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Objective: The sodium-glucose co-transporter-2 inhibitor empagliflozin was approved for treatment of adults with chronic kidney disease (CKD) on the basis of its demonstrated ability to slow CKD progression and reduce the risk of cardiovascular death. This analysis was performed to assess the cost-effectiveness of empagliflozin plus standard of care (SoC) vs SoC alone in the treatment of CKD in the UK., Methods: A comprehensive, patient-level CKD progression model that simulates the evolution of risk factors for disease progression based on CKD-specific equations and clinical data was used to project a broad range of CKD-related complications. Patient baseline characteristics, distribution across Kidney Disease Improving Global Outcomes (KDIGO) health states, and changes in estimated glomerular filtration rate (eGFR), urine albumin-creatinine ratio (uACR), and other parameters while on treatment were derived from the EMPA-KIDNEY trial. UK cost and utilities/disutilities were sourced from the literature. Univariate and probabilistic sensitivity analyses were conducted. Annual discounting of 3.5% was applied on costs and outcomes., Results: Over a 50-year horizon, SoC resulted in per-patient costs, life years, and QALYs of £95,930, 8.55, and 6.28, respectively. Empagliflozin plus SoC resulted in an incremental gain in life years (+1.04) and QALYs (+0.84), while decreasing per-patient costs by £6,019. Empagliflozin was more effective and less costly (dominant) with a net monetary benefit of £22,849 at the willingness-to-pay threshold of £20,000. Although treatment cost was higher for empagliflozin, this was more than offset by savings in kidney replacement therapy. Empagliflozin remained highly cost-effective in patients with and without diabetes, and across scenario and sensitivity analyses., Limitations: This analysis is limited by reliance on short-term clinical trial data and by uncertainties in modelling CKD progression., Conclusions: Empagliflozin as an add-on to SoC for treatment of adults with CKD represents cost-effective use of UK National Health Service (NHS) resources.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major adverse cardiovascular (CV) events and hospitalization for heart failure (HF) in patients with type 2 diabetes (T2D). Using CV MRI (CMR) and 31 P-MRS in a longitudinal cohort study, we aimed to investigate the effects of the selective SGLT2 inhibitor empagliflozin on myocardial energetics and cellular volume, function, and perfusion. Eighteen patients with T2D underwent CMR and 31 P-MRS scans before and after 12 weeks' empagliflozin treatment. Plasma N-terminal prohormone B-type natriuretic peptide (NT-proBNP) levels were measured. Ten volunteers with normal glycemic control underwent an identical scan protocol at a single visit. Empagliflozin treatment was associated with significant improvements in phosphocreatine-to-ATP ratio (1.52 to 1.76, P = 0.009). This was accompanied by a 7% absolute increase in the mean left ventricular ejection fraction ( P = 0.001), 3% absolute increase in the mean global longitudinal strain ( P = 0.01), 8 mL/m 2 absolute reduction in the mean myocardial cell volume ( P = 0.04), and 61% relative reduction in the mean NT-proBNP ( P = 0.05) from baseline measurements. No significant change in myocardial blood flow or diastolic strain was detected. Empagliflozin thus ameliorates the "cardiac energy-deficient" state, regresses adverse myocardial cellular remodeling, and improves cardiac function, offering therapeutic opportunities to prevent or modulate HF in T2D., (© 2021 by the American Diabetes Association.)

Sodium glucose co-transporter 2 inhibitors (SGLT2i) are a promising second-line treatment strategy for type 2 diabetes mellitus (T2DM) with a developing landscape of both beneficial cardio- and nephroprotective properties and emerging adverse drug reactions (ADRs) including diabetic ketoacidosis (DKA), genetic mycotic infections, and amputations among others. A national register study (MHRA Yellow Card, UK) was used to quantify the SGLT2i's suspected ADRs relative to their Rx rate (OpenPrescribing, UK). The polypharmacology profiles of SGLT2i were data-mined (ChEMBL) for the first time. The ADR reports (n = 3629) and prescribing numbers (R x n = 5,813,325) for each SGLT2i in the United Kingdom (from launch date to the beginning December 2019) were determined. Empagliflozin possesses the most selective SGLT2/SGLT1 inhibition profile at ~2500-fold, ~10-fold more selective than cangliflozin (~260-fold). Canagliflozin was found to also inhibit CYP at clinically achievable concentrations. We find that for overall ADR rates, empagliflozin versus dapagliflozin and empagliflozin versus canagliflozin are statistically significant (χ 2 , p < .05), while dapagliflozin versus canagliflozin is not. In terms of overall ADRs, there is a greater relative rate for canagliflozin > dapagliflozin > empagliflozin. For fatalities, there is a greater relative rate for dapagliflozin > canagliflozin > empagliflozin. An organ classification that resulted in a statistically significant difference between SGLT2i was suspected infection/infestation ADRs between empagliflozin and dapagliflozin. Our findings at this stage of SGLT2i usage in the United Kingdom suggest that empagliflozin, the most selective SGLT2i, had the lowest suspected ADR incident rate (relative to prescribing) and in all reported classes of ADRs identified including infections, amputations, and DKA., (© 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Dapagliflozin (SGLT-2 inhibitor) and sotagliflozin (SGLT1/2 inhibitor) are two of the drugs of SGLT inhibitor class which have been recommended by the National Institute for Health and Care Excellence (NICE) in people with type 1 diabetes with BMI ≥27 kg/m 2 . Dapagliflozin is licensed in the UK for use in the NHS while sotagliflozin may be available in future. These and possibly other SGLT inhibitors may be increasingly used in people with type 1 diabetes as new licences are obtained. These drugs have the potential to improve glycaemic control in people with type 1 diabetes with the added benefit of weight loss, better control of blood pressure and more time in optimal glucose range. However, SGLT inhibitors are associated with a higher incidence of diabetic ketoacidosis without significant hyperglycaemia. The present ABCD/Diabetes UK joint updated position statement is to guide people with type 1 diabetes and clinicians using these drugs help mitigate this risk and other potential complications. Particularly, caution needs to be exercised in people who are at risk of diabetic ketoacidosis due to low calorie diets, illnesses, injuries, starvation, excessive exercise, excessive alcohol consumption and reduced insulin administration among other precipitating factors for diabetic ketoacidosis., (© 2020 Diabetes UK.)

Background and Aims: We examined HbA1c and cardiovascular risk factors with a median follow-up of 44 months therapy with dapagliflozin., Methods: We undertook a clinical practice evaluation of 101 patients attending our clinic., Results: Dapagliflozin resulted in a significant reduction in HbA1c 82.6 ± 15.7 v 68.7 ± 17.8 mmol/mol., Conclusion: Dapagliflozin maintains glycaemic control along with sustained improvements in weight and no decline in renal function., Competing Interests: Declaration of competing interest Professor Stephens has received research funding from Astra Zeneca for different work along with speaker fees., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Aims: Early treatment intensification for type 2 diabetes mellitus (T2DM) is often required to achieve glycaemic control and avoid longer-term complications. We assessed associations between early versus later dapagliflozin initiation with changes in glucose control, weight, and blood pressure using UK Clinical Practice Research Datalink (CPRD) data., Methods: People with T2DM aged ≥18 years, initiating dapagliflozin between November 2012 and August 2016 and with prior oral T2DM therapy (N = 3774), were included. The relationship between early (first intensification after metformin or sulfonylurea monotherapy) and later (second or higher-order intensification) dapagliflozin use and baseline changes in glycated haemoglobin A1c (HbA1c; ≥1.0% absolute reduction), weight (≥5.0% relative loss), and systolic blood pressure (SBP; ≥2 mmHg absolute reduction) after 6-12 months were assessed., Results: Overall, 25% of patients (951 of 3774) were early users and 75% (2823 of 3774) were later users. Later users were older, more likely to be men, and had longer disease duration. Early and later users had similar baseline mean HbA1c levels. For early versus later users, respectively, baseline-adjusted mean (95% confidence interval [CI]) reductions were 1.54% (-1.65, -1.44) versus 1.02% (-1.08, -0.97) in HbA1c, 3.31% (-4.37, -2.25) versus 4.06% (-5.05, -3.07) in weight, and 2.50 mm Hg (-3.89, -1.11) versus 2.84 mm Hg (-3.67, -2.01) in SBP. Early versus later use was associated with a greater likelihood of adjusted HbA1c reduction of ≥1% (odds ratio: 1.68, 95% CI: 1.15-2.45)., Conclusions: Glycaemic benefits were greater with early versus later dapagliflozin intensification. These results support broader and earlier dapagliflozin use., (Copyright © 2019. Published by Elsevier B.V.)

Aims: To investigate prescribing patterns and effect of dapagliflozin among individuals with T2DM using UK primary care data., Methods: Adult patients with T2DM initiating dapagliflozin treatment were identified from the Clinical Practice Research Datalink. Changes in HbA1c, body weight and systolic blood pressure were assessed in subgroups defined by glucose lowering treatment at baseline and compliance with the Summary of Product Characteristics. Logistic regression examined the association of baseline characteristics with achievement of target HbA1c (≤53mmol/mol) and weight reduction (by ≥3.0%)., Results: Among 5828 eligible individuals, HbA1c was reduced from a baseline mean of 80.0mmol/mol (SD 17.6) by -12.8 (95% CI -13.8, -11.8)mmol/mol at >12-24 months. The corresponding value for weight reduction (baseline mean 101.7kg) was -5.0 (-5.4, -4.5)kg, and for systolic blood pressure reduction (baseline mean 134.1mmHg) was -3.1 (-4.0, -2.2) mmHg. Lower baseline HbA1c values (<69; 69-85 versus ≥86mmol/mol) were positively associated with achievement of target HbA1c <53mmol/mol., Conclusions: Treatment with dapagliflozin in T2DM was associated with reductions in HbA1c, weight and systolic blood pressure over time periods up to 2 years. Changes in these parameters were consistent with those reported in RCTs., (Copyright © 2017 Primary Care Diabetes Europe. All rights reserved.)

Background: Type 2 diabetes mellitus (T2DM) is a chronic, progressive condition where the primary treatment goal is to maintain control of glycated haemoglobin (HbA1c). In order for healthcare decision makers to ensure patients receive the highest standard of care within the available budget, the clinical benefits of each treatment option must be balanced against the economic consequences. The aim of this study was to assess the cost-effectiveness of dapagliflozin, the first-in-class sodium-glucose co-transporter 2 (SGLT2) inhibitor, compared with a dipeptidyl peptidase-4 inhibitor (DPP-4i), when added to metformin for the treatment of patients with T2DM inadequately controlled on metformin alone., Methods: The previously published and validated Cardiff diabetes model was used as the basis for this economic evaluation, with treatment effect parameters sourced from a systematic review and network meta-analysis. Costs, derived from a UK healthcare system perspective, and quality-adjusted life years (QALYs), were used to present the final outcome as an incremental cost-effectiveness ratio (ICER) over a lifetime horizon. Univariate and probabilistic sensitivity analyses (PSA) were carried out to assess uncertainty in the model results., Results: Compared with DPP-4i, dapagliflozin was associated with a mean incremental benefit of 0.032 QALYs (95% confidence interval [CI]: -0.022, 0.140) and with an incremental cost of £216 (95% CI: £-258, £795). This resulted in an ICER point estimate of £6,761 per QALY gained. Sensitivity analysis determined incremental costs to be insensitive to variation in most parameters, with only the treatment effect on weight having a notable impact on the incremental QALYs; however, there were no scenarios which raised the ICER above £15,000 per QALY. The PSA estimated that dapagliflozin had an 85% probability of being cost-effective at a willingness-to-pay threshold of £20,000 per QALY gained., Conclusions: Dapagliflozin in combination with metformin was shown to be a cost-effective treatment option from a UK healthcare system perspective for patients with T2DM who are inadequately controlled on metformin alone.

Aims: To assess the cost-effectiveness of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, compared with a sulfonylurea, when added to metformin for treatment of UK people with Type 2 diabetes mellitus inadequately controlled on metformin alone., Methods: Clinical inputs sourced from a head-to-head randomized controlled trial (RCT) informed the Cardiff diabetes decision model. Risk equations developed from the United Kingdom Prospective Diabetes Study (UKPDS) were used in conjunction with the clinical inputs to predict disease progression and the incidence of micro- and macrovascular complications over a lifetime horizon. Cost and utility data were generated to present the incremental cost-effectiveness ratio (ICER) for both treatment arms, and sensitivity and scenario analyses were conducted to assess the impact of uncertainty on the final model results., Results: The dapagliflozin treatment arm was associated with a mean incremental benefit of 0.467 quality-adjusted life years (QALYs) [95% confidence interval (CI): 0.420; 0.665], with an incremental cost of £1246 (95% CI: £613; £1637). This resulted in an ICER point estimate of £2671 per QALY gained. Incremental costs were shown to be insensitive to parameter variation, with only treatment-related weight change having a significant impact on the incremental QALYs. Probabilistic sensitivity analysis determined that dapagliflozin had a 100% probability of being cost-effective at a willingness-to-pay threshold of £20,000 per QALY., Conclusions: Dapagliflozin in combination with metformin was shown to be a cost-effective treatment option compared with sulfonylurea from a UK healthcare perspective for people with Type 2 diabetes mellitus who are inadequately controlled on metformin monotherapy., (© 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.)

Objective: Economic evaluations of new diabetes therapies rely heavily upon the UK Prospective Diabetes Study (UKPDS) equations for prediction of cardiovascular events; however, concerns persist regarding their relevance to current clinical practice and appropriate use in populations other than newly diagnosed patients. This study refits the UKPDS 68 event equations, using contemporary data describing low- and intermediate-risk patients., Research Design and Methods: Anonymized patient data describing demographics, risk factors and incidence of cardiovascular and microvascular events were extracted from The Health Improvement Network (THIN) database over the 10-year period from 1 January 2000 to 31 December 2009. Following multiple imputation of missing values, accelerated failure-time Weibull regression equations were refitted to produce new coefficients for each risk group. Discriminatory performance was assessed and compared with both UKPDS 68 and UKPDS 82 risk equations, and the implication of coefficient choice within an economic evaluation was assessed using the Cardiff type 2 diabetes model., Results: When applied to patient-level data, the three sets of coefficients (UKPDS, THIN low-risk and intermediate-risk) lead to fairly consistent predictions of the 5-year risk of events. Exceptions include lower predicted rates of myocardial infarction and higher rates of ischaemic heart disease, congestive heart failure and end-stage renal disease with both sets of revised THIN coefficients compared with UKPDS. Over a modelled lifetime, the coefficients derived from the low-risk data predict fewer total cardiovascular events compared with UKPDS, while those from the intermediate-risk data predict a greater number. The areas under the receiver-operating characteristic curves demonstrated a marginal improvement in the discriminatory performance of the refitted equations. The incremental cost-effectiveness ratio associated with dapagliflozin versus sulphonylurea in addition to metformin changed from £7,708 to £7,519 and £6,906 per QALY gained, using the THIN intermediate- and low-risk coefficients, respectively., Conclusion: The results suggest that while the UKPDS equations perform best in newly diagnosed patients, they may overpredict the lifetime risk in this group and underpredict it in patients with more advanced diabetes. Implementation of the revised coefficients will result in different absolute numbers of predicted diabetes-related events; however, they are not expected to significantly affect the conclusions of economic modelling.

In the UK, diabetes mellitus affects around 3 million people, of whom over 90% have type 2 diabetes. Aims of treatment include minimising long-term complications (e.g. cardiovascular disease, blindness, chronic kidney disease, premature mortality) and avoiding unwanted effects of treatment (e.g. severe hypoglycaemia, weight gain). Management of diabetes includes patient support and education; addressing symptoms; lifestyle modification; targeting associated risk factors for cardiovascular disease; and surveillance for, and management of, complications including treatment-related hypoglycaemia. Dapagliflozin (Forxiga) belongs to a new class of oral glucose-lowering drugs that inhibit renal glucose reabsorption and promote glycosuria. It is licensed in the UK in adults with type 2 diabetes as monotherapy when diet and exercise alone do not provide adequate glycaemic control and who are unable to tolerate metformin; or, as add-on therapy, with other glucose-lowering agents including insulin, when these, with diet and exercise, do not provide adequate glycaemic control. The company's advertising materials claim that dapagliflozin provides a "novel method of controlling excess glucose" with "secondary benefit of weight loss". Here, we review the evidence for the use of dapagliflozin in the management of type 2 diabetes mellitus.