Blood pressure effects of sodium–glucose co-transport 2 (SGLT2) inhibitors

doi:10.1016/j.jash.2014.02.003

Journal of the American Society of Hypertension

Volume 8, Issue 5, May 2014, Pages 330-339

https://doi.org/10.1016/j.jash.2014.02.003 Get rights and content

Abstract

Management of hypertension in diabetes is critical for reduction of cardiovascular mortality and morbidity. While blood pressure (BP) control has improved over the past two decades, the control rate is still well below 50% in the general population of patients with type 2 diabetes mellitus (T2DM). A new class of oral glucose-lowering agents has recently been approved; the sodium–glucose co-transporter 2 (SGLT2) inhibitors, which act by eliminating large amounts of glucose in the urine. Two agents, dapagliflozin and canagliflozin, are currently approved in the United States and Europe, and empagliflozin and ipragliflozin have reported Phase 3 trials. In addition to glucose lowering, SGLT2 inhibitors are associated with weight loss and act as osmotic diuretics, resulting in a lowering of BP. While not approved for BP-lowering, they may potentially aid BP goal achievement in people within 7–10 mm Hg of goal. It should be noted that the currently approved agents have side effects that include an increased incidence of genital infections, predominantly in women. The approved SGLT2 inhibitors have limited use based on kidney function and should be used only in those with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m² for dapagliflozin and ≥45 mL/min/1.73 m² for canagliflozin. Cardiovascular outcome trials are ongoing with these agents and will be completed within the next 4–5 years.

Section snippets

Role of the Kidneys in Regulating Glucose

The main function of the kidney is to maintain fluid and electrolyte homeostasis. It does this in part by filtering the composition of blood and removal of waste products, such as urea, ammonium, and uric acid, by urinary excretion. During this filtration process, useful molecules are also filtered, and must be reabsorbed by the kidney to prevent their loss in the urine. One such useful molecule is glucose; plasma glucose is freely filtered in the kidney glomeruli, with kidneys of a healthy

Blood Pressure and T2DM

In addition to maintaining fluid and electrolyte homeostasis, the kidneys also play an important role in maintaining and regulating BP. They do this through the maintenance of extracellular fluid, regulated by the renin-angiotensin-aldosterone system.⁶ If BP increases, the kidneys increase their excretion of salt and water, so that blood volume decreases and BP returns to normal. Conversely, if BP decreases, the kidneys decrease their excretion of salt and water, so that blood volume increases

SGLT2 Inhibitors and BP Reduction: Clinical Data

As with all new therapies for T2DM, SGLT2 inhibitors have been extensively studied as monotherapy as well as in a range of treatment regimens, and in different types of patients. Glucose control was the primary endpoint of these studies, and effects on BP and weight were typically studied as secondary endpoints or reported as safety outcomes. A recent meta-analysis of 21 placebo-controlled studies published by April 2013 showed a mean change in SBP of −3.77 mm Hg (95% confidence interval [CI],

SGLT2 Inhibitors, BP, and Weight Reduction

Treatment with SGLT2 inhibitors has consistently been associated with a reduction in body weight in Type 2 diabetic patients, with reductions around 2–3 kg over 3-month clinical trials.⁵ Table 1 summarizes the changes in weight reported in the 12-week trials that reported BP outcomes.

Glucose excreted in the urine as a result of SGLT2 inhibition corresponds to approximately 200–300 calories per day, which could in turn lead to a reduction in body fat. The weight reduction could also be a result,

Summary

SGLT2 inhibitors are a new class of drugs, with a substantial body of clinical trial evidence supporting their use in patients with T2DM. It is clear that these drugs can provide significant improvements in measures of glucose control, and offer a useful addition to the range of therapies for glycemic control. It is also established that patients taking SGLT2 inhibitors can expect to lose weight, and that the majority of weight lost corresponds to fat mass.

While not approved as antihypertensive

Acknowledgments

The authors are fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version of the review that reflects the authors' interpretation and conclusions. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Sarah Knott and Geraldine Thompson, of Envision Scientific Solutions, during the preparation of this review. Boehringer Ingelheim was given the opportunity to check the

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Cited by (184)

Dapagliflozin and Blood Pressure in Patients with Chronic Kidney Disease and Albuminuria
2024, American Heart Journal
Sodium–glucose cotransporter 2 inhibitors decrease blood pressure in patients with type 2 diabetes, but the consistency and magnitude of blood pressure lowering with dapagliflozin in patients with chronic kidney disease (CKD) is unknown. We conducted a prespecified analysis of the DAPA-CKD trial to investigate the effect of dapagliflozin on systolic blood pressure (SBP) in patients with CKD, with and without type 2 diabetes.
A total of 4304 adults with baseline estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73m² and urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g were randomized to either dapagliflozin 10 mg or placebo once daily; median follow-up was 2.4 years. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or death from a kidney or cardiovascular cause. Change in SBP was a prespecified outcome.
Baseline mean (SD) SBP was 137.1 mmHg (17.4). By Week 2, dapagliflozin compared to placebo reduced SBP by 3.6 mmHg (95% CI 2.8-4.4 mmHg), an effect maintained over the duration of the trial (2.9 mmHg, 2.3-3.6 mmHg). Time-averaged reductions in SBP were 3.2 mmHg (2.5-4.0 mmHg) in patients with diabetes and 2.3 mmHg (1.2-3.4 mmHg) in patients without diabetes. The time-averaged effect of dapagliflozin on diastolic blood pressure (DBP) was 1.0 mmHg (0.6-1.4 mmHg); 0.8 mmHg (0.4-1.3 mmHg) in patients with diabetes and 1.4 mmHg (0.7-2.1 mmHg) in patients without diabetes. Benefits of dapagliflozin on the primary composite and secondary endpoints were evident across the spectrum of baseline SBP and DBP.
In patients with CKD and albuminuria, randomization to dapagliflozin was associated with modest reductions in systolic and diastolic BP.
Simultaneous SGLT2 inhibition and caloric restriction improves insulin resistance and kidney function in OLETF rats
2023, Molecular and Cellular Endocrinology
Citation Excerpt :
We suggest that two factors in the liver have a major influence in maintaining a normal basal glucose in OLETF: (1) increased gluconeogenesis as a response to the combination of treatments, observed in the form of increased liver glucose: G6P ratio, and (2) a reduction of glycolysis in response to SGLT2i, shown as a reduction in hexokinase activity in the liver, and in response to CR, shown as a reduction in the concentration of glyceric acid, a product of glycolysis, in plasma. Several clinical trials have shown a modest but consistent reduction in SBP in SGLT2i treated patients compared to other antidiabetic drugs after one to two weeks of treatment (Oliva and Bakris, 2014). However, the mechanisms are not well-defined, but may not be associated with reducing extracellular volume or a reduction of the RAAS activity in the present study.
SGLT2 inhibitors (SGLT2i) are emerging as a novel therapy for type 2 diabetes due to their effective hypoglycemic and potential cardio- and nephroprotective effects, while caloric restriction (CR) is a common behavioral modification to improve adiposity and insulin resistance. Therefore, both interventions simultaneously may potentially further improve metabolic syndrome by enhancing carbohydrate metabolism. To test this hypothesis, cohorts of 10-week old, male Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats were treated with SGLT2i (10 mg luseoglifozin/kg/day x 4 wks) (OLETF only) and/or 30% CR (2 wks at 12 weeks of age). CR maintained body mass in both strains while SGLT2i alone did not have any effect on body mass. Simultaneous treatments decreased SBP in OLETF vs SGLT2i alone, decreased insulin resistance index (IRI), and increased creatinine clearance vs OLETF ad lib. Conversely, CR decreased albuminuria independent of SGLT2i. In conclusion, SGLT2i treatment by itself did not elicit significant improvements in insulin resistance, kidney function or blood pressure. However, when combined with CR, these changes where more profound than with CR alone without inducing chronic hypoglycemia.
Information and consensus document for the detection and management of chronic kidney disease
2022, Nefrologia
Chronic kidney disease (CKD) is a major public health problem worldwide that affects more than 10% of the Spanish population. CKD is associated with high comorbidity rates, poor prognosis and major consumption of health system resources. Since the publication of the last consensus document on CKD seven years ago, little evidence has emerged and few clinical trials on new diagnostic and treatment strategies in CKD have been conducted, apart from new trials in diabetic kidney disease. Therefore, CKD international guidelines have not been recently updated. The rigidity and conservative attitude of the guidelines should not prevent the publication of updates in knowledge about certain matters that may be key in detecting CKD and managing patients with this disease. This document, also prepared by 10 scientific associations, provides an update on concepts, clarifications, diagnostic criteria, remission strategies and new treatment options.
The evidence and the main studies published on these aspects of CKD have been reviewed. This should be considered more as an information document on CKD. It includes an update on CKD detection, risk factors and screening; a definition of renal progression; an update of remission criteria with new suggestions in the older population; CKD monitoring and prevention strategies; management of associated comorbidities, particularly in diabetes mellitus; roles of the Primary Care physician in CKD management; and what not to do in Nephrology.
The aim of the document is to serve as an aid in the multidisciplinary management of the patient with CKD based on current recommendations and knowledge.
La enfermedad renal crónica (ERC) es un importante problema de salud pública a nivel mundial afectando a mas del 10% de la población española. Se asocia a elevada comorbilidad, mal pronóstico, así como a un gran consumo de recursos en el sistema sanitario. Desde la publicación del último documento de consenso sobre ERC publicado hace siete años, han sido escasas las evidencias y los ensayos clínicos que hayan mostrado nuevas estrategias en el diagnóstico y tratamiento de la ERC, con excepción de los nuevos ensayos en la enfermedad renal diabética. Esta situación ha condicionado que no se hayan actualizado las guías internacionales en este aspecto. Esta rigidez y actitud conservadora de las guías no debe impedir la publicación de actualizaciones en el conocimiento en algunos aspectos, que pueden ser clave en la detección y manejo del paciente con ERC. En este documento, elaborado en conjunto con diez sociedades científicas, se muestra una actualización sobre conceptos, aclaraciones, criterios diagnósticos, estrategias de remisión y nuevas opciones terapéuticas.
Se han revisado las evidencias y los principales estudios publicados en estos aspectos de la ERC, considerándose más bien un documento de información sobre este padecimiento. El documento incluye una actualización sobre la detección de la ERC, factores de riesgo, cribado, definición de progresión renal, actualización en los criterios de remisión con nuevas sugerencias en la población anciana, monitorización y estrategias de prevención de la ERC, manejo de comorbilidades asociadas, especialmente en diabetes mellitus, funciones del médico de Atención Primaria en el manejo de la ERC y qué no hacer en Nefrología.
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Use of Sodium-Glucose Cotransporter-2 Inhibitors in Renal Transplant Patients With Diabetes: A Brief Review of the Current Literature
2022, Canadian Journal of Diabetes
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of oral hypoglycemic agents commonly prescribed in type 2 diabetes (T2D). They have been shown to slow the progression of diabetic nephropathy and improve cardiovascular outcomes in high-risk individuals, although major cardiovascular and renal outcome clinical trials have excluded renal transplant patients. The aim of this review was to determine the outcomes and safety with use of SGLT2 inhibitors in renal transplant patients with diabetes. We conducted a review of randomized controlled trials, cohort studies, case series and case reports that assessed use of SGLT2 inhibitors in patients post–renal transplant with either pre-existing T2D or new-onset diabetes after transplant. The outcomes assessed included blood pressure, renal allograft function (estimated glomerular filtration rate), proteinuria (urinary albumin-to-creatinine ratio), glycemic control, body weight and adverse effects. A total of 9 studies, which included 144 patients, were reviewed. SGLT2 inhibitor use in renal transplant patients demonstrates either a small or nonsignificant reduction in blood pressure and results in overall stable renal allograft function. It also results in modest improvement in glycemic control as well as weight reduction. The incidence of adverse effects is low and reversible, as reported in previous nontransplant clinical trials. Overall, our findings suggest beneficial outcomes with no significant adverse effects or complications with the use of SGLT2 inhibitors in renal transplant patients with diabetes; however, these findings are based on small trials, and thus well-designed trials in this population are warranted.
Les inhibiteurs SGLT-2 (sodium-glucose cotransporter-2) font partie d’une nouvelle classe d’hypoglycémiants par voie orale communément prescrits contre le diabète de type 2 (DT2). Il a été démontré que les individus exposés à un risque élevé connaissent un ralentissement de la progression de la néphropathie diabétique et ont de meilleurs résultats cardiovasculaires, bien que les patients qui ont une greffe rénale aient été exclus des essais cliniques sur les résultats rénaux et cardiovasculaires. L’objectif de cette revue était de déterminer les résultats et l’innocuité des inhibiteurs SGLT-2 chez les patients diabétiques qui ont une greffe rénale. Nous avons réalisé une revue d’essais cliniques à répartition aléatoire, d’études de cohorte, des séries de cas et d’observations cliniques qui portaient sur l’utilisation des inhibiteurs SGLT-2 chez les patients après la greffe rénale qui avaient soit un DT2 préexistant ou un diabète post-greffe d’apparition récente. Les résultats évalués étaient les suivants : la pression artérielle, le fonctionnement de l’allogreffe rénale (débit de filtration glomérulaire estimé), la protéinurie (ratio albuminurie:créatininurie), la régulation de la glycémie, le poids corporel et les effets indésirables. Nous avons passé en revue un total de 9 études, qui portaient sur 144 patients. L’utilisation des inhibiteurs SGLT-2 chez les patients qui ont une greffe rénale démontre soit une réduction modeste ou non significative de la pression artérielle et des résultats du fonctionnement global stable de l’allogreffe rénale. Elle entraîne aussi une amélioration modeste de la régulation de la glycémie ainsi que la diminution du poids. La fréquence des effets indésirables est faible et réversible, selon les essais cliniques précédents portant sur les patients non greffés. Dans l’ensemble, nos résultats montrent des résultats bénéfiques sans complications ou effets indésirables significatifs avec l’utilisation des inhibiteurs SGLT-2 chez les patients diabétiques qui ont une greffe rénale. Toutefois, ces résultats portent sur des essais de petite envergure et, par conséquent, des essais bien conçus dans cette population sont justifiés.
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Understanding glucose homeostasis is critical to the study of both health and disease. In this chapter, we follow carbohydrates as they start their journey from a planned meal to food on the plate, through consumption and secretion. We focus on glucose transport from the gastrointestinal tract to the blood and from the blood and into cells, glucose storage and release, and glucose secretion. Special attention is given to diabetes, of which the prevalence has risen dramatically in countries of all income levels during recent years. We also describe current approaches to pharmaceutical management of diabetes, highlighting the roles of peptidomimetic molecules in the field.

View all citing articles on Scopus

: The authors received no compensation related to the development of the manuscript.

: Dr Bakris is a consultant for Medtronic, Relapsya, Takeda, Abbott, CVRx, Johnson & Johnson, Eli Lilly, and the US Food and Drug Administration.

: Dr Oliva has no conflicts of interest to report.

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Review ArticleBlood pressure effects of sodium–glucose co-transport 2 (SGLT2) inhibitors

Abstract

Section snippets

Role of the Kidneys in Regulating Glucose

Blood Pressure and T2DM

SGLT2 Inhibitors and BP Reduction: Clinical Data

SGLT2 Inhibitors, BP, and Weight Reduction

Summary

Acknowledgments

Lancet

Lancet

Lancet Diabetes Endocrinol

J Diabetes Complications

Biology of human sodium glucose transporters

Physiol Rev

Molecular physiology of sodium-glucose cotransporters

Physiol Rev

Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes

Diabetes Care

Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications

Diabet Med

Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis

Ann Int Med

KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease

Am J Kidney Dis

Diabetes and hypertension: is there a common metabolic pathway?

Curr Atheroscler Rep

Standards of medical care in diabetes−2014

Diabetes Care

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group

Lancet

Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin: a dose-finding study

Diabetes Obes Metab

Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin

J Clin Endocrinol Metab

Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes

Diabetes Obes Metab

Sodium-glucose co-transporter 2 inhibitors and the potential for cardiovascular risk reduction in patients with type 2 diabetes mellitus

Postgrad Med

Review Article
Blood pressure effects of sodium–glucose co-transport 2 (SGLT2) inhibitors