Antihypertensive effects of SGLT2 inhibitors in type 2 diabetes

Muskiet, Marcel H.A.; Bommel, Erik J.M. van; Raalte, Daniël H. van

doi:10.1016/s2213-8587(15)00457-x

Cited by 33 publications

(18 citation statements)

References 9 publications

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“…Moreover, there are data showing that the blood pressure-lowering effect of SGLT2 inhibitors persists in patients with reduced glomerular filtration rate, diuresis, and natriuresis, suggesting that there is a mechanism other than natriuresis. 18) In the present study, tofogliflozin did not increase the natriuretic activity, but tofogliflozin tended to decrease a rise of the systolic blood pressure, relative to the control, throughout the treatment period in both DR and DS rats, and significantly decreased a rise of the systolic blood pressure, relative to the control, at the 9th week in DS rats. Other mechanism rather than increase of natriuresis might play an important role in lowering the blood pressure in this study.…”

Section: Discussioncontrasting

confidence: 51%

Inhibitory Effects of Tofogliflozin on Cardiac Hypertrophy in Dahl Salt-Sensitive and Salt-Resistant Rats Fed a High-Fat Diet

et al. 2019

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors are drugs for diabetes and might prevent heart failure. In this study, we investigated the effects of tofogliflozin, an SGLT2 inhibitor, on cardiac hypertrophy and metabolism in hypertensive rats fed a high-fat diet. Dahl salt-sensitive (DS) rats, hypertensive model rats, and Dahl salt-resistant (DR) rats, non-hypertensive model rats, were fed a high-salt and high-fat diet containing tofogliflozin (0.005%) for 9 weeks to examine the effects of this drug on cardiac hypertrophy and metabolism. Tofogliflozin tended to suppress a rise of the systolic blood pressure, relative to the control, throughout the treatment period in both DR and DS rats, and significantly suppress a rise of the systolic blood pressure, relative to the control, at the 9th week in DS rats. Tofogliflozin reduced cardiac hypertrophy (heart weight/body weight) not only in DS rats but also in DR rats. Histological analysis showed that tofogliflozin significantly decreased cardiomyocyte hypertrophy and perivascular fibrosis in both DS and DR rats. Tofogliflozin significantly decreased the expression levels of genes related to cardiac hypertrophy (encoding for natriuretic peptides A and B and interleukin-6), and to cardiac fibrosis (encoding for transforming growth factor-β1 and collagen type IV), in DS rats. Recent studies have shown that hypertrophied and failing hearts shift to oxidizing ketone bodies as a significant fuel source. We also performed metabolome analysis for ventricular myocardial tissue. Tofogliflozin reduced 3-hydroxybutyrate, a ketone body, and significantly decreased the expression levels of βhydroxybutyrate dehydrogenase 1 and 3-oxoacid CoA-transferase, which are related to ketone oxidization. In conclusion, tofogliflozin ameliorated cardiac hypertrophy and fibrosis along with reduction of ketone usage in myocardial tissue.

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Section: Discussioncontrasting

confidence: 51%

Inhibitory Effects of Tofogliflozin on Cardiac Hypertrophy in Dahl Salt-Sensitive and Salt-Resistant Rats Fed a High-Fat Diet

et al. 2019

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“…Second, according to a 2017 meta-analysis, SGLT2is cause persistent reductions in systolic BP (SBP) and diastolic BP (DBP) of ;5 and 2 mmHg, respectively (15). Several mechanisms that may underlie this antihypertensive effect have been suggested: 1) plasma volume contraction by osmotic diuresis; 2) weight loss; 3) improvements in vascular stiffness by reductions in body weight, hyperglycemia-associated oxidative stress, and/or endothelial glycocalyx protection from sodium overload; 4) reduced sympathetic nervous system activity; and 5) lower serum uric acid concentrations (16). Third, SGLT2is modestly alter lipid profiles by reductions in plasma triglycerides and increases in HDL cholesterol and LDL cholesterol (11).…”

Section: Pleiotropic Effectsmentioning

confidence: 99%

SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management

et al. 2018

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The progressive nature of type 2 diabetes (T2D) requires practitioners to periodically evaluate patients and intensify glucose-lowering treatment once glycemic targets are not attained. With guidelines moving away from a one-size-fits-all approach toward setting patient-centered goals and allowing flexibility in choosing a second-/third-line drug from the growing number of U.S. Food and Drug Administration-approved glucose-lowering agents, keen personalized management in T2D has become a challenge for health care providers in daily practice. Among the newer generation of glucose-lowering drug classes, sodium-glucose cotransporter 2 inhibitors (SGLT2is), which enhance urinary glucose excretion to lower hyperglycemia, have made an imposing entrance to the T2D treatment armamentarium. Given their unique insulin-independent mode of action and their favorable efficacy-to-adverse event profile and given their marked benefits on cardiovascular-renal outcome in moderate-to-high risk T2D patients, which led to updates of guidelines and product monographs, the role of this drug class in multidrug regimes is promising. However, despite many speculations based on pharmacokinetic and pharmacodynamic properties, physiological reasoning, and potential synergism, the effects of these agents in terms of glycemic and pleiotropic efficacy when combined with other glucose-lowering drug classes are largely understudied. In this perspective, we review the currently emerging evidence, discuss prevailing hypotheses, and elaborate on necessary future studies to clarify the potential risks and benefits of using an SGLT2i in dual combination with metformin and triple combination with a glucagon-like peptide 1 receptor agonist, dipeptidyl peptidase 4 inhibitor, or other glucose-lowering agent that is recommended by the American Diabetes Association and European Association for the Study of Diabetes (i.e., a sulfonylurea, thiazolidinedione, or insulin) to treat patients with T2D.

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“…Long-term weight loss and improvement in body fat distribution are proposed as additional pathways (26). Notably, clinical data dissociate longterm weight reduction with BP lowering, suggesting that only the initial weight lossdthat is mediated through plasma volume contractiondmay partially explain the BP-lowering effect of SGLT-2 inhibitors (1,21,27). Suppression of the renin-angiotensin-aldosterone and sympathetic nervous systems and improvement in nitric oxide bioactivity are less likely mechanistic explanations for cardiovascular protection in light of studies showing that these neuro-hormonal pathways remain unchanged in response to SGLT-2 inhibition (1,24,27).…”

Section: Discussionmentioning

confidence: 99%

Ambulatory Blood Pressure Reduction With SGLT-2 Inhibitors: Dose-Response Meta-analysis and Comparative Evaluation With Low-Dose Hydrochlorothiazide

Georgianos

Agarwal

2019

Diabetes Care

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Sodium-glucose cotransporter (SGLT)-2 inhibitors lower clinic and ambulatory blood pressure (BP), possibly through their natriuretic action. However, it remains unclear whether this BP-lowering effect is dose dependent and different from that of low-dose hydrochlorothiazide. The purpose of this meta-analysis was to quantify the association of the dose with response of ambulatory BP to SGLT-2 inhibition and to provide comparative evaluation with low-dose hydrochlorothiazide. RESEARCH DESIGN AND METHODS PubMed/MEDLINE, Embase, and Cochrane database of clinical trials from inception of each database through 22 August 2018. Randomized controlled trials (RCTs) reporting treatment effects of SGLT-2 inhibitors on ambulatory BP. We extracted data on the mean difference between the active treatment and placebo groups in change from baseline (CFB) of ambulatory systolic and diastolic BP. RESULTS We identified seven RCTs (involving 2,381 participants) comparing SGLT-2 inhibitors with placebo. Of these, two RCTs included low-dose hydrochlorothiazide as active comparator. CFB in 24-h systolic BP between SGLT-2 inhibitor and placebo groups was 23.62 mmHg (95% CI 24.29, 22.94) and in diastolic BP was 21.70 mmHg (95% CI 22.13, 21.26). BP lowering with SGLT-2 inhibition was more potent during daytime than during nighttime. The CFB in ambulatory BP was comparable between low-dose and high-dose subgroups and was similar to that for low-dose hydrochlorothiazide. Eligible RCTs did not evaluate cardiovascular outcomes/mortality. CONCLUSIONS This meta-analysis shows that SGLT-2 inhibitors provoke an average reduction of systolic/diastolic BP 3.62/1.70 mmHg in 24-h ambulatory BP. This BP-lowering effect remains unmodified regardless of the dose of SGLT-2 inhibitor and is comparable with BP-lowering efficacy of low-dose hydrochlorothiazide.

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Antihypertensive effects of SGLT2 inhibitors in type 2 diabetes

Cited by 33 publications

References 9 publications

Inhibitory Effects of Tofogliflozin on Cardiac Hypertrophy in Dahl Salt-Sensitive and Salt-Resistant Rats Fed a High-Fat Diet

Inhibitory Effects of Tofogliflozin on Cardiac Hypertrophy in Dahl Salt-Sensitive and Salt-Resistant Rats Fed a High-Fat Diet

SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management

Ambulatory Blood Pressure Reduction With SGLT-2 Inhibitors: Dose-Response Meta-analysis and Comparative Evaluation With Low-Dose Hydrochlorothiazide

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