Excretion of glucose analogue with SGLT2 affinity predicts response effectiveness to sodium glucose transporter 2 inhibitors in patients with type 2 diabetes mellitus

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Abstract

Purpose

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) regulation, developed as treatment for patients with type 2 diabetes, can be imaged with the glucose analogue alpha-methyl-4-deoxy-4-[ ¹⁸F]fluoro- d-glucopyranoside (Me4FDG), a positron emission tomography (PET) tracer with a high affinity for SGLT1 and SGLT2 proteins. With regard to therapy effectiveness, we aimed to investigate whether clinical parameters or Me4FDG excretion could predict response to SGLT2i in patients with type 2 diabetes.

Methods

In a longitudinal, prospective study, 19 patients with type 2 diabetes underwent Me4FDG combined PET and magnetic resonance imaging (PET/MRI) scans at baseline and 2 weeks after initiation of therapy with SGLT2i, accompanied by the collection of blood and urine samples. Me4FDG-excretion was determined from the Me4FDG uptake in the bladder. Long-term response was determined by HbA1c level after 3 months; a strong response to the therapy was defined as a reduction of HbA1c by at least 10% from baseline.

Results

SGLT2i resulted in significantly increased Me4FDG excretion (4.8 vs. 45.0, P < 0.001) and urine glucose (56 vs. 2806 mg/dl, P < 0.001). Baseline urine glucose and baseline Me4FDG excretion correlated both with long-term decline in HbA1c with r = 0.55 ( P < 0.05). However, only Me4FDG excretion was a predictor of a strong response to SGLT2i ( P = 0.005, OR 1.9).

Conclusions

Using Me4FDG-PET, we demonstrated for the first time renal SGLT2-related excretion before and after short-term SGLT2i treatment. In contrary to other clinical parameters, SGLT2-related excretion before treatment was a robust predictor of long-term HbA1c response in patients with type 2 diabetes, suggesting that therapy effectiveness is only dependent of endogenous SGLT2 processes.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00259-023-06256-7.

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Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.

Hiddo J.L. Heerspink, Bruce A. Perkins, David H. Fitchett … (2016)

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate 30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.

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Empagliflozin in Patients with Chronic Kidney Disease

William G. Herrington, Natalie Staplin, Christoph Wanner … (2022)

Background This study, the EMPA-KIDNEY trial, was designed to assess the effects of empagliflozin in a broad range of patients with chronic kidney disease (CKD) at risk of progression. Methods We randomly assigned 6609 participants to empagliflozin (10mg once daily) versus matching placebo. Eligibility required an estimated glomerular filtration rate (eGFR) of ≥20 to <45 ml/minute/1.73m 2 ; or ≥45 to <90 ml/minute/1.73m 2 with a urinary albumin-to-creatinine ratio (ACR) of ≥200 mg/g. The primary outcome was a composite of kidney disease progression (end-stage kidney disease, a sustained eGFR <10 ml/minute/1.73m 2 , a sustained decline in eGFR of ≥40%, or a renal death) or death from cardiovascular causes. Results During a median of 2.0 years follow-up, a primary outcome event occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% CI 0.64 to 0.82; P<0.001), with consistent results in those with or without diabetes and across the range of eGFR studied. There were fewer hospitalizations from any cause in the empagliflozin group (0.86; 0.78 to 0.95, P=0.003), but no statistically significant effect on hospitalization for heart failure or cardiovascular death (4.0% vs 4.6%), or death from any cause (4.5% vs 5.1%). The rates of serious adverse events were broadly similar in the two groups. Conclusions Empagliflozin reduced the risk of the composite outcome of kidney disease progression or cardiovascular death in a wide range of patients at risk of CKD progression. (Funding:Boehringer Ingelheim, Eli Lilly and others; Clinicaltrials.gov:NCT03594110, EuDRACT: 2017-002971-24).

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Impact of Diabetes on The Effects Of Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors on Kidney Outcomes: Collaborative Meta-Analysis of Large Placebo-Controlled Trials

(2022)

Background Large trials have shown sodium glucose co-transporter-2 (SGLT2) inhibitors reduce risk of kidney and cardiovascular outcomes in patients with heart failure and chronic kidney disease (CKD), but were not powered to assess outcomes in patients with and without diabetes separately. Methods We did a meta-analysis of large placebo-controlled SGLT2 inhibitor trials (PROSPERO:CRD42022351618). The main outcomes were kidney disease progression (standardised to a definition of a sustained ≥50% decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease, or death from kidney failure), acute kidney injury (AKI), mortality and the composite of cardiovascular death or hospitalisation for heart failure. Findings 13 trials involving a total of 90,413 participants were included (15,605 [17%] without diabetes; trial average baseline eGFR range: 37-85 ml/min/1·73m 2 ). Compared with placebo, allocation to an SGLT2 inhibitor reduced the risk of kidney disease progression by 37% (relative risk [RR] 0·63, 95% confidence interval 0·58-0·69) with similar RRs in patients with and without diabetes (heterogeneity p=0·31). In the 4 CKD trials, RRs were similar irrespective of primary kidney diagnoses (heterogeneity p=0·67). SGLT2 inhibitors reduced the risk of AKI by 23% (0·77, 0·70-0·84) and the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77, 0·74-0·81), again with similar effects in those with and without diabetes (heterogeneity p values=0·12 and 0·67, respectively. Allocation to an SGLT2 inhibitor did not significantly reduce the risk of non-cardiovascular death (0·94, 0·88-1·02), with similar RRs in patients with or without diabetes. For all outcomes, results were also broadly similar irrespective of trial-average baseline eGFR (all trend tests p>0·05). In the trial populations studied to date, the absolute benefits of SGLT2-inhibition outweigh any serious hazards. Interpretation The totality of the randomised data supports the use of SGLT2 inhibitors to modify risk of kidney disease progression and AKI, not only in patients with type 2 diabetes, but also in patients with CKD or heart failure irrespective of diabetes status, primary kidney disease or kidney function. Funding MRC-UK&KRUK.

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Author and article information

Contributors

Marcus Hacker:

ORCID: http://orcid.org/0000-0002-4222-4083

marcus.hacker@meduniwien.ac.at

Journal

Journal ID (nlm-ta): Eur J Nucl Med Mol Imaging

Journal ID (iso-abbrev): Eur J Nucl Med Mol Imaging

Title: European Journal of Nuclear Medicine and Molecular Imaging

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 1619-7070

ISSN (Electronic): 1619-7089

Publication date (Electronic): 17 May 2023

Publication date PMC-release: 17 May 2023

Publication date (Print): 2023

Volume: 50

Issue: 10

Pages: 3034-3041

Affiliations

[1 ]GRID grid.22937.3d, ISNI 0000 0000 9259 8492, Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, , Medical University of Vienna, ; Waehringer Guertel 18-20, 1090 Vienna, Austria

[2 ]Diabetes & Metabolic Outpatient Clinic, Health Centre Vienna South, Vienna, Austria

[3 ]GRID grid.22937.3d, ISNI 0000 0000 9259 8492, Department of Biomedical Imaging and Image-Guided Therapy, Division of General and Pediatric Radiology, , Medical University of Vienna, ; Vienna, Austria

[4 ]GRID grid.22937.3d, ISNI 0000 0000 9259 8492, Department of Internal Medicine III, Division of Endocrinology and Metabolism, Gender Medicine Unit, , Medical University of Vienna, ; Vienna, Austria

Author information

Marcus Hacker http://orcid.org/0000-0002-4222-4083

Article

Publisher ID: 6256

DOI: 10.1007/s00259-023-06256-7

PMC ID: 10382381

PubMed ID: 37195445

SO-VID: f0ccb810-e5de-4de8-a011-12c32cc0f21b

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 6 March 2023

Date accepted : 25 April 2023

Funding

Funded by: Medical University of Vienna

Open Access :

Open access funding provided by Medical University of Vienna.

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ScienceOpen disciplines: Radiology & Imaging

Keywords: diabetes type 2,pet,sglt2 inhibitors,sodium glucose cotransporter 2,therapy response

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ScienceOpen disciplines: Radiology & Imaging

Keywords: diabetes type 2, pet, sglt2 inhibitors, sodium glucose cotransporter 2, therapy response

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Excretion of glucose analogue with SGLT2 affinity predicts response effectiveness to sodium glucose transporter 2 inhibitors in patients with type 2 diabetes mellitus

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Probing cerebral hemodynamics with BOLD fMRI

Most cited references 20

Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.

Empagliflozin in Patients with Chronic Kidney Disease

Impact of Diabetes on The Effects Of Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors on Kidney Outcomes: Collaborative Meta-Analysis of Large Placebo-Controlled Trials

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