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Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence.

ABSTRACT: Patients with type 2 diabetes (T2D) are often overweight/obese and affected by arterial hypertension, dyslipidaemia, and have high serum levels of uric acid. Moreover, T2D patient have a higher risk of developing cardiovascular or renal complications, which are leading causes of morbidity and mortality in this population. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a new class of glucose-lowering medications that block the reabsorption of glucose in the kidney, thereby increasing urinary glucose excretion, and lowering blood glucose levels. The beneficial effects of SGLT2 inhibition extend beyond glycaemic control, and include improvement in blood pressure, body weight, uric acid concentrations, liver steatosis, oxidative stress, and inflammation. In dedicated cardiovascular outcome trials, SGLT2i treatment was associated with a significant reduction in the rate of cardiovascular events and renal endpoints. In this review, we summarize the evidence for extra-glycemic effects of SGLT2i and the potential mechanisms driving cardiorenal protection exerted by this class of medications.

SUBMITTER: Bonora BM

PROVIDER: S-EPMC6982447 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence.

Bonora Benedetta Maria BM Avogaro Angelo A Fadini Gian Paolo GP

Diabetes, metabolic syndrome and obesity : targets and therapy 20200121

Patients with type 2 diabetes (T2D) are often overweight/obese and affected by arterial hypertension, dyslipidaemia, and have high serum levels of uric acid. Moreover, T2D patient have a higher risk of developing cardiovascular or renal complications, which are leading causes of morbidity and mortality in this population. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a new class of glucose-lowering medications that block the reabsorption of glucose in the kidney, thereby increasing urin ...[more]

PMID: 32021362

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Project description:Aims/hypothesisGlucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are novel drugs which have recently seen rapid uptake in the treatment of type 2 diabetes and obesity. The paucity of data regarding their safety during pregnancy and lactation causes a dilemma for the physician. The aim of the present study was to systematically review all available data on the offspring effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation.MethodsWe systematically searched PubMed, clinicaltrials.gov, FDA and EMA product information on GLP-1 agonists and SGLT2 inhibitors in pregnancy and lactation from inception up to 19 April 2022 without language restrictions. We approached both the Netherlands Pharmacovigilance Centre Lareb on January 17th 2023 and the Teratology Information Service (TIS) of Switzerland on February 6th 2023. Eligible studies investigating the safety (including congenital anomalies, fetal growth, perinatal demise) in animals or humans, or reporting the degree of transfer of these drugs to the fetus, breast milk or breastfed neonate. Two reviewers independently assessed and selected studies for inclusion and subsequently resolved discrepancies by discussion.ResultsWe included 39 records (n=9 theoretical; based on drug properties, n=7 human; n=23 animal, including 76 human offspring, and an unknown number of animal offspring as these numbers could not be retrieved from the FDA and EMA product information). In animal studies, GLP1-agonists were associated with reduced fetal weight and/or growth, delayed ossification and skeletal variants, usually associated with a reduction in maternal weight gain and decreased food consumption. Exendin-4 (GLP1-agonist) was not transported across the maternal-fetal placental interface. In human studies, exenatide (GLP1-agonist) showed a fetal-to-maternal peptide concentration ratio of ≤ 0.017 in ex vivo human placental perfusion in a single placenta. Liraglutide (GLP1-agonist) showed no significant maternal to fetal transfer at least 3.5 hours after maternal exposure in a human study with one subject. In animal studies, GLP-1 agonists were excreted in breast milk; human data on excretion were not available. In animal studies, SGLT2 inhibitors were generally safe during the first trimester but exposure during postnatal day 21 to 90 in juvenile rats, a period coinciding with the late second and third trimester of human renal development, caused dilatation of the renal pelvis and tubules. Human data consisted of a pharmaceutical database of inadvertent pregnancies during SGLT2 inhibitor use, which found an increase in miscarriages and congenital malformations. In animal studies SGLT2 inhibitors were excreted in breast milk and affected neonatal growth, but human data are not available.Conclusion/interpretationWe found evidence for adverse offspring effects of GLP-1 agonists and SGLT2 inhibitors also in human studies. Our findings broadly support the advice to discontinue GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation, and also support the ongoing registration of pregnancy outcomes in pharmacological databases since the amount of available data is scarce and mostly limited to animal studies.Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=219877.

Project description:AimsNo studies have comprehensively compared the efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitors, renin-angiotensin system (RAS) inhibitors, and angiotensin receptor neprilysin (ARN) inhibitors based on different type of heart failure, including heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). The aim of this network meta-analysis was to evaluate the relative efficacy of SGLT2 inhibitor (SGLT2i), RAS inhibitor (RASi) and ARN inhibitor (ARNI) in different types of heart failure.MethodsA systemic literature search was performed from inception to 19 November 2022 for randomized control trials assessing the risk of cardiovascular (CV) death or hospitalization for heart failure (HHF) of these drugs in HF. A network meta-analysis was performed. Risk ratio (RR) with 95% confidence intervals (CI) were synthesized.ResultsSeventeen studies were selected with a total of 61 489 patients. In patients with HFrEF, ARNI led to a reduced risk of a composite outcome of CV death or HHF when compared with placebo (RR = 0.83, 95% CI 0.77-0.89). Similar trends were observed when focusing on the outcome of CV death or HHF alone. In patients with HFpEF, SGLT2i showed the beneficial effects on the CV death or HHF events when compared with placebo and RASi (RR = 0.82, 95% CI 0.74-0.92; RR = 1.16, 95% CI 1.02-1.31). For CV death, all these three drugs could not show beneficial effects in HFpEF. For the incidence of HHF in HFpEF, both SGLT2i and ARNI demonstrated the beneficial effects but SGLT2i was superior to ARNI. There were no differences in the events of discontinuation under these drugs when compared with placebo or each other in either HFrEF or HFpEF patients. SGLT2i showed the least renal injury among these interventions in HFrEF and there were no differences in the incidence of renal injury of these interventions in HFpEF.ConclusionsAmong these drugs, ARNI showed the greatest ability to lower the incidence of CV death or HHF and SGLT2i exerted the least renal injury in patients with HFrEF. In patients with HFpEF, SGLT2i was associated with a reduction in the risk of CV death or HHF. There were no differences in the incidence of renal injury of these interventions in HFpEF. The intolerance of these drugs were comparable in both HFrEF and HFpEF.

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Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence.

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Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence.

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