effect of the dual-acting agent may go beyond those due to its BP-lowering ability.