No evidence of compensatory changes in energy balance, despite reductions in body weight and liver fat, during dapagliflozin treatment in type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled, cross-over trial (ENERGIZE).

AIM: This study assessed the impact of dapagliflozin on food intake, eating behaviour, energy expenditure, magnetic resonance imaging (MRI)-determined brain response to food cues and body composition in patients with type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: Patients were given dapagliflozin 10 mg once daily in a randomized, double-blind, placebo-controlled trial with short-term (1 week) and long-term (12 weeks) cross-over periods. The primary outcome was the difference in test meal food intake between long-term dapagliflozin and placebo treatment. Secondary outcomes included short-term differences in test meal food intake, short- and long-term differences in appetite and eating rate, energy expenditure and functional MRI brain activity in relation to food images. We determined differences in glycated haemoglobin, weight, liver fat (by 1 H magnetic resonance spectroscopy) and subcutaneous/visceral adipose tissue volumes (by MRI). RESULTS: In total, 52 patients (43% were women) were randomized; with the analysis of 49 patients: median age 58 years, weight 99.1 kg, body mass index 35 kg/m2 , glycated haemoglobin 49 mmol/mol. Dapagliflozin reduced glycated haemoglobin by 9.7 mmol/mol [95% confidence interval (CI) 3.91-16.27, p = .004], and body weight (-2.84 vs. -0.87 kg) versus placebo. There was no short- or long-term difference in test meal food intake between dapagliflozin and placebo [mean difference 5.7 g (95% CI -127.9 to 139.3, p = .933); 15.8 g (95% CI -147.7 to 116.1, p = .813), respectively] nor in the rate of eating, energy expenditure, appetite, or brain responses to food cues. Liver fat (median reduction -4.7 vs. 1.95%), but not subcutaneous/visceral adipose tissue, decreased significantly with 12 weeks of dapagliflozin. CONCLUSIONS: The reduction in body weight and liver fat with dapagliflozin was not associated with compensatory adaptations in food intake or energy expenditure.

Dapagliflozin (SGLT2-i) induced euglycaemic diabetic ketoacidosis.

Sodium glucose co-transporter-2 inhibitors (SGLT2-i) have become a popular therapeutic strategy in the management of hyperglycaemia in type 2 diabetes mellitus. The primary site of action of SGLT2-i is at the proximal renal convoluted tubule. They work by blocking SGLT2 receptors, sodium-dependent glucose co-transport molecules, which in turn prevents glucose reabsorption, facilitating glucosuria, improving glycaemic control as well as a moderate degree of weight loss. We report the case of a 51-year-old woman admitted to the acute medical unit with abdominal pain and vomiting, who was diagnosed with euglycaemic diabetic ketoacidosis secondary to recent initiation of an SGLT2-i medication (dapagliflozin). Clinicians should be aware of this rare side effect of SGLT2-i, to circumvent delays in patient management.

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.

INTRODUCTION: Sodium glucose cotransporter 2 (SGLT2) inhibitors are effective blood-glucose-lowering medications with beneficial effects on body weight in patients with type 2 diabetes mellitus (T2DM). However, observed weight loss is less than that predicted from quantified glycosuria, suggesting a compensatory increase in energy intake or a decrease in energy expenditure. Studies using dual-energy X-ray absorptiometry (DEXA) have suggested most body weight change is due to loss of adipose tissue, but organ-specific changes in fat content (eg, liver, skeletal muscle) have not been determined. In this randomised, double-blind, placebo-controlled crossover study, we aim to study the compensatory changes in energy intake, eating behaviour and energy expenditure accompanying use of the SGLT2 inhibitor, dapagliflozin. Additionally, we aim to quantify changes in fat distribution using MRI, in liver fat using proton magnetic resonance spectroscopy (1H-MRS) and in central nervous system (CNS) responses to food images using blood oxygen level dependent (BOLD) functional MRI (fMRI). METHODS AND ANALYSIS: This outpatient study will evaluate the effect of dapagliflozin (10 mg), compared with placebo, on food intake and energy expenditure at 7 days and 12 weeks. 52 patients with T2DM will be randomised to dapagliflozin or placebo for short-term and long-term trial interventions in a within participants, crossover design. The primary outcome is the difference in energy intake during a test meal between dapagliflozin and placebo. Intake data are collected automatically using a customised programme operating a universal eating monitor (UEM). Secondary outcomes include (1) measures of appetite regulation including rate of eating, satiety quotient, appetite ratings (between and within meals), changes in CNS responses to food images measured using BOLD-fMRI, (2) measures of energy expenditure and (3) changes in body composition including changes in liver fat and abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). ETHICAL APPROVAL: This study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/0340) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice (GCP). TRIAL REGISTRATION NUMBER: ISRCTN14818531. EUDRACT number 2013-004264-60.

GLP-1 as a target for therapeutic intervention.

Glucagon-like peptide receptor agonists (GLP-1 RA) have multiple effects, including control of glycaemia via stimulation of insulin and suppression of glucagon secretion and reduction of adiposity by enhancing satiety, so are an attractive therapeutic option in type 2 diabetes management. Five GLP-1 RA are used currently and more are in development. The HbA1c reduction obtained varies from 1 to 2%; they reduce body weight by about 2-3kg when used to treat T2DM, while liraglutide results in greater weight loss at a higher dose and has recently been approved for the management of obesity. GLP-1 RA are usually used in combination with other glucose-lowering drugs, but dual combinations with basal insulin in a single injection have recently become available. The next decade is likely to see the development of more potent and longer lasting agents as well as hybrid molecules with dual or triple actions.

Positioning SGLT2 Inhibitors/Incretin-Based Therapies in the Treatment Algorithm.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recent addition to the therapeutic options available for the treatment of type 2 diabetes and became available after the introduction of incretin-based therapies, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs). These agents have potential advantages with regard to their weight loss-promoting effect, low risk of hypoglycemia, reduction in blood pressure, and reduction in cardiovascular events in high-risk patients (with empagliflozin). Apart from these clinically important outcomes, they may also correct core defects present in type 2 diabetes (i.e., improvement in ß-cell function and insulin sensitivity). They do, however, have some adverse effects, notably, nausea with GLP-1 RAs and genital tract infections and potential for volume depletion with SGLT2i. Whether incretin-based therapies are associated with an increased risk of pancreatitis is unclear. Most recently, diabetic ketoacidosis has been reported with SGLT2i. Therefore, a key clinical question in relation to guidelines is whether these clinical advantages, in the context of the adverse effect profile, outweigh the additional cost compared with older, more established therapies. This article reviews the therapeutic rationale for the use of these newer drugs for diabetes treatment, considers their place in current guidelines, and discusses how this may change as new data emerge about their long-term efficacy and safety from ongoing outcome trials.

Set individualized targets for patients with type 2 diabetes.

Type 2 diabetes is a chronic, progressive, metabolic disorder caused by defects in insulin secretion and action resulting in hyperglycaemia. Fasting blood glucose, random blood glucose, the oral glucose tolerance test and glycated haemoglobin (HbA1c) tests are all used in diagnosis. In patients with impaired fasting glucose, impaired glucose tolerance or prediabetes there are minor variations in the risk of developing overt diabetes. The mainstay of management is lifestyle intervention i.e. diet and physical activity aiming for at least 5% weight loss for all these three states which can halve the risk of developing type 2 diabetes. Structured education is an integral part of diabetes care and this should be provided at diagnosis. Nutritional advice from a dietitian is essential. Regular physical activity totalling 30 minutes most days of the week improves muscle insulin sensitivity, lipid profile and blood pressure although a total of 60-75 minutes a day is required for reduction in body weight and better metabolic profiles. NICE guidelines acknowledge the need for individualised treatment targets. Lowering HbA1c is beneficial in reducing microvascular complications and may have macrovascular benefits in the long term. However, intensive glycaemic control in the elderly with more advanced disease may not have similar benefits and poses a risk due to hypoglycaemia.

Evolution in functionality of a metastatic pancreatic neuroendocrine tumour (pNET) causing Cushing's syndrome: treatment response with chemotherapy.

BACKGROUND: We report the case of a patient who had a non-functional metastatic pancreatic neuroendocrine tumour (pNET), which changed in functionality during the course of the disease. This case demonstrates the effectiveness of conventional cytotoxic chemotherapy in the management of select group of patients with this rare, challenging condition. CASE PRESENTATION: Our patient was a 34 year old man under oncology follow up, diagnosed with a non-functional metastatic pancreatic neuroendocrine tumour treated with a Whipple's procedure two years ago. Despite treatment with somatostatin analogues and sunitinib, a tyrosine kinase inhibitor, he had demonstrated radiological progression of his metastatic disease. He now presented with a short history of Cushing's syndrome. A presumptive diagnosis of a rapidly progressive, metastatic, functional pNET with ectopic ACTH production was made, confirmed biochemically and with liver biopsy. The proliferative index, Ki-67 of 20% of the liver biopsy prompted us to treat him with conventional cytotoxic chemotherapy using streptozocin, 5-fluorouracil and doxorubicin. Prior to its administration clinical and biochemical control of the hypercortisolemic state was achieved with metyrapone. However the clinical, biochemical and radiological response to chemotherapy was so dramatic obviating the need for metyrapone therapy. CONCLUSIONS: Non-functional pNETs may evolve in their clinical and biologic behaviour producing functional hormonal syndromes. Chemotherapy may be an effective therapeutic modality in such circumstances.