Combination Treatment of SGLT2 Inhibitors and GLP-1 Receptor Agonists: Symbiotic Effects on Metabolism and Cardiorenal Risk

Goncalves, Edison; Bell, David S. H.

doi:10.1007/s13300-018-0420-6

Cited by 44 publications

(35 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…41 Clearly, a targeted therapy for AEC is needed, one that integrates mechanism of action of drugs with the clinical impact of these medications on AEC bleeding. 42,43 Our in vitro findings are consistent with earlier studies that have shown increased VEGF and basic fibroblast growth factor expression in human colonic AEC along with increased VEGF in circulating plasma. 44,45 In this study, we observed increased VEGFA expression in the involved (AEC) tissue, whereas expression of HIF1α was increased in noninvolved tissue (tissue surrounding the AEC).…”

Section: Discussionsupporting

confidence: 91%

Therapeutic Opportunities for Intestinal Angioectasia‐ Targeting PPARγ and Oxidative Stress

Sarangdhar

Yacyshyn

Gruenzel

et al. 2020

Clinical Translational Sci

View full text Add to dashboard Cite

Recurrent and acute bleeding from intestinal tract angioectasia (AEC) presents a major challenge for clinical intervention. Current treatments are empiric, with frequent poor clinical outcomes. Improvements in understanding the pathophysiology of these lesions will help guide treatment. Using data from the US Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS), we analyzed 12 million patient reports to identify drugs inversely correlated with gastrointestinal bleeding and potentially limiting AEC severity. FAERS analysis revealed that drugs used in patients with diabetes and those targeting PPARγ-related mechanisms were associated with decreased AEC phenotypes (P < 0.0001). Electronic health records (EHRs) at University of Cincinnati Hospital were analyzed to validate FAERS analysis. EHR data showed a 5.6% decrease in risk of AEC and associated phenotypes in patients on PPARγ agonists. Murine knockout models of AEC phenotypes were used to construct a gene-regulatory network of candidate drug targets and pathways, which revealed that wound healing, vasculature development and regulation of oxidative stress were impacted in AEC pathophysiology. Human colonic tissue was examined for expression differences across key pathway proteins, PPARγ, HIF1α, VEGF, and TGFβ1. In vitro analysis of human AEC tissues showed lower expression of PPARγ and TGFβ1 compared with controls (0.55 ± 0.07 and 0.49 ± 0.05). National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) RNA-Seq data was analyzed to substantiate human tissue findings. This integrative discovery approach showing altered expression of key genes involved in oxidative stress and injury repair mechanisms presents novel insight into AEC etiology, which will improve targeted mechanistic studies and more optimal medical therapy for AEC. Angioectasia (AEC) lesions are common vascular abnormalities characterized by ectatic, dilated, and proliferated blood vessels, and are a significant source of obscure gastrointestinal (GI) bleeding. These aberrant blood vessels are typically < 10 mm in diameter, thin walled with little or no smooth muscle, malformed, and uncommunicative, 1,2 and symptomatically present with overt and occult GI hemorrhage, 1 melena, hematochezia, and resulting anemia. 1,3 The clinical

show abstract

Section: Discussionsupporting

confidence: 91%

Therapeutic Opportunities for Intestinal Angioectasia‐ Targeting PPARγ and Oxidative Stress

Sarangdhar

Yacyshyn

Gruenzel

et al. 2020

Clinical Translational Sci

View full text Add to dashboard Cite

show abstract

“…For example, the incidence of MACE in the placebo group of the SGLT2i studies is higher than that of the GLP-1a studies, generating substantial, non-statistically scalable heterogeneity. The combination of GLP-1RAs and SGLT2i is an exciting speculation for the future, as this combined therapy may produce additive cardiovascular benefits in patients with T2DM [155]. The development of other peptide hormones that stimulate insulin secretion and regulate appetite is promising, such as dual co-agonists developed in a single molecule, the stimulation of both the GLP-1 and peptide-YY receptor pathways and the co-administration of glucagon and GLP-1 [42].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data

Sposito

Berwanger

Carvalho

et al. 2018

Cardiovasc Diabetol

111

View full text Add to dashboard Cite

Patients with type 2 diabetes (T2DM) have a substantial risk of developing cardiovascular disease. The strong connection between the severity of hyperglycaemia, metabolic changes secondary to T2DM and vascular damage increases the risk of macrovascular complications. There is a challenging demand for the development of drugs that control hyperglycaemia and influence other metabolic risk factors to improve cardiovascular outcomes such as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina and heart failure (major adverse cardiovascular events). In recent years, introduction of the new drug class of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has changed the treatment landscape as GLP-1RAs have become well-established therapies in T2DM. The benefits of GLP-1RAs are derived from their pleiotropic effects, which include appetite control, glucose-dependent secretion of insulin and inhibition of glucagon secretion. Importantly, their beneficial effects extend to the cardiovascular system. Large clinical trials have evaluated the cardiovascular effects of GLP-1RAs in patients with T2DM and elevated risk of cardiovascular disease and the results are very promising. However, important aspects still require elucidation, such as the specific mechanisms involved in the cardioprotective effects of these drugs. Careful interpretation is necessary because of the heterogeneity across the trials concerning the definition of cardiovascular risk or cardiovascular disease, baseline characteristics, routine care and event rates. The aim of this review is to describe the main clinical aspects of the GLP-1RAs, compare them using data from both the mechanistic and randomized controlled trials and discuss potential reasons for improved cardiovascular outcomes observed in these trials. This review may help clinicians to decide which treatment is most appropriate in reducing cardiovascular risk in patients with T2DM.

show abstract

“…The effects of SGLT2 inhibitors and GLP-1 receptor agonists are favourable in patients with T2DM and various cardiovascular risk factors. As these agents exert their antihyperglycaemic and cardiovascular protective effects via different mechanisms, combination therapy is expected to provide additive effects over those achieved with either agent as monotherapy or in combination with other glucose-lowering agents [ 14 – 16 ].…”

Section: Introductionmentioning

confidence: 99%

Safety and Efficacy of Empagliflozin as Add-On Therapy to GLP-1 Receptor Agonist (Liraglutide) in Japanese Patients with Type 2 Diabetes Mellitus: A Randomised, Double-Blind, Parallel-Group Phase 4 Study

et al. 2019

View full text Add to dashboard Cite

Introduction Empagliflozin, a highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, improves glycaemic control in patients with type 2 diabetes mellitus (T2DM) by inducing urinary glucose excretion. Combination therapy with empagliflozin and glucagon-like peptide-1 (GLP-1) receptor agonists had not previously been assessed, so we investigated the safety, tolerability and efficacy of empagliflozin as an add-on therapy to liraglutide, a GLP-1 receptor agonist. Methods This was a randomised, double-blind, parallel-group phase 4 trial of empagliflozin (10 mg or 25 mg) for 52 weeks as an add-on therapy to liraglutide (0.9 mg/day) in Japanese patients with T2DM insufficiently controlled by liraglutide alone. Results 59.4% (19/32) and 66.7% (22/33) of patients in the empagliflozin 10 mg and 25 mg groups, respectively, reported at least one adverse event (AE). 9.4% (3/32) and 21.2% (7/33) of patients, respectively, reported drug-related AEs (primary endpoint). From baseline to week 52, adjusted mean changes with empagliflozin 10 mg and 25 mg, respectively, were: − 0.55 (standard error: 0.15) and − 0.77 (0.14)% for glycated haemoglobin; − 32.5 (4.6) and − 36.0 (4.5) mg/dL for fasting plasma glucose; − 2.6 (0.4) and −3.1 (0.3) kg for body weight; − 6.7 (2.2) and − 8.4 (2.1) mmHg for systolic blood pressure; and − 3.0 (1.2) and − 4.7 (1.1) mmHg for diastolic blood pressure. Conclusion Empagliflozin as an add-on to liraglutide for 52 weeks was well tolerated and led to clinically meaningful and sustained improvements in glycaemic control, body weight and blood pressure in Japanese patients with T2DM. Trial Registration ClinicalTrials.gov with the identifier NCT02589626. Funding Nippon Boehringer Ingelheim Co. Ltd. Electronic supplementary material The online version of this article (10.1007/s13300-019-0604-8) contains supplementary material, which is available to authorized users.

show abstract

Combination Treatment of SGLT2 Inhibitors and GLP-1 Receptor Agonists: Symbiotic Effects on Metabolism and Cardiorenal Risk

Cited by 44 publications

References 33 publications

Therapeutic Opportunities for Intestinal Angioectasia‐ Targeting PPARγ and Oxidative Stress

Therapeutic Opportunities for Intestinal Angioectasia‐ Targeting PPARγ and Oxidative Stress

GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data

Safety and Efficacy of Empagliflozin as Add-On Therapy to GLP-1 Receptor Agonist (Liraglutide) in Japanese Patients with Type 2 Diabetes Mellitus: A Randomised, Double-Blind, Parallel-Group Phase 4 Study

Contact Info

Product

Resources

About