The long-term effects of dapagliflozin in chronic kidney disease: a time-to-event analysis.

BACKGROUND AND HYPOTHESIS: Chronic kidney disease (CKD) presents a significant clinical and economic burden to healthcare systems worldwide, which increases considerably with progression towards kidney failure. The DAPA-CKD trial demonstrated that patients with or without type 2 diabetes (T2D) who were treated with dapagliflozin experienced slower progression of CKD versus placebo. Understanding the effect of long-term treatment with dapagliflozin on the timing of kidney failure beyond trial follow-up can assist informed decision-making by healthcare providers and patients. The study objective was therefore to extrapolate the outcome-based clinical benefits of treatment with dapagliflozin in patients with CKD via a time-to-event analysis using trial data. METHODS: Patient-level data from the DAPA-CKD trial were used to parameterise a closed cohort-level partitioned survival model that predicted time-to-event for key trial endpoints (kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure). Data were pooled with a subpopulation of the DECLARE-TIMI 58 trial to create a combined CKD population spanning a range of CKD stages; a parallel survival analysis was conducted in this population. RESULTS: In the DAPA-CKD and pooled CKD populations, treatment with dapagliflozin delayed time to first event for kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure. Attenuation of CKD progression was predicted to slow the time to kidney failure by 6.6 years (dapagliflozin: 25.2, 95%CI: 19.0-31.5; standard therapy: 18.5, 95%CI: 14.7-23.4) in the DAPA-CKD population. A similar result was observed in the pooled CKD population with an estimated delay of 6.3 years (dapagliflozin: 36.0, 95%CI: 31.9-38.3; standard therapy: 29.6, 95%CI: 25.5-34.7). CONCLUSION: Treatment with dapagliflozin over a lifetime time horizon may considerably delay the mean time to adverse clinical outcomes for patients who would go on to experience them, including those at modest risk of progression.

Examining the impact of structural uncertainty across ten type 2 diabetes models: Results from the 2022 Mount Hood Challenge.

OBJECTIVE: The Mount Hood Diabetes Challenge Network aimed to examine the impact of model structural uncertainty on the estimated cost-effectiveness of interventions for type 2 diabetes. METHODS: Ten independent modelling groups completed a blinded simulation exercise to estimate the cost-effectiveness of three interventions in two type 2 diabetes populations. Modelling groups were provided with a common baseline population, cost and utility values associated with different model health states, and instructions regarding time horizon and discounting. We collated the results to identify variation in predictions of net monetary benefit (NMB), and the drivers of those differences. RESULTS: Overall, modelling groups agreed which interventions had a positive NMB (i.e. were cost-effective), though estimates of NMB varied substantially- by up to £23,696 for one intervention. Variation was mainly driven through differences in risk equations for complications of diabetes and their implementation between models. The number of modelled health states was also a significant predictor of NMB. CONCLUSIONS: This exercise demonstrates that structural uncertainty between different health economic models impacts cost-effectiveness estimates. Whilst it is reassuring that a decision maker would likely reach similar conclusions on which interventions were cost-effective using most models, the range in numerical estimates generated across different models would nevertheless be important for price-setting negotiations with intervention developers. Minimising the impact of structural uncertainty on healthcare decision making therefore remains an important priority. Model registries, which record and compare the impact of structural assumptions, offer one potential avenue to improve confidence in the robustness of health economic modelling.

Extrapolated longer-term effects of the DAPA-CKD trial: a modelling analysis.

BACKGROUND: The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial assessed dapagliflozin versus placebo, in addition to standard therapy, in patients with chronic kidney disease (CKD) and albuminuria, and was terminated prematurely due to overwhelming efficacy. The study objective was to model the long-term clinical outcomes of DAPA-CKD beyond the trial follow-up. METHODS: A Markov model extrapolated event incidence per 1000 patients and CKD progression rates for patients receiving dapagliflozin or placebo over a 10-year time horizon. We derived treatment-specific CKD stage transition matrices using DAPA-CKD trial data. We extrapolated relevant efficacy endpoints using parametric survival equations for all-cause mortality and generalized estimating equations for recurrent events. RESULTS: When extrapolated over a 10-year period, patients randomized to dapagliflozin spent more time in CKD stages 1-3 and less in stages 4-5 than placebo [0.65 (95% CrI 0.41, 0.90) and -0.23 (95% CrI -0.45, 0.00) years per patient, respectively]. Dapagliflozin prevented an estimated 83 deaths and 51 patients initiating kidney replacement therapy per 1000 patients over 10 years. Predicted rates of hospitalized heart failure and abrupt declines in kidney function were reduced (19 and 39 estimated events per 1000 patients, respectively). CONCLUSIONS: Adding dapagliflozin to standard therapeutic management of CKD is expected to have long-term cardiorenal benefit beyond what has been demonstrated in the DAPA-CKD trial, with patients predicted to live longer with fewer complications.

Estimating the value of sodium-glucose cotransporter-2 inhibitors within the context of contemporary guidelines and the totality of evidence.

AIMS: To comprehensively estimate the cost-effectiveness of sodium glucose cotransporter-2 (SGLT2) inhibitor usage in the management of type 2 diabetes mellitus (T2DM) at established clinical review points, incorporating the totality of proven health benefits. MATERIALS AND METHODS: This study considered the cardio- and reno-protective effects of SGLT2 inhibitors using the Cardiff type 2 diabetes model. Conventional cost-effectiveness evaluations were undertaken for eligible populations at relevant intensification points reflecting the 2022 guidelines versus the 2015 National Institute of Health and Care Excellence (NICE) guidelines; incremental cost-effectiveness ratio lifetime trajectories and timepoints for complete cost-offset were estimated for each pathway. Treatment effects, utility decrements and costs (applied additively and discounted at 3.5%) were sourced from the published literature. RESULTS: For all subpopulations on treatment pathways reflecting the NG28-2022 guidelines, SGLT2 inhibitor introduction was cost-effective, becoming cost-saving between 2 and 16 years post-initiation. Despite increases in pharmacy costs, predicted lifetime costs were lower than for pathways reflecting the NG28-2015 guidelines, driven by a reduction in heart failure hospitalization and chronic kidney disease costs. Incremental gains in quality-adjusted life years (ranging from 0.58-1.12) resulted in dominance for the updated NG28-2022 guidance in all scenarios. CONCLUSIONS: Our results show that SGLT2 inhibitors have the potential to lower healthcare costs while improving health outcomes in eligible patient subpopulations.

Clinical Trial Considerations in Developing Treatments for Early Stages of Common, Chronic Kidney Diseases: A Scientific Workshop Cosponsored by the National Kidney Foundation and the US Food and Drug Administration.

In the past decade, advances in the validation of surrogate end points for chronic kidney disease (CKD) progression have heightened interest in evaluating therapies in early CKD. In December 2020, the National Kidney Foundation sponsored a scientific workshop in collaboration with the US Food and Drug Administration (FDA) to explore patient, provider, and payor perceptions of the value of treating early CKD. The workshop reviewed challenges for trials in early CKD, including trial designs, identification of high-risk populations, and cost-benefit and safety considerations. Over 90 people representing a range of stakeholders including experts in clinical trials, nephrology, cardiology and endocrinology, patient advocacy organizations, patients, payors, health economists, regulators and policy makers attended a virtual meeting. There was consensus among the attendees that there is value to preventing the development and treating the progression of early CKD in people who are at high risk for progression, and that surrogate end points should be used to establish efficacy. Attendees also concluded that cost analyses should be holistic and include aspects beyond direct savings for treatment of kidney failure; and that safety data should be collected outside/beyond the duration of a clinical trial. Successful drug development and implementation of effective therapies will require collaboration across sponsors, patients, patient advocacy organizations, medical community, regulators, and payors.

Cost effectiveness of sodium zirconium cyclosilicate for the treatment of hyperkalaemia in patients with CKD in Norway and Sweden.

BACKGROUND: Hyperkalaemia is common in patients with chronic kidney disease (CKD) and is associated with a range of adverse outcomes. Historically, options for management of chronic hyperkalaemia in the outpatient setting have been limited. Novel oral potassium binders provide a safe, effective therapy for maintenance of normokalaemia in patients with CKD, but despite being approved for reimbursement in many countries, prescription data indicate uptake has been slower than anticipated. This analysis aimed to demonstrate the value to patients and the healthcare system of the potassium binder sodium zirconium cyclosilicate (SZC) for treatment of hyperkalaemia in patients with CKD in Norway and Sweden. METHODS: A published simulation model reflecting the natural history of CKD was adapted to the Norwegian and Swedish settings and used to predict long-term health economic outcomes of treating hyperkalaemia with SZC versus usual care. RESULTS: SZC was highly cost effective compared to usual care in Norway and Sweden, with incremental cost-effectiveness ratios of €14,838/QALY in Norway and €14,352/QALY in Sweden, over a lifetime horizon. The acquisition cost of SZC was largely offset by cost savings associated with reductions in hyperkalaemia events and hospitalisations; a modest overall increase in costs was predominantly attributable to costs associated with gains in life years compared with usual care. SZC remained cost effective in all scenarios examined. CONCLUSIONS: SZC was estimated to be cost effective for treating hyperkalaemia. Consequently, improving access to a clinically effective, safe and cost-effective therapy, such as SZC, may result in considerable benefits for CKD patients with hyperkalaemia.

Weight loss and risk reduction of obesity-related outcomes in 0.5 million people: evidence from a UK primary care database.

High body mass index (BMI) is known to be associated with various conditions, including type 2 diabetes (T2D), osteoarthritis, cardiovascular disease (CVD) and sleep apnoea; however, the impact of intentional weight loss on the risk of these and other outcomes is not well quantified. We examined the effect of weight loss on ten selected outcomes in a population from the UK Clinical Practice Research Datalink (CPRD) GOLD database. Included individuals were >18 years old at the index date (first BMI value between January 2001 and December 2010). They were categorised by their weight pattern between year 1 post-index and year 4 post-index (baseline period) as having stable weight (-5% to +5%) or weight loss (-25% to -10%, plus evidence of intervention or dietary advice to confirm intention to lose weight). For inclusion, individuals also required a BMI of 25.0-50.0 kg/m2 at the start of the follow-up period, during which the occurrence of ten obesity-related outcomes was recorded. Cox proportional hazard models adjusted for BMI, comorbidities, age, sex and smoking status were used to estimate relative risks for weight loss compared with stable weight. Individuals in the weight-loss cohort had median 13% weight loss. Assuming a BMI of 40 kg/m2 before weight loss, this resulted in risk reductions for T2D (41%), sleep apnoea (40%), hypertension (22%), dyslipidaemia (19%) and asthma (18%). Furthermore, weight loss was associated with additional benefits, with lower risk of T2D, chronic kidney disease, hypertension and dyslipidaemia compared with maintaining the corresponding stable lower BMI throughout the study. This study provides objective, real-world quantification of the effects of weight loss on selected outcomes, with the greatest benefits observed for the established CVD risk factors T2D, hypertension and dyslipidaemia.

The cost-effectiveness of dapagliflozin in treating high-risk patients with type 2 diabetes mellitus: An economic evaluation using data from the DECLARE-TIMI 58 trial.

AIM: To undertake a cost-effectiveness analysis of dapagliflozin in treating high-risk patients with type 2 diabetes mellitus (T2DM), using both directly observed events in the DECLARE-TIMI 58 trial and surrogate risk factors to predict endpoints not captured within the trial. METHODS: An established T2DM model was adapted to integrate survival curves derived from the DECLARE-TIMI 58 trial, and extrapolated over a lifetime for all-cause mortality, hospitalization for heart failure, stroke, myocardial infarction, hospitalization for unstable angina, and end-stage kidney disease. The economic analysis considered the overall DECLARE trial population, as well as reported patient subgroups. Total and incremental costs, life-years and quality-adjusted life-years associated with dapagliflozin versus placebo were estimated from the perspective of the UK healthcare payer. RESULTS: In the UK setting, treatment with dapagliflozin compared to placebo was estimated to be dominant, with an expected increase in quality-adjusted life-years from 10.43 to 10.48 (+0.06) and a reduction in lifetime total costs from £39 451 to £36 899 (-£2552). Across all patient subgroups, dapagliflozin was estimated to be dominant, with the greatest absolute benefit in the prior heart failure subgroup (incremental lifetime costs -£4150 and quality-adjusted life-years +0.11). CONCLUSIONS: The results of this study demonstrate that dapagliflozin compared to placebo appears to be cost-effective, when considering evidence reported from the DECLARE-TIMI 58 trial, at established UK willingness-to-pay thresholds. The findings highlight the potential of dapagliflozin to have a meaningful impact in reducing the economic burden of T2DM and its associated complications across a broad T2DM population.

Risk factors associated with the incidence and recurrence of hyperkalaemia in patients with cardiorenal conditions.

INTRODUCTION: Hyperkalaemia (HK) is associated with increased mortality risk. Prior studies suggest that the causes of HK are multifactorial. This study aimed to examine risk factors for incident and recurrent HK in six large real-world cohorts of UK patients that could be considered at elevated HK risk because of underlying disease pathology and/or medication use. METHODS: This retrospective, observational cohort study utilised UK primary and secondary care data from Clinical Practice Research Datalink (CPRD) and linked Hospital Episode Statistics (HES), respectively. Patients were included if they were aged ≥18 years and had a record of ≥1 condition of interest (chronic kidney disease [CKD] stage 3+, heart failure, resistant hypertension [RHTN], dialysis, diabetes) and/or renin-angiotensin-aldosterone system inhibitors (RAASi) use between 01 January 2003 and 30 June 2018. Based on their diagnosis/ RAASi prescription record, patients were assigned to overlapping cohorts. The outcomes assessed were HK and recurrent HK, the latter defined as second or subsequent HK episode during follow-up. HK was defined as a serum K+ measurement ≥5.0 mmol/L; thresholds of ≥5.5 and ≥ 6.0 mmol/L were also explored. RESULTS: Of 931 460 meeting the eligibility criteria, 310 535 (33.3%) patients experienced ≥1 HK event and 187 719 (20.2%) experienced HK recurrence. The probability of subsequent HK events increased with event number from 60.5% for the second event to 76.5% for the sixth and the corresponding time to the next HK event decreased from 15.8 months to 6.1 months. Amongst the key risk factors, serum creatinine, serum phosphorus, systolic blood pressure, and white cell count demonstrated direct relationships with incidence and recurrence of HK, while inverse relationships were observed for estimated glomerular filtration rate (eGFR), haemoglobin and diastolic blood pressure. The relationship for Charlson's Comorbidity Index was mixed. The use of RAASi and anti-hyperglycaemic agents was associated with an increased risk of HK, while the use of diuretics (non-K+ -sparing) was protective against HK. CONCLUSION: Several risk factors for HK that are easily measured in routine clinical practice were identified, facilitating the identification of patients who are at the highest risk of experiencing HK, including recurrent HK.

The effect of hyperkalemia and long inter-dialytic interval on morbidity and mortality in patients receiving hemodialysis: a systematic review.

BACKGROUND: Patients with chronic kidney disease, especially those receiving hemodialysis (HD), are at risk of hyperkalemia (HK). This systematic review aimed to evaluate the prevalence of HK in patients with renal disease receiving HD and collate evidence on the effect of HK and differing HD patterns (i.e., long vs. short inter-dialytic intervals [LIDI and SIDI, respectively] in a thrice weekly schedule) on mortality. METHODS: Comprehensive searches were conducted across six databases and selected conference proceedings by two independent reviewers up to September 2020. A hundred and two studies reporting frequency of HK, mortality, or cardiovascular (CV) outcomes in adult patients with acute, chronic or end-stage renal disease in receipt of HD were included. Narrative synthesis of results was undertaken with key findings presented in tables and figures. RESULTS: Median prevalence of HK in patients with renal disease receiving HD was 21.6% and increased in patients receiving concomitant medications - mainly renin-angiotensin-aldosterone system inhibitors and potassium-sparing diuretics. Associations between elevated potassium levels and increased risk of both all-cause and CV mortality in the HD population were consistent across the included studies. In addition, there was a rise in all-cause and CV mortality on the day following LIDI compared with the day after the two SIDIs in patients on HD. CONCLUSIONS: Evidence identified in this systematic review indicates a relationship between HK and LIDI with mortality in patients with renal disease receiving HD, emphasizing the need for effective monitoring and management to control potassium levels both in emergency and chronic HD settings.

Cost-effectiveness of dapagliflozin as an adjunct to insulin for the treatment of type 1 diabetes mellitus in the United Kingdom.

AIMS: To assess the cost-effectiveness of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, as an adjunct to insulin in adults with type 1 diabetes mellitus (T1DM) inadequately controlled by insulin alone in the UK setting. METHODS: A cost-utility analysis was conducted to compare dapagliflozin (5 mg or 10 mg) added to insulin versus insulin monotherapy (standard of care) over a lifetime horizon. Treatment efficacy and safety data were obtained from 52-week results of the DEPICT-1 and DEPICT-2 trials and a network meta-analysis of SGLT2 inhibitors in T1DM. Direct healthcare costs, life-years, and quality-adjusted life-years (QALYs) were estimated from a UK payer perspective and discounted at 3.5% annually, using the Cardiff T1DM Model. Sensitivity analyses assessed uncertainty in estimated incremental cost-effectiveness ratios (ICERs). RESULTS: Dapagliflozin 5 mg was associated with gains of 0.23 life-years and 0.42 QALYs, at an additional cost of £4240 per person; corresponding to an ICER of £10 143 versus standard of care. For dapagliflozin 10 mg, incremental life-years, QALYs and costs were 0.24, 0.49 and £2964, respectively; corresponding to an ICER of £6103 versus standard of care. In probabilistic sensitivity analysis, ICER estimates fell below £20 000/QALY in 78% to 90% of simulations. Cost-effectiveness results were sensitive to changes in baseline patient characteristics and treatment effects on glycated haemoglobin; however, ICERs remained below £20 000. CONCLUSIONS: At cost-effectiveness thresholds conventionally applied in the UK, dapagliflozin as an adjunct to insulin appears to be a cost-effective treatment option for people with T1DM inadequately controlled by insulin alone.

Relationship between hypoglycaemia, body mass index and quality of life among patients with type 1 diabetes: Observations from the DEPICT clinical trial programme.

AIMS: To demonstrate the relationships between hypoglycaemia, body mass index (BMI) and quality of life, and to examine the impact of dapagliflozin on patient-reported treatment satisfaction in patients with type 1 diabetes mellitus (T1DM), using data from the DEPICT (Dapagliflozin Evaluation in Patients With Inadequately Controlled Type 1 Diabetes) clinical trial programme. METHODS: A two-stage modelling approach, using a linear regression framework, was adopted to evaluate the relationship between hypoglycaemia, BMI and quality of life. Hypoglycaemia fear score (HFS) was modelled as a function of hypoglycaemic events (non-severe documented symptomatic and severe) and, subsequently, quality of life (as measured by the EQ-5D questionnaire) was modelled as a function of HFS and BMI. A linked evidence approach correlated the relationship between treatment, hypoglycaemic events and glycated haemoglobin (HbA1c), to the relationships captured within the regression models. The proportion of patients achieving increased patient-reported treatment satisfaction, as measured by the Diabetes Treatment Satisfaction Questionnaire (DTSQ) total score, was compared between study arms. RESULTS: Incident severe hypoglycaemia was associated with significantly higher HFS (coefficient estimate [CE] 14.62, P=0.004). The frequency of symptomatic hypoglycaemic events was associated with a significantly higher HFS (log transposed, CE 1.32, P=0.026). Higher HFS and higher BMI were both independently associated with a significantly lower EQ-5D score (HFS: CE -0.0024, P<0.001; BMI: CE -0.0026, P=0.016). Significantly higher proportions of dapagliflozin-treated patients achieved ≥3-point increases in DTSQ total score compared to patients in the placebo group. CONCLUSION: The results of this study demonstrated that increases in hypoglycaemia and BMI were associated with reduced quality of life in people with T1DM. Dapagliflozin-treated patients achieved a reduction in HbA1c whilst avoiding an increase in hypoglycaemic events. The results also showed that treatment with dapagliflozin was associated with an improvement in treatment satisfaction.

Assessing the cost-effectiveness of sodium-glucose cotransporter-2 inhibitors in type 2 diabetes mellitus: A comprehensive economic evaluation using clinical trial and real-world evidence.

AIMS: The economic burden of diabetes is driven by the management of vascular complications. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated reductions in cardiovascular and renal complications, including hospitalization for heart failure (HHF) and renal disease progression, in randomized clinical trials. The objective of this study was to evaluate the cost-effectiveness of the SGLT2i class versus standard of care in type 2 diabetes mellitus (T2DM), using evidence from both clinical trial and real-world studies. METHODS: An established T2DM model was adapted to use contemporary outcomes evidence from real-world studies and randomized controlled trial evaluations of SGLT2i, and extrapolated over a lifetime for HHF, myocardial infarction, stroke, end-stage renal disease and all-cause mortality. The economic analysis considered adults with T2DM, with and without established cardiovascular disease, and was conducted over a lifetime from the perspective of the health care payer in the United Kingdom, United States and China, discounted at country-specific rates. RESULTS: SGLT2i were consistently associated with increased treatment costs, reduced complication costs and gains in quality-adjusted life years driven by differences in projected life expectancy, cardiovascular and microvascular morbidity and weight loss. SGLT2i were estimated to be cost-saving or cost-effective at relevant thresholds for the overall population in the United Kingdom, United States and China, with cost-effectiveness being the greatest in higher risk subgroups. CONCLUSIONS: The findings highlight the need to take into account cost savings from reducing common, morbid and preventable T2DM complications when considering the cost of diabetes medications.

Evaluating the Ability of Economic Models of Diabetes to Simulate New Cardiovascular Outcomes Trials: A Report on the Ninth Mount Hood Diabetes Challenge.

OBJECTIVES: The cardiovascular outcomes challenge examined the predictive accuracy of 10 diabetes models in estimating hard outcomes in 2 recent cardiovascular outcomes trials (CVOTs) and whether recalibration can be used to improve replication. METHODS: Participating groups were asked to reproduce the results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program. Calibration was performed and additional analyses assessed model ability to replicate absolute event rates, hazard ratios (HRs), and the generalizability of calibration across CVOTs within a drug class. RESULTS: Ten groups submitted results. Models underestimated treatment effects (ie, HRs) using uncalibrated models for both trials. Calibration to the placebo arm of EMPA-REG OUTCOME greatly improved the prediction of event rates in the placebo, but less so in the active comparator arm. Calibrating to both arms of EMPA-REG OUTCOME individually enabled replication of the observed outcomes. Using EMPA-REG OUTCOME-calibrated models to predict CANVAS Program outcomes was an improvement over uncalibrated models but failed to capture treatment effects adequately. Applying canagliflozin HRs directly provided the best fit. CONCLUSIONS: The Ninth Mount Hood Diabetes Challenge demonstrated that commonly used risk equations were generally unable to capture recent CVOT treatment effects but that calibration of the risk equations can improve predictive accuracy. Although calibration serves as a practical approach to improve predictive accuracy for CVOT outcomes, it does not extrapolate generally to other settings, time horizons, and comparators. New methods and/or new risk equations for capturing these CV benefits are needed.

Associations between serum potassium and adverse clinical outcomes: A systematic literature review.

BACKGROUND AND OBJECTIVES: Despite the growing body of evidence characterising the association between serum potassium levels and adverse clinical outcomes, a contemporary summary of available evidence is currently lacking. The objective of this study, therefore, was to undertake a systematic literature review to identify all relevant evidence assessing risk factors associated with the incidence of hyperkalaemia (HK) and also quantifying the effect of serum potassium levels on risk of adverse clinical outcomes. METHODS: PubMed (Medline and Medline In-Process), Embase and the Cochrane Library were searched for studies published between January 2002 and November 2018. Search inclusion criteria included studies describing either the incidence of HK events and any associated risk factors, or associations between HK or serum potassium concentration and adverse clinical outcomes including mortality, hospitalisation, major adverse cardiac events (MACE) and renin-angiotensin-aldosterone system inhibitors (RAASi) discontinuation in adult patients with chronic kidney disease (CKD), heart failure (HF), type 2 diabetes (T2DM) or hypertension. RESULTS: The search identified 1,897 publications. From these, a total of 123 studies met the inclusion criteria and were included in the review. The most commonly identified risk factors associated with HK events were the presence of CKD or renal impairment, T2DM, HF, hypertension, RAASi use and mineralocorticoid receptor antagonist use. Potassium levels both above and below the normal range were consistently associated with adverse clinical outcomes, with relative and absolute risks of outcomes increasing with severity of hyper- or hypokalaemia. These associations were consistently reported across a broad range of patient population types and study types. CONCLUSION: The current body of published evidence is compelling in its confirmation of the associations between serum potassium levels and adverse clinical outcomes. This review further highlights the importance of avoiding both hyper- and hypokalaemia, in order to reduce risk of mortality, hospitalisation, MACE and RAASi discontinuation or down-titration.

Modelling the long-term benefits of tolvaptan therapy on renal function decline in autosomal dominant polycystic kidney disease: an exploratory analysis using the ADPKD outcomes model.

BACKGROUND: The short-term efficacy of tolvaptan in patients with autosomal dominant polycystic kidney disease (ADPKD) has been demonstrated across several phase 3 trials, while the ADPKD Outcomes Model (ADPKD-OM) represents a validated approach to predict natural disease progression over a lifetime horizon. This study describes the implementation of a tolvaptan treatment effect within the ADPKD-OM and explores the potential long-term benefits of tolvaptan therapy in ADPKD. METHODS: The effect of tolvaptan on ADPKD progression was modelled by applying a constant treatment effect to the rate of renal function decline, consistent with that observed in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes trial (TEMPO 3:4; ClinicalTrials.gov identifier NCT00428948 ). Predictions generated by the ADPKD-OM were compared against aggregated data from a subsequent extension trial (TEMPO 4:4; ClinicalTrials.gov identifier NCT01214421 ) and the Replicating Evidence of Preserved Renal Function an Investigation of Tolvaptan Safety Efficacy in ADPKD trial (REPRISE; ClinicalTrials.gov identifier NCT02160145 ). Following validation, an application of the ADPKD-OM sought to estimate the benefit of tolvaptan therapy on time to end-stage renal disease (ESRD), in a range of ADPKD populations. RESULTS: Model validation against TEMPO 4:4 and REPRISE demonstrated the accuracy and generalisability of the tolvaptan treatment effect applied within the ADPKD-OM. In simulated patients matched to the overall TEMPO 3:4 trial population at baseline, tolvaptan therapy was predicted to delay the mean age of ESRD onset by five years, compared to natural disease progression (57 years versus 52 years, respectively). In subgroup and sensitivity analyses, the estimated delay to ESRD was greatest among patients with CKD stage 1 at baseline (6.6 years), compared to CKD 2 and 3 subgroups (4.7 and 2.7 years, respectively); and ADPKD patients in Mayo subclasses 1C-1E. CONCLUSIONS: This study demonstrated the potential for tolvaptan therapy to delay time to ESRD, particularly among patients with early-stage CKD and evidence of rapidly progressing disease. Data arising from this study highlight the value to be gained by early intervention and long-term treatment with tolvaptan, which may alleviate the economic and societal costs of providing care to patients who progress to ESRD.

The value of maintaining normokalaemia and enabling RAASi therapy in chronic kidney disease.

BACKGROUND: People with chronic kidney disease (CKD) are at an increased risk of developing hyperkalaemia due to their declining kidney function. In addition, these patients are often required to reduce or discontinue guideline-recommended renin-angiotensin-aldosterone system inhibitor (RAASi) therapy due to increased risk of hyperkalaemia. This original research developed a model to quantify the health and economic benefits of maintaining normokalaemia and enabling optimal RAASi therapy in patients with CKD. METHODS: A patient-level simulation model was designed to fully characterise the natural history of CKD over a lifetime horizon, and predict the associations between serum potassium levels, RAASi use and long-term outcomes based on published literature. The clinical and economic benefits of maintaining sustained potassium levels and therefore avoiding RAASi discontinuation in CKD patients were demonstrated using illustrative, sensitivity and scenario analyses. RESULTS: Internal and external validation exercises confirmed the predictive capability of the model. Sustained potassium management and ongoing RAASi therapy were associated with longer life expectancy (+ 2.36 years), delayed onset of end stage renal disease (+ 5.4 years), quality-adjusted life-year gains (+ 1.02 QALYs), cost savings (£3135) and associated net monetary benefit (£23,446 at £20,000 per QALY gained) compared to an absence of RAASi to prevent hyperkalaemia. CONCLUSION: This model represents a novel approach to predicting the long-term benefits of maintaining normokalaemia and enabling optimal RAASi therapy in patients with CKD, irrespective of the strategy used to achieve this target, which may support decision making in healthcare.

Cost-effectiveness of fluocinolone acetonide implant (ILUVIEN®) in UK patients with chronic diabetic macular oedema considered insufficiently responsive to available therapies.

BACKGROUND: Diabetic macular oedema (DMO) may lead to visual loss and blindness. Several pharmacological treatments are available on the National Health Service (NHS) to United Kingdom patients affected by this condition, including intravitreal vascular endothelial growth factor inhibitors (anti-VEGFs) and two types of intravitreal steroid implants, releasing dexamethasone or fluocinolone acetonide (FAc). This study aimed to assess the value for money (cost-effectiveness) of the FAc 0.2 µg/day implant (ILUVIEN®) in patients with chronic DMO considered insufficiently responsive to other therapies. METHODS: We developed a Markov model with a 15-year time horizon to estimate the impact of changes in best-corrected visual acuity in DMO patients on costs and quality-adjusted life years. The model considered both eyes, designated as the "study eye", defined at model entry as phakic with an ongoing cataract formation or pseudophakic, and the "fellow eye". The model compared the FAc 0.2 µg/day implant with a 700 µg dexamethasone implant (pseudophakic patients only) or with usual care, defined as a mixture of laser photocoagulation and anti-VEGFs (phakic and pseudophakic patients). Costs were estimated from the perspective of the NHS and Personal Social Services; full NHS prices were used for drugs. RESULTS: In patients who were pseudophakic at baseline, at 36 months, the FAc implant provided an additional gain of 4.01 and 3.64 Early Treatment Diabetic Retinopathy Study (ETDRS) letters compared with usual care and the dexamethasone implant, respectively. Over the 15-year time horizon, this translated into 0.185 additional quality-adjusted life years (QALYs) at an extra cost of £3066 compared with usual care, and 0.126 additional QALYs at an extra cost of £1777 compared with dexamethasone. Thus, incremental cost-effectiveness ratios (ICERs) were £16,609 and £14,070 per QALY gained vs. usual care and dexamethasone, respectively. In patients who were phakic at baseline, the FAc 0.2 µg/day implant provided an additional gain of 2.96 ETDRS letters at 36 months compared with usual care, which, over 15 years, corresponded to 0.11 additional QALYs at an extra cost of £3170, resulting in an ICER of £28,751 per QALY gained. CONCLUSION: The FAc 0.2 µg/day implant provided good value for money compared with other established treatments, especially in pseudophakic patients.

Computer Modeling of Diabetes and Its Transparency: A Report on the Eighth Mount Hood Challenge.

OBJECTIVES: The Eighth Mount Hood Challenge (held in St. Gallen, Switzerland, in September 2016) evaluated the transparency of model input documentation from two published health economics studies and developed guidelines for improving transparency in the reporting of input data underlying model-based economic analyses in diabetes. METHODS: Participating modeling groups were asked to reproduce the results of two published studies using the input data described in those articles. Gaps in input data were filled with assumptions reported by the modeling groups. Goodness of fit between the results reported in the target studies and the groups' replicated outputs was evaluated using the slope of linear regression line and the coefficient of determination (R2). After a general discussion of the results, a diabetes-specific checklist for the transparency of model input was developed. RESULTS: Seven groups participated in the transparency challenge. The reporting of key model input parameters in the two studies, including the baseline characteristics of simulated patients, treatment effect and treatment intensification threshold assumptions, treatment effect evolution, prediction of complications and costs data, was inadequately transparent (and often missing altogether). Not surprisingly, goodness of fit was better for the study that reported its input data with more transparency. To improve the transparency in diabetes modeling, the Diabetes Modeling Input Checklist listing the minimal input data required for reproducibility in most diabetes modeling applications was developed. CONCLUSIONS: Transparency of diabetes model inputs is important to the reproducibility and credibility of simulation results. In the Eighth Mount Hood Challenge, the Diabetes Modeling Input Checklist was developed with the goal of improving the transparency of input data reporting and reproducibility of diabetes simulation model results.

Serum potassium as a predictor of adverse clinical outcomes in patients with chronic kidney disease: new risk equations using the UK clinical practice research datalink.

BACKGROUND: To address a current paucity of European data, this study developed equations to predict risks of mortality, major adverse cardiac events (MACE) and renin angiotensin-aldosterone system inhibitor (RAASi) discontinuation using time-varying serum potassium and other covariates, in a UK cohort of chronic kidney disease (CKD) patients. METHODS: This was a retrospective observational study of adult CKD patients listed on the Clinical Practice Research Datalink, with a first record of CKD (stage 3a-5, pre-dialysis) between 2006 and 2015. Patients with heart failure at index were excluded. Risk equations developed using Poisson Generalized Estimating Equations were utilised to estimate adjusted incident rate ratios (IRRs) between serum potassium and adverse outcomes, and identify other predictive clinical factors. RESULTS: Among 191,964 eligible CKD patients, 86,691 (45.16%), 30,629 (15.96%) and 9440 (4.92%) experienced at least one hyperkalaemia episode, when defined using serum potassium concentrations 5.0-< 5.5 mmol/L, 5.5-< 6.0 mmol/L and ≥ 6.0 mmol/L, respectively. Relative to the reference category (4.5 to < 5.0 mmol/L), adjusted IRRs for mortality and MACE exhibited U-shaped associations with serum potassium, with age being the most important predictor of both outcomes (P < 0.0001). A J-shaped association between serum potassium and RAASi discontinuation was observed; estimated glomerular filtration rate was most predictive of RAASi discontinuation (P < 0.0001). CONCLUSIONS: Hyperkalaemia was associated with increased mortality and RAASi discontinuation risk. These risk equations represent a valuable tool to predict clinical outcomes among CKD patients; and identify those likely to benefit from strategies that treat hyperkalaemia, prevent RAASi discontinuation, and effectively manage serum potassium levels.