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British Journal of Diabetes & Vascular Disease-2013-Day-2-6

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    http://dvd.sagepub.com/  DiseaseThe British Journal of Diabetes & Vascular  http://dvd.sagepub.com/content/13/1/2The online version of this article can be found at: DOI: 10.1177/1474651413479981 2013 13: 2 British Journal of Diabetes & Vascular Disease  Caroline Day and Andrew V Bailey Glucosuria: a counter intuitive treatment for diabesity  Published by:  http://www.sagepublications.com  can be found at: The British Journal of Diabetes & Vascular Disease  Additional services and information for http://dvd.sagepub.com/cgi/alerts Email Alerts: http://dvd.sagepub.com/subscriptions Subscriptions:  http://www.sagepub.com/journalsReprints.nav Reprints:  http://www.sagepub.com/journalsPermissions.nav Permissions:  What is This? - Mar 5, 2013Version of Record >> by guest on September 18, 2014dvd.sagepub.comDownloaded from by guest on September 18, 2014dvd.sagepub.comDownloaded from   The British Journal of Diabetes & Vascular Disease13(1) 2  –6© The Author(s) 2013Reprints and permission: sagepub.co.uk/journalsPermissions.navDOI: 10.1177/1474651413479981dvd.sagepub.com Introduction Discourses on the treatment of long-term conditions often refer to unmet needs, one such need is to improve glycaemic control whilst facilitating weight loss in over-weight and obese individuals with type 2 diabetes. It is well known that weight loss is more difficult to achieve in people with type 2 diabetes, despite energy intake and output appearing to be the same as in weight-matched non-diabetic subjects. 1,2  Efforts to improve glycaemic control tend to be compromised by weight gain as fewer calories are lost via glucosuria and compensatory dietary reductions are not implemented. Hypoglycaemic or antihyperglycaemic? Hypoglycaemic agents, as monotherapy can cause hypo-glycaemia to the point of neuroglycopenia, whereas antihyperglycaemic agents as monotherapy will not lower glycaemia beyond euglycaemia. 3  Thus exogenous insulin and insulin secretagogues are hypoglycaemic agents, although the rapid onset and short duration of the meglitinides mean that these agents are rarely asso-ciated with hypoglycaemia. 4,5  Although the DPP4 inhib-itors (gliptins) and GLP-1 analogues exert glucose lowering activity by facilitating increased insulin secre-tion, the effects of these ‘incretin’ agents are based on potentiation of nutrient/glucose-induced insulin secre-tion, rather than initiation and maintenance of insulin secretion. 4,5  The other currently available agents, such as the antihyperglycaemic drug metformin, do not have glucose-lowering effects mediated via insulin secretion, but they are not substitutes for insulin and require the presence of insulin. 4,5 Established glucose lowering agents Treatment with hypoglycaemic agents such as insulin or sulphonylureas may increase appetite, but more particu-larly stimulate increased consumption of ‘uncounted’ calories as patients snack to avoid a hypo or over con-sume in response to hypo symptoms. 6  Indeed fear of hypo may condition a preventive snacking habit. Although these ‘anti-hypo’ calories may be considered ‘medicinal’ they are nevertheless additions to the energy quota of the daily diet: thus exacerbating the potential for weight gain with lowering of hyperglycaemia.The firstline pharmacological therapy in the treat-ment of type 2 diabetes is the antihyperglycaemic met-formin, which at worst is considered weight neutral and at best is associated with a small weight loss. Its novel mechanisms of action enhance sensitivity to endogenous insulin, especially in the liver to decrease hepatic glucose production, and to improve glucose uptake and utilisa-tion by muscle; and as metformin passes through into the blood there is also futile cycling of glucose in the splanchnic bed 7  - it has been suggested that this action contributes to the gastrointestinal incommode associ-ated with metformin. Thus there is energy expenditure and decreased energy consumption; at least in the early days of treatment. Metformin has pleiotropic effects which offer benefits beyond glycaemic control in type 2 diabetes. Indeed metformin is currently generating inter-est as an anti-mitogenic agent, thought to operate via the mTOR pathway. 8 The DPP4 inhibitors (gliptins) which facilitate an increase in the half-life of incretin hormones, such as GLP-1, also offer improved glycaemic control whilst being weight neutral. The GLP-1 analogues, which are administered via injection, potentiate nutrient/glu-cose-induced insulin secretion, have a direct glucose-dependent effect on the pancreatic alpha cells to Glucosuria: a counter intuitive treatment for diabesity Caroline Day 1  and Andrew V Bailey 2 1 School of Life and Health Sciences, Aston University, Birmingham, UK 2 Queen Elizabeth Hospital Birmingham, Birmingham, UK Corresponding author: Dr Caroline Day School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK Email: cday@mededuk.com DVD   131   10.1177/1474651413479981EditorialEditorial Editorial  Abbreviations: CHMP Committee for Medicinal Products for Human UseDPP dipeptidylpeptidaseGLP-1 glucagon-like peptide 1PPAR peroxisome proliferator activated receptorSGLT sodium glucose transporter  by guest on September 18, 2014dvd.sagepub.comDownloaded from   Editorial 3 decrease glucagon secretion and additionally have centrally mediated effects which enhance satiety and reduce the rate of gastric emptying – the latter can cause the associated nausea and potentially decrease food consumption . In consequence longer term GLP-1 agonist treatment can reduce body weight by 2-4kg.The PPARgamma agonist pioglitazone is associ-ated with weight gain and a redistribution of body fat from the viscera to the periphery. However much of the weight gain with the insulin sensitising thiazo-lidindiones (glitazones) can often be attributed to fluid retention. New class of glucose lowering agent In November 2012 the European Commission granted marketing authorisation to dapagliflozin (BMS-512148), the first in a new class of glucose lowering agents – the SGLT2 inhibitors. 9  As reviewed previously in this  journal 10  (http://www.bjdvd.com/content/10/4/193.full.pdf+html) inhibition of SGLT2 transporters, which are located almost exclusively in the proximal renal tubule reduce the amount of glucose reabsorbed back into the circulation, thus excess glucose is eliminated in the urine (Figure 1). This glucuretic effect results in improved gly-caemic control and weight loss – a happy coincidence for the treatment of people with type 2 diabetes who are gen-erally overweight or obese. Dapagliflozin In Europe dapagliflozin – a selective, reversible SGLT2 inhibitor - has been approved for use in adults with type 2 diabetes in whom diet and exercise alone or in associa-tion with other glucose lowering agents – including insulin - fail to provide adequate glycaemic control. 9,11  However there are no reported studies on dapagliflozin in combination with DPP4 inhibitors or GLP-1 ana-logues. Its monotherapy indication is only in patients for whom metformin treatment is inappropriate. The results of several randomised clinical trials with dapagliflozin as monotherapy or in combination with other glucose-low-ering agents in patients with type 2 diabetes are already in the published literature. 12–26 The recommended once daily dose of dapagliflozin (Forxiga ® ) is 10mg, although 5mg tablets are also avail-able. Tablets can be taken at any time of day with or with-out food. Dapagliflozin is 91% protein bound and is metabolised via hepatic glucuronidation rather than via CYP450, thus obviating drug interactions. 11,27,28  The metabolite is inactive and is eliminated via the kidney. Since dapagliflozin exposure is increased (12-67%) in patients with hepatic impairment it is advisable to Figure 1.  Regulation of glucose excretion in the renal tubule. 10 Reproduced with permission from Bailey & Day, Br J Diabetes Vasc Dis 2010 10  by guest on September 18, 2014dvd.sagepub.comDownloaded from   4 Editorial    13(1) commence treatment with a 5mg dose in patients with severe impairment (Child-Pugh class C) . 11 The efficacy of dapagliflozin is dependent upon an adequate rate of renal perfusion, therefore it is not recommended in patients with moderate or severe renal impairment (eGFR <60 ml/min//1.73m 2  or creatinine clearance <60 ml/min). Additionally these renally impaired patients may also show increased creatinine, phosphorous, parathyroid hormone and hypotension. Thus renal monitoring is recommended prior to initia-tion of therapy and at least yearly thereafter. 11 As an SGLT2 inhibitor dapagliflozin also exerts lim-ited effects on sodium reabsorption which in associa-tion with urinary glucose excretion results in a small osmotic diuresis (~375 ml/day). Thus it may be addi-tive to the diuretic effects of thiazide and loop diuretics. However the mild diuresis is beneficial in reducing sys-tolic (4.4 mmHg) and diastolic (2.1 mmgHg) blood pressure. 11 In hyperglycaemic states dapagliflozin achieves a glu-cosuria of about 70-80 g glucose/day. This equates to a decrease in HbA1c of 0.5-1% and the caloric loss reduces body weight by 2-3kg. 10,11  As monotherapy or in combi-nation with metformin, glimepiride or insulin the glu-cose lowering efficacy of dapagliflozin was maintained at 2yrs. The inhibition of SGLT2 carries glucose along the nephron where there is increased glucose reabsorption by SGLT1 in the third segment of the proximal tubule. This represents a mechanism that blunts the fall in glucose such that SGLT1 can almost completely reabsorb all glucose at low plasma glucose concentrations – there-fore preventing severe hypoglycaemia.The glucosuria is associated with increased reports of genital tract infection (< 1in 100 subjects) and urinary tract infection (< 1 in 10 subjects) although they were generally self-managed in the clinical trials. These infec-tions were also more frequent in females and in people with a prior history of infections. 11 In July 2011 the FDA advisory committee voted 9 to 6 against recommending marketing authorisation for dapagliflozin. 29  A major reason for concern was an apparent increase in some malignancies; thus more data were considered desirable. Interestingly media reports of the incidence of malignancies generally failed to note that in the trials there were almost twice as many sub- jects in the treatment than placebo/comparator groups. In July 2012, when the CHMP recommended EU mar-keting authorisation 30  it was evident that the proportion of malignant and unspecified tumours was similar between the dapagliflozin (1.47%) and the placebo//comparator (1.35%) groups. Although the relative risk of ovarian, renal tract and other cancers was <1, the rel-ative risk of prostate, breast and bladder cancer was >1, prompting post authorisation studies. However a causal relationship is considered unlikely due to the short time between initial drug exposure and tumour diagnosis and the ascertainment bias attached to these tumours in clinical trials. 31 Figure 2.  SGLT2 inhibitors to treat diabetes – phase of development 32–35 Note: 10th January 2013. US FDA advisory committee recommended approval of cangliflozin (http://www.nelm.nhs.uk/en/)  by guest on September 18, 2014dvd.sagepub.comDownloaded from 
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