Compensatory changes in energy balance during dapagliflozin treatment in type 2 diabetes mellitus: a randomised double-blind, placebo-controlled, cross-over trial (ENERGIZE)—study protocol

Rajeev, Surya Panicker; Sprung, Victoria S.; Roberts, Carl A.; Harrold, Jo; Halford, Jason C.G.; Stančák, Andrej; Boyland, Emma; Kemp, Graham J.; Cuthbertson, Daniel J.; Wilding, John

doi:10.1136/bmjopen-2016-013539

Cited by 16 publications

(15 citation statements)

References 21 publications

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“…[7][8][9] Long-term prospective studies investigating this effect in larger populations with T2DM are warranted, and currently under way. 24 Understanding the effect of SGLT2 inhibitors on weight loss and caloric intake will enable providers to better educate patients on optimizing weight loss with SGLT2 inhibitor therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Current information suggests that the mechanism behind hyperphagia is more likely related to long‐term pharmacodynamic effects such as weight loss, as increased energy intake takes a significant time to manifest . Long‐term prospective studies investigating this effect in larger populations with T2DM are warranted, and currently under way . Understanding the effect of SGLT2 inhibitors on weight loss and caloric intake will enable providers to better educate patients on optimizing weight loss with SGLT2 inhibitor therapy.…”

Section: Discussionmentioning

confidence: 99%

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Does Dapagliflozin Affect Energy Intake and Appetite? A Randomized, Controlled Exploratory Study in Healthy Subjects

Bertran

Berlie

Nixon

et al. 2018

Clinical Pharm in Drug Dev

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The primary aims of this study were to assess the effects of dapagliflozin versus placebo on energy intake and appetite ratings in healthy individuals. This was a randomized, single-blind, placebo-controlled, 2-period crossover study. In each period, healthy individuals received either dapagliflozin or placebo for 2 weeks. On assessment days, participants were asked to consume a standard preload breakfast. Appetite ratings were measured with 100-mm visual analog scales immediately before and during the 4.25-hour period after breakfast. Energy intake was measured at an ad libitum lunch. Energy intake and appetite responses were assessed at the end of each 2-week treatment period by mixed-design analysis of variance. Eighteen individuals completed all assessments (44% female; mean age, 22.8 years; 44% Caucasian; mean BMI, 25.2 kg/m ). There was no difference in energy intake on dapagliflozin compared to placebo (mean difference, -19.8 kcal; P = .516). Mean differences in prebreakfast desire for salty foods (11.3 mm, P = .094) and postbreakfast desire for sweet foods (8.1 mm, P = .054) trended higher with dapagliflozin relative to placebo. Our data do not support an effect of dapagliflozin on energy intake or appetite measures in young, healthy subjects. Although not statistically significant, the size of the mean differences in prebreakfast desire for salty foods and postbreakfast desire for sweet foods on dapagliflozin were larger than placebo and reflect the drug's natriuretic and glucuretic effects. These findings should be further evaluated in patients with type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Does Dapagliflozin Affect Energy Intake and Appetite? A Randomized, Controlled Exploratory Study in Healthy Subjects

Bertran

Berlie

Nixon

et al. 2018

Clinical Pharm in Drug Dev

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“…SGLT2 inhibition has been shown to cause preferential increase in hunger for sugar‐rich foods similar to that seen with low carbohydrate diets . However, we were unable to demonstrate an compensatory increase in energy intake in the ENERGIZE study, a prospective randomized, double blind, cross‐over trial, in people with type 2 diabetes which compared the effects of dapagliflozin with placebo on food intake and energy expenditure over 12 weeks . Dapagliflozin treatment was associated with reduction in body weight compared to placebo (−2.84 vs −0.87 kg), but with no significant increase in test meal food intake (2.63 g, 95% confidence interval: −31.65, 36.91; P = 0.659) measured by the Sussex Ingestion Pattern Monitor .…”

Section: Metabolic Effects Of Sglt2 Inhibitionmentioning

confidence: 81%

A review of the mechanism of action, metabolic profile and haemodynamic effects of sodium‐glucose co‐transporter‐2 inhibitors

Brown

Rajeev

Cuthbertson

et al. 2019

Diabetes Obesity Metabolism

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Inhibition of glucose transport in the kidney, to produce glucosuria and thus directly lower blood glucose seems a remarkably simple way to treat diabetes (type 1 or type 2). The development of sodium-glucose co-transporter-2 (SGLT2) inhibitors and their subsequent clinical development has on one hand shown this to be true, but at another level has helped reveal a complex web of interacting effects starting in the kidney and modulating multiple metabolic pathways in a variety of other organs. These underlie the now clear benefits of this class of drugs in the management of type 2 diabetes from glucose lowering, weight loss and blood pressure reduction through to the reductions in cardiovascular and renal complications observed in long-term outcomes trials. They also explain some of the adverse effects that have emerged, including the risk of diabetic ketoacidosis. This review describes the effects of SGLT2 inhibition in relation to this complex physiology, and shows how this can favourably alter the pathophysiology of type 2 diabetes.anti-diabetic drug, clinical physiology, type 2 diabetes, SGLT2 inhibitor 1 | INTRODUCTION Sodium glucose transporter 2 inhibitors (SGLT2i) are one of the newest classes of drugs available to lower glucose in people with type 2 diabetes, but their origins go back to the 19th century, when phlorizin, extracted from the bark of apple trees was shown to induce glucosuria. Phlorizin was later used experimentally as a tool to help understand renal glucose transport and the effects of glucose toxicity, as it could be used to lower blood glucose without directly affecting insulin secretion or sensitivity. 1 However its therapeutic potential was limited, due to poor oral bioavailability, and effects on gut glucose absorption that resulted in diarrhoea; phlorizin also has an active metabolite (phloretin) that inhibits the GLUT1 glucose transporter that is important for normal glucose transport in many tissues. 2 Research conducted in the last 20 years has now identified the specific mechanisms by which phlorizin is able to induce glucosuria and lower blood glucose, and led to the development of drugs that are highly selective inhibitors of renal (and/or gut) glucose transport. These drugs work by inhibiting the facilitative sodium glucose co-transporters (SGLTs) that are responsible for renal glucose reabsorption (predominantly SGLT2 with some contribution from SGLT1, which also has a major role in gut glucose absorption). 3 Despite early concerns about some adverse effects that occur as a result of glucosuria, the development of SGLTi (and potentially dual inhibitors of SGLT1 and SGLT2) has led to greater understanding of the fundamental physiological processes involved in glucose transport in the kidney and gastrointestinal (GI) tract. These medications have both predictable and surprising effects that underpin some of their observed therapeutic benefits and adverse effects. This review will focus on the underlying physiology and show how this is modified by pharmacological inhibition of SG...

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“…Another meta‐analysis evaluating randomized control trials gave similar results . However, in order to evaluate organ‐specific variations in fat content, a randomized, double‐blind, placebo controlled, cross trial (ENERGIZE)‐study is currently in progress in which dapagliflozin is being used as the test drug …”

Section: Effect Of Sglt2 Inhibitors On Obesitymentioning

confidence: 87%

“…29 However, in order to evaluate organ-specific variations in fat content, a randomized, double-blind, placebo controlled, cross trial (ENERGIZE)-study is currently in progress in which dapagliflozin is being used as the test drug. 30 Obesity and T2DM have often been associated with inflammation in various systemic organs. In a rodent study on C57BL/6J mice fed with high fat diet, it was observed that canagliflozin led to reductions in subcutaneous and visceral fat as well as body and liver weight.…”

Section: Effec T Of Sg Lt2 Inhib Itor S On Ob E S It Ymentioning

confidence: 99%

Exploring novel pharmacotherapeutic applications and repurposing potential of sodium glucose CoTransporter 2 inhibitors

Madaan

Husain

Akhtar

et al. 2018

Clin Exp Pharma Physio

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Sodium glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of anti-hyperglycaemic drugs with a distinctive mechanism of action focusing on renal absorption of glucose. Apart from its anti-hyperglycaemic effects, a multitude of research studies on this class have revealed that these drugs have far more versatile and comprehensive pharmacological effects than previously believed. Approximately 30% of FDA approved drugs are repurposed and used for indications other than those for which they were initially intended. Repurposing already approved drugs leads to significant reduction in pre-clinical and clinical R&D costs as well as minimizing the burden with respect to obtaining regulatory approval. SGLT2 inhibitors have been found to exhibit cardioprotective, renoprotective, anti-hyperlipidaemic, anti-atherosclerotic, anti-obesity, anti-neoplastic, hepatoprotective, and renoprotective effects in in vitro, pre-clinical, and clinical studies. The pleiotropic effects of this class have been attributed to a variety of its pharmacodynamic actions such as natriuresis, haemoconcentration, deactivation of RAAS, ketone body formation, alterations in energy homeostasis, glycosuria, lipolysis, anti-inflammatory, and anti-oxidative actions. These favourable observations encourage further research on this multifaceted class in order to effectively explore and harness its full potential and consequently lead to clinical outcomes.

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Compensatory changes in energy balance during dapagliflozin treatment in type 2 diabetes mellitus: a randomised double-blind, placebo-controlled, cross-over trial (ENERGIZE)—study protocol

Cited by 16 publications

References 21 publications

Does Dapagliflozin Affect Energy Intake and Appetite? A Randomized, Controlled Exploratory Study in Healthy Subjects

Does Dapagliflozin Affect Energy Intake and Appetite? A Randomized, Controlled Exploratory Study in Healthy Subjects

A review of the mechanism of action, metabolic profile and haemodynamic effects of sodium‐glucose co‐transporter‐2 inhibitors

Exploring novel pharmacotherapeutic applications and repurposing potential of sodium glucose CoTransporter 2 inhibitors

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