Making a case for the combined use of SGLT2 inhibitors and GLP1 receptor agonists for cardiorenal protection

ABSTRACT Sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) were initially approved to improve glycemic control in the treatment of type 2 diabetes. Clinical trials have also demonstrated beneficial effects with regards to cardiovascular and renal parameters. Beyond improving glycemic control, these therapies promote weight loss and lower blood pressure when used individually, and in an additive manner when used together. Accordingly, taking advantage of complementary mechanisms of action with the combined use of these two classes of agents to further improve cardiorenal outcomes is conceptually appealing, but has yet to be explored in detail in clinical trials. In this review, we discuss proposed mechanisms for renal protection, clinical benefits, and adverse events associated with the individual and combined use of SGLT2 inhibitors and GLP-1RA. The management of type 2 diabetes has significantly changed over the last few years, moving away from solely glycemic control towards the concurrent management of associated comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors and GLP-1RA in patients with type 2 diabetes.

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Effects of GLP-1RA and SGLT2i, Alone or in Combination, on Mouse Models of Type 2 Diabetes Representing Different Disease Stages

International Journal of Molecular Sciences ◽

10.3390/ijms222111463 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11463

Author(s):

Masao Koike ◽

Hitoki Saito ◽

Genta Kohno ◽

Masahiro Takubo ◽

Kentaro Watanabe ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glycemic Control ◽

Fatty Liver ◽

Glucose Transporter ◽

Hepatic Lipid Accumulation ◽

Beneficial Effects ◽

Glucose Transporter 2 ◽

Combined Use ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-dependent glucose transporter 2 inhibitor (SGLT2i), in addition to lowering glucose, have pleiotropic effects on the heart, kidneys, and liver. These drugs have thus come into widespread use for treating type 2 diabetes (T2DM). However, mechanistic comparisons and effects of combining these drugs have not been adequately studied. Employing diet-induced obese (DIO) mice and db/db mice as models of the early and advanced stages of T2DM, we evaluated effects of single or combined use of liraglutide (a GLP-1RA) and ipragliflozin (a SGLT2i). Treatments with liraglutide and/or ipragliflozin for 28 days improved glycemic control and reduced hepatic lipid accumulation similarly in DIO mice. In contrast, in db/db mice, despite similar favorable effects on fatty liver, liraglutide exerted no beneficial effects on glycemic control. Improved glycemic control in db/db mice treated with ipragliflozin was accompanied by increased pancreatic β-cell area and insulin content, both of which tended to rise further when ipragliflozin was combined with liraglutide. Our data suggest that liraglutide is more efficient at an earlier stage and ipragliflozin can be effective in both stages. In addition, their combined use is a potential option for treating advanced stage diabetes with fatty liver disease.

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Recent Advances in the Development of Type 2 Sodium-Glucose Cotransporter Inhibitors for the Treatment of Type 2 Diabetes Mellitus

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666210805112416 ◽

2021 ◽

Vol 21 ◽

Author(s):

Ana Karen Estrada ◽

Timoteo Delgado-Maldonado ◽

Edgar E. Lara-Ramírez ◽

Ana Verónica Martínez-Vázquez ◽

Eyra Ortiz-Lopez ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Clinical Trials ◽

Type 2 Diabetes Mellitus ◽

Adverse Effects ◽

Clinical Results ◽

Sglt2 Inhibitors ◽

Beneficial Effects ◽

Sodium Glucose Cotransporter

Background: Type 2 diabetes mellitus (T2DM) is one of the most serious and prevalent diseases worldwide. In the last decade, type 2 sodium-glucose cotransporter inhibitors (iSGLT2) were approved as alternative drugs for the pharmacological treatment of T2DM. The anti-hyperglycemic mechanism of action of these drugs involves glycosuria. In addition, SGLT2 inhibitors cause beneficial effects such as weight loss, a decrease in blood pressure, and others. Objective: This review aimed to describe the origin of SGLT2 inhibitors and analyze their recent development in preclinical and clinical trials. Results: In 2013, the FDA approved SGLT2 inhibitors as a new alternative for the treatment of T2DM. These drugs have shown good tolerance with few adverse effects in clinical trials. Additionally, new potential anti-T2DM agents based on iSGLT2 (O-, C-, and N-glucosides) have exhibited a favorable profile in preclinical evaluations, making them candidates for advanced clinical trials. Conclusion: The clinical results of SGLT2 inhibitors show the importance of this drug class as new anti-T2DM agents with a potential dual effect. Additionally, the preclinical results of SGLT2 inhibitors favor the design and development of more selective new agents. However, several adverse effects could be a potential risk for patients.

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Glucose Control and Cardiovascular Outcomes in Clinical Trials of Sodium Glucose Co-transporter 2 Inhibitor Treatments in Type 2 Diabetes

US Endocrinology ◽

10.17925/use.2014.10.01.8 ◽

2014 ◽

Vol 10 (01) ◽

pp. 8

Author(s):

Rene A Oliveros ◽

Son V Pham ◽

Steven R Bailey ◽

Robert J Chilton ◽

◽

...

Keyword(s):

Type 2 Diabetes ◽

Clinical Trials ◽

Glycemic Control ◽

Safety Data ◽

Sglt2 Inhibitors ◽

Phase Iii ◽

Phase Iii Clinical Trials ◽

Urinary Glucose ◽

Reduce Blood Glucose

Currently available medications for the treatment of type 2 diabetes have limitations, and many patients do not achieve glycemic control. Recently, a new approach has emerged using sodium glucose co-transporter 2 (SGLT2) inhibitors that decrease glucose reabsorption in the kidneys, increasing urinary glucose excretion. These agents offer the potential to improve glycemic control independently of insulin pathways while avoiding hypoglycemia. Two drugs of this class, canagliflozin and dapagliflozin, have been approved by the US Food and Drug Administration (FDA); another, empagliflozin, has been filed for regulatory approval and several others are in advanced development. These drugs have been shown to effectively reduce blood glucose, fasting plasma glucose, and glycated hemoglobin (HbA1C) levels in phase III clinical trials when used as monotherapy and as add-on therapy to other diabetes medications, including insulin. Another advantage of the SGLT2 inhibitors over existing treatments is the improvement in cardiovascular risk factors, particularly in terms of reductions in blood pressure and body weight. SGLT2 inhibitors have been generally well tolerated. While more long-term safety data are required to elucidate the benefit–risk profile of SGLT2 inhibitors, the rationale for their use in type 2 diabetes therapy is strong.

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Personalized Behavioral Nutrition Intervention in Older Asian Americans with Type 2 Diabetes during COVID-19 Pandemic: Study Protocol for a Pilot, Hybrid, Randomized Controlled Trial (Preprint)

10.2196/preprints.23522 ◽

2020 ◽

Author(s):

Jisook Ko ◽

Yan Du ◽

Rozmin Jiwani ◽

Chengdong Li ◽

Jing Wang

Keyword(s):

Type 2 Diabetes ◽

Clinical Trials ◽

Pilot Study ◽

Glycemic Control ◽

Asian Americans ◽

Control Group ◽

Management Approach ◽

Self Monitoring ◽

Behavioral Nutrition

BACKGROUND The COVID-19 pandemic has challenged the in-person-based self-management approach (i.e., face-to-face or group approach) of type 2 diabetes (T2D). Older adults with T2D, including Asian Americans (AAs), have experienced worsening of diabetes control due to various reasons, including uncertainty of continuous access to essential diabetes medications, devices, education, limited health literacy, as well as constant anxiety and stress. Hybrid clinical trials that incorporate virtual elements into the in-person-based study could provide these vulnerable populations with accessible and timely interventions OBJECTIVE The primary aims of this pilot study are to determine (1) the effect of personalized behavioral nutrition (PBN) intervention on glycemic control, weight control, and metabolites profiles; and (2) the acceptability of PBN. to enhance glycemic control using personalized behavioral nutrition. METHODS Participants will be recruited with a web-based registry, advertisements in ethnic newspapers, and social network services popular among AAs. A total of 60 AAs, aged 65 years or older, who are descendants of Chinese, Korean, or South Asian, and have a diagnosis of T2D will be randomized into two groups: a PBN group (n=30) and a control group (n=30). A 4-week PBN intervention comprises three components: 1) digital self-monitoring; 2) personal nutrition change goals and recommendations; and 3) diabetes nutrition educations. All participants will complete digital self-monitoring on diet, physical activity, and blood glucose. In addition, all participants will access an interactive digital platform to track their self-monitoring data and communicate with the research team. The effectiveness and acceptability of implementing the intervention will be assessed. RESULTS Funding support and institutional review board approval for this study have been secured. Data collection started in August 2020 and is ongoing. CONCLUSIONS To our knowledge, this is the first study to determine the effectiveness and acceptability of PBN utilizing a metabolomics approach and digital-assisted intervention with hybrid RCT among older AAs. The findings of this pilot study will inform the development of a full-scale PBN protocol and hybrid clinical trials that can be adapted for people with T2D in the ongoing pandemic.

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