Effect of exenatide twice daily and dapagliflozin, alone and in combination, on markers of kidney function in obese patients with type 2 diabetes: A prespecified secondary analysis of a randomized controlled clinical trial

Ruiten, Charlotte C. van; Beek, Annemarie B van der Aart-van der; IJzerman, Richard G.; Nieuwdorp, Max; Hoogenberg, Klaas; Raalte, Daniël H. van; Heerspink, Hiddo J.L.

doi:10.1111/dom.14410

Cited by 33 publications

(42 citation statements)

References 26 publications

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“…We included men and postmenopausal women, aged 18‐75 years, with a stable body weight (<5% reported change during the previous 3 months), a body mass index >27 kg/m 2 , and diagnosed with T2D 25,27 . For the current treatment of T2D, metformin with or without sulphonylurea derivatives was allowed (stable dose for ≥3 months).…”

Section: Methodsmentioning

confidence: 99%

“…The design of this randomized double blind placebo controlled trial has been described in detail previously 25,27 . In summary, patients were randomized 1:1:1:1, performed by an independent trial pharmacist using computer‐generated numbers, to dapagliflozin 10 mg with exenatide‐matched placebo, exenatide twice daily 10 μg with dapagliflozin‐matched placebo, dapagliflozin and exenatide (n = 16, or placebo dapagliflozin and placebo exenatide for 16 weeks.…”

Section: Methodsmentioning

confidence: 99%

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Combination therapy with exenatide decreases the dapagliflozin‐induced changes in brain responses to anticipation and consumption of palatable food in patients with type 2 diabetes: A randomized controlled trial

Ruiten¹,

Veltman

Wijdeveld³

et al. 2022

Diabetes Obesity Metabolism

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Aims: Sodium-glucose cotransporter-2 inhibitors induce less weight loss than expected. This may be explained by sodium-glucose cotransporter-2 inhibitorinduced alterations in central reward-and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists reduce appetite and body weight because of direct and indirect effects on the brain. We investigated the separate and combined effects of dapagliflozin and exenatide on the brain in response to the anticipation and consumption of food in people with obesity and type 2 diabetes. Materials and Methods:As part of a larger study, this was a 16 week, double-blind, randomized, placebo-controlled trial. Subjects with obesity and type 2 diabetes were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice-daily 10 μg with dapagliflozin-matched placebo, dapagliflozin plus exenatide, or double placebo. Using functional magnetic resonance imaging, the effects of treatments on brain responses to the anticipation of food and food receipt were assessed after 10 days and 16 weeks.Results: After 10 days, dapagliflozin increased activation in right amygdala and right caudate nucleus in response to the anticipation of food, and tended to decrease activation in right amygdala in response to actual food receipt. After 16 weeks, no changes in brain activation were observed with dapagliflozin. Dapagliflozin plus exenatide reduced activation in right caudate nucleus and amygdala to the anticipation of food, and decreased activation in the right amygdala in response to food receipt after 16 weeks. Conclusions:The dapagliflozin-induced changes in brain activation may contribute to the discrepancy between observed and expected weight loss with dapagliflozin.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Combination therapy with exenatide decreases the dapagliflozin‐induced changes in brain responses to anticipation and consumption of palatable food in patients with type 2 diabetes: A randomized controlled trial

Ruiten¹,

Veltman

Wijdeveld³

et al. 2022

Diabetes Obesity Metabolism

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“…This was an exploratory analysis of the Dapagliflozin plus Exenatide on Central REgulation of Appetite in diabeteS typE 2 (DECREASE) study ( 3 , 23 ) (NCT03361098). The study was approved by the Medical Ethics Committee of the Amsterdam University Medical Center, location Vumc, the Netherlands, and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.…”

Section: Methodsmentioning

confidence: 99%

“…The design of this randomized double-blind placebo-controlled trial has been described in detail previously ( 3 , 23 ). In summary, patients were randomized 1:1:1:1, performed by an independent trial pharmacist using computer-generated numbers, to 1. dapagliflozin 10 mg plus exenatide-matched placebo; 2. exenatide twice-daily 10 µg plus dapagliflozin-matched placebo; 3. dapagliflozin plus exenatide; or 4. placebo dapagliflozin plus placebo exenatide for 16 weeks.…”

Section: Methodsmentioning

confidence: 99%

Brain Activation in Response to Low-Calorie Food Pictures: An Explorative Analysis of a Randomized Trial With Dapagliflozin and Exenatide

Ruiten¹,

Veltman²,

Nieuwdorp

et al. 2022

Front. Endocrinol.

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Background and AimSodium-glucose cotransporter-2 inhibitors (SGLT2i) induce less weight loss than expected. This may be explained by SGLT2i-induced alterations in central reward and satiety circuits, contributing to increased appetite and food intake. This hyperphagia may be specific to high-calorie foods. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are associated with lower preferences for high-calorie foods, and with decreased activation in areas regulating satiety and reward in response to high-calorie food pictures, which may reflect this lower preference for energy-dense foods. To optimize treatment, we need a better understanding of how intake is controlled, and how [(un)healthy] food choices are made. The aim of the study was to investigate the effects of dapagliflozin, exenatide, and their combination on brain activation in response to low-calorie food pictures.MethodsWe performed an exploratory analysis of a larger, 16-week, double-blind, randomized, placebo-controlled trial. Sixty-eight subjects with obesity and type 2 diabetes were randomized to dapagliflozin, exenatide, dapagliflozin plus exenatide, or double placebo. Using functional MRI, the effects of treatments on brain responses to low-calorie food pictures were assessed after 10 days and 16 weeks.ResultsDapagliflozin versus placebo decreased activity in response to low-calorie food pictures, in the caudate nucleus, insula, and amygdala after 10 days, and in the insula after 16 weeks. Exenatide versus placebo increased activation in the putamen in response to low-calorie food pictures after 10 days, but not after 16 weeks. Dapagliflozin plus exenatide versus placebo had no effect on brain responses, but after 10 days dapagliflozin plus exenatide versus dapagliflozin increased activity in the insula and amygdala in response to low-calorie food pictures.ConclusionDapagliflozin decreased activation in response to low-calorie food pictures, which may reflect a specific decreased preference for low-calorie foods, in combination with the previously found increased activation in response to high-calorie foods, which may reflect a specific preference for high-calorie foods, and may hamper SGLT2i-induced weight loss. Exenatide treatment increased activation in response to low-calorie foods. Combination treatment may lead to more favorable brain responses to low-calorie food cues, as we observed that the dapagliflozin-induced decreased response to low-calorie food pictures had disappeared.

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“…In the last years, glucagon-like peptide 1 receptor agonists (GLP1-RA) including liraglutide, semaglutide, albiglutide, dulaglutide, and efpeglenatide have been shown to decrease the risk of cardiovascular (CV) events in patients with type 2 diabetes and atherosclerotic CV disease or at high CV risk ( Gerstein et al, 2021 ; Tuttle et al, 2021 ). In addition, GLP1-RA have been shown to slow the progression of kidney function decline particularly in patients with chronic kidney disease ( Tuttle et al, 2018 ; Kristensen et al, 2019 ; van Ruiten et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Prediction of the Effects of Liraglutide on Kidney and Cardiovascular Outcomes Based on Short-Term Changes in Multiple Risk Markers

et al. 2022

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Aims: The LEADER trial demonstrated that the glucagon-like peptide-1 receptor agonist (GLP1-RA) liraglutide reduces kidney and cardiovascular (CV) risk in patients with type 2 diabetes. We previously developed a Parameter Response Efficacy (PRE) score that translates multiple short-term risk marker changes, from baseline to first available follow-up measurement, into a predicted long-term drug effect on clinical outcomes. The objective of this study was to assess the accuracy of the PRE score in predicting the efficacy of liraglutide in reducing the risk of kidney and CV outcomes.Methods: Short-term changes in glycated hemoglobin (HbA1c), systolic blood pressure (BP), urinary-albumin-creatinine-ratio (UACR), hemoglobin, body weight, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol, and potassium were monitored in the LEADER trial. Associations between risk markers and kidney or CV outcomes were established using a multivariable Cox proportional hazards model in a separate pooled database of 6,355 patients with type 2 diabetes. The regression coefficients were then applied to the short-term risk markers in the LEADER trial to predict the effects of liraglutide on kidney (defined as a composite of doubling of serum creatinine or end-stage kidney disease) and CV (defined as a composite of non-fatal myocardial infarction, non-fatal stroke, and CV death) outcomes.Results: Liraglutide compared to placebo reduced HbA1c (1.4%), systolic BP (3.0 mmHg), UACR (13.2%), body weight (2.3 kg), hemoglobin (2.6 g/L), and increased HDL-cholesterol (0.01 mmol/L) (all p-values <0.01). Integrating multiple risk marker changes in the PRE score resulted in a predicted relative risk reduction (RRR) of 16.2% (95% CI 13.7–18.6) on kidney outcomes which was close to the observed RRR of 15.5% (95% CI -9.0–34.6). For the CV outcome, the PRE score predicted a 7.6% (95% CI 6.8–8.3) RRR, which was less than the observed 13.2% (95% CI 3.2–22.2) RRR.Conclusion: Integrating multiple short-term risk markers using the PRE score adequately predicted the effect of liraglutide on the composite kidney outcome. However, the PRE score underestimated the effect of liraglutide for the composite CV outcome, suggesting that the risk markers included in the PRE score do not fully capture the CV benefit of liraglutide.

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Effect of exenatide twice daily and dapagliflozin, alone and in combination, on markers of kidney function in obese patients with type 2 diabetes: A prespecified secondary analysis of a randomized controlled clinical trial

Cited by 33 publications

References 26 publications

Combination therapy with exenatide decreases the dapagliflozin‐induced changes in brain responses to anticipation and consumption of palatable food in patients with type 2 diabetes: A randomized controlled trial

Combination therapy with exenatide decreases the dapagliflozin‐induced changes in brain responses to anticipation and consumption of palatable food in patients with type 2 diabetes: A randomized controlled trial

Brain Activation in Response to Low-Calorie Food Pictures: An Explorative Analysis of a Randomized Trial With Dapagliflozin and Exenatide

Prediction of the Effects of Liraglutide on Kidney and Cardiovascular Outcomes Based on Short-Term Changes in Multiple Risk Markers

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