Cost-effectiveness of Dapagliflozin for the Treatment of Heart Failure With Reduced Ejection Fraction.

Importance: Heart failure with reduced ejection fraction produces substantial morbidity, mortality, and health care costs. Dapagliflozin is the first sodium-glucose cotransporter 2 inhibitor approved for the treatment of heart failure with reduced ejection fraction. Objective: To examine the cost-effectiveness of adding dapagliflozin to guideline-directed medical therapy for heart failure with reduced ejection fraction in patients with or without diabetes. Design, Setting, and Participants: This economic evaluation developed and used a Markov cohort model that compared dapagliflozin and guideline-directed medical therapy with guideline-directed medical therapy alone in a hypothetical cohort of US adults with similar clinical characteristics as participants of the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial. Dapagliflozin was assumed to cost $4192 annually. Nonparametric modeling was used to estimate long-term survival. Deterministic and probabilistic sensitivity analyses examined the impact of parameter uncertainty. Data were analyzed between September 2019 and January 2021. Main Outcomes and Measures: Lifetime incremental cost-effectiveness ratio in 2020 US dollars per quality-adjusted life-year (QALY) gained. Results: The simulated cohort had a starting age of 66 years, and 41.8% had diabetes at baseline. Median (interquartile range) survival in the guideline-directed medical therapy arm was 6.8 (3.5-11.3) years. Dapagliflozin was projected to add 0.63 (95% uncertainty interval [UI], 0.25-1.15) QALYs at an incremental lifetime cost of $42 800 (95% UI, $37 100-$50 300), for an incremental cost-effectiveness ratio of $68 300 per QALY gained (95% UI, $54 600-$117 600 per QALY gained; cost-effective in 94% of probabilistic simulations at a threshold of $100 000 per QALY gained). Findings were similar in individuals with or without diabetes but were sensitive to drug cost. Conclusions and Relevance: In this study, adding dapagliflozin to guideline-directed medical therapy was projected to improve long-term clinical outcomes in patients with heart failure with reduced ejection fraction and be cost-effective at current US prices. Scalable strategies for improving uptake of dapagliflozin may improve long-term outcomes in patients with heart failure with reduced ejection fraction.

Effects of anti-diabetes medications on cardiovascular and kidney outcomes in Asian patients with type 2 diabetes: a rapid evidence assessment and narrative synthesis.

BACKGROUND: The cardiovascular and kidney safety of glucose-lowering drugs is a key concern in type 2 diabetes (T2D). We evaluated cardiorenal outcomes with glucose-lowering drugs in Asian patients, who comprise over half of T2D cases globally. RESEARCH DESIGN AND METHODS: A rapid evidence assessment was conducted for phase III or IV, double-blind, randomized clinical trials of glucose-lowering drugs reporting cardiovascular or kidney outcomes for Asian T2D patients (Embase, Medline, Cochrane Library databases: 1 January 2008-14 June 2020). RESULTS: Fifty-four publications reported exploratory data for Asians from 18 trials of dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and insulin analogs. SGLT2 inhibitors and several GLP-1 receptor agonists were associated with reduced cardiovascular risk in Asian T2D patients, while DPP-4 inhibitors exhibited cardiovascular safety. SGLT2 inhibitors also appeared to reduce renal risk; however, kidney outcomes were lacking for DPP-4 inhibitors other than linagliptin and GLP-1 receptor agonists in Asian patients. Insulin data were inconclusive as the only trial conducted used different types of insulin as both treatment and comparator. CONCLUSIONS: Cardiorenal outcomes with glucose-lowering drugs in Asian T2D patients were similar to outcomes in the overall multinational cohorts of these trials. DPP-4 inhibitors appear to demonstrate cardiovascular safety in Asians, while SGLT2 inhibitors and some GLP-1 receptor agonists may reduce cardiorenal and cardiovascular risk, respectively.

Best practices for safe use of SGLT-2 inhibitors developed from an expert panel Delphi consensus process.

PURPOSE: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have demonstrated glycemic efficacy and cardiovascular and renal benefits in people with type 2 diabetes mellitus (T2DM). However, they are also associated with serious adverse events (AEs), but little consensus exists for clinicians regarding AE management. This study aimed to develop a list of best practices for the safe use and monitoring of SGLT-2 inhibitors in people with T2DM. METHODS: A 15-member interprofessional panel was surveyed in a four-round Delphi process. Panelists were asked to comment on and rank statements regarding initial prescribing considerations and actions for minimizing and managing eight specific AEs and a broad category for other AEs. In the final round, panelists selected if the statements should be considered a best practice specific to SGLT-2 inhibitors, a best practice for general safe medication use in T2DM, or if the statement should not be considered as a best practice for safe medication use. RESULTS: Consensus was achieved for 36 best practice statements specific to SGLT-2 inhibitors and 24 statements as general best practices for safe medication use. Fifty-six percent of the best practice statements for SGLT-2 inhibitors related to managing and/or preventing hypotension, urinary tract infections, and genital infections. The general best practices for safe medication use primarily focused on medication histories, past medical history considerations, physical exam components, and patient education. CONCLUSION: A list of best practice statements was developed using the Delphi method, which can be utilized by clinicians to guide the safe use and monitoring of SGLT-2 inhibitors in people with T2DM.

Prévention d'événements cardiovasculaires et innocuité des inhibiteurs du SGLT2 comparativement aux inhibiteurs de la DPP-4 en contexte réel chez les personnes atteintes de diabète de type 2 / Prevention of cardiovascular events and safety of SGLT2 inhibitors compared to DPP-4 inhibitors in a real-world setting in patients with type 2 diabetes

INTRODUCTION: Les inhibiteurs du cotransporteur sodium-glucose de type 2 (SGLT2) constituent une nouvelle classe d'antidiabétiques oraux. Des essais comparatifs à répartition aléatoire ont indiqué qu'ils réduisaient le risque d'événements cardiovasculaires majeurs (ECM) chez les personnes atteintes de diabète de type 2. Plusieurs avis de sécurité entourant leur utilisation ont été émis, concernant notamment un risque accru d'infection sévère des voies urinaires, d'acidocétose diabétique et d'amputation des membres inférieurs. Toutefois, le risque d'événements cardiovasculaires ainsi que l'innocuité associés à leur utilisation dans un contexte de vie réelle demeurent incertains. MÉTHODOLOGIE: Une étude de cohorte rétrospective multicentrique a été menée à l'aide des bases de données médico-administratives provenant de sept provinces canadiennes et de la base de données cliniques du Clinical Practice Research Datalink du Royaume-Uni. L'utilisation des trois nouvelles classes de médicaments antidiabétiques, soit les inhibiteurs de la dipeptidyl peptidase-4 (DPP-4), les inhibiteurs du SGLT2 et les analogues du glucagon-like peptide-1 (GLP-1), a été décrite pour les nouveaux utilisateurs entre 2016 et 2018. Une approche méthodologique incluant à la fois les nouveaux utilisateurs incidents et les nouveaux utilisateurs prévalents a permis de comparer les inhibiteurs du SGLT2 aux inhibiteurs de la DPP-4 quant au risque d'événements cardiovasculaires ainsi qu'à l'innocuité associés à leur utilisation. Les utilisateurs du SGLT2 ont été appariés à des utilisateurs de DPP-4 sur la base du score de propension le plus proche et selon un niveau comparable de traitement du diabète. Le critère d'évaluation principal était un ECM, défini comme un critère composite de l'infarctus du myocarde, de l'accident vasculaire cérébral ischémique ou d'un décès d'origine cardiovasculaire. Les critères secondaires comprenaient chacun des critères individuels des ECM en plus de la mortalité toutes causes confondues et d'une hospitalisation pour insuffisance cardiaque. Les critères secondaires visant à évaluer l'innocuité étaient l'urosepsie, l'acidocétose diabétique et l'amputation des membres inférieurs. Une cohorte a été créée pour l'ensemble des critères d'évaluation cardiovasculaire ainsi que pour chacun des trois critères d'évaluation portant sur l'innocuité. L'incidence de la gangrène de Fournier a également été évaluée de manière descriptive. Un modèle à risques proportionnels de Cox a été utilisé pour estimer les rapports de risques instantanés (RRI) ajustés et leurs intervalles de confiance (IC) à 95 % comparant l'utilisation des inhibiteurs du SGLT2 à celle des inhibiteurs de la DPP-4 selon une approche dite « telle que traitée dans la réalité ¼. Les analyses ont été réalisées pour chaque critère et dans chacune des régions participantes. Les résultats des sept provinces canadiennes et ceux provenant du Royaume-Uni ont ensuite été regroupés à l'aide d'une méta-analyse utilisant un modèle à effets aléatoires. RÉSULTATS: Entre le 1er janvier 2016 et le 30 juin 2018, un total de 2 175 815 utilisateurs de médicaments antidiabétiques ont été identifiés, dont 166 722 nouveaux utilisateurs d'un inhibiteur du SGLT2 et 194 070 nouveaux utilisateurs d'un inhibiteur de la DPP-4. Parmi les utilisateurs de SGLT2, 36,0 % ont amorcé un traitement avec l'empagliflozine, 33,4 % avec la dapagliflozine et 30,6 % avec la canagliflozine. La proportion de nouveaux utilisateurs de DPP-4 ou de SGLT2 était généralement similaire entre les régions. Certaines variations dans les caractéristiques des nouveaux utilisateurs ont été observées entre les trois classes d'antidiabétiques et entre les régions à l'étude. Au total, 209 867 nouveaux utilisateurs de SGLT2 ont été appariés à 209 867 utilisateurs de DPP-4. Une diminution du risque d'ECM a été observée chez les personnes recevant un inhibiteur du SGLT2 comparativement à celles recevant un inhibiteur de la DPP-4 (RRI : 0,76; IC à 95 % : 0,69-0,84). Une diminution du risque a également été observée pour la mortalité toutes causes confondues (RRI : 0,60; IC à 95 % : 0,54-0,67) et les hospitalisations pour insuffisance cardiaque (RRI : 0,43; IC à 95 % : 0,37-0,51). Des résultats comparables ont été observés pour chacun des critères individuels des ECM. Une diminution du risque d'urosepsie a été observée chez les personnes recevant un inhibiteur du SGLT2 par rapport à celles recevant un inhibiteur de la DPP-4 (RRI : 0,58; IC à 95 % : 0,42-0,80). Le taux d'incidence brut de la gangrène de Fournier était similaire chez les utilisateurs de SGLT2 et de DPP-4 (0,08 contre 0,14 par 1 000 personnesannées). L'utilisation d'un inhibiteur du SGLT2 était également associée à un risque accru d'acidocétose diabétique comparativement à l'utilisation d'un inhibiteur de la DPP-4 (RRI : 2,85; IC à 95 % : 1,99-4,08). Aucune différence n'a cependant été observée pour le risque d'amputation des membres inférieurs entre ces deux classes de médicaments (RRI : 0,88; IC à 95 % : 0,71-1,09). CONCLUSIONS: Dans cette large étude de cohorte rétrospective multicentrique, l'utilisation d'un inhibiteur du SGLT2 est associée à une diminution du risque d'ECM comparativement à l'utilisation d'un inhibiteur de la DPP-4 chez les personnes atteintes de diabète de type 2. Des résultats comparables ont été observés pour les critères individuels des ECM, la mortalité toutes causes confondues et l'insuffisance cardiaque. L'utilisation d'un inhibiteur du SGLT2 est également associée à une diminution du risque d'urosepsie, mais à une augmentation du risque d'acidocétose diabétique. Aucune différence significative n'a été observée entre les utilisateurs de SGLT2 et de DPP-4 concernant l'amputation des membres inférieurs.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of oral antidiabetics. Randomized controlled trials have shown that they reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes. A number of safety advisories concerning their use have been issued, specifically with regard to an increased risk of severe urinary tract infection, diabetic ketoacidosis and lower extremity amputation. However, the risk of cardiovascular events and the safety associated with the use of these inhibitors in a real-world setting remain uncertain. METHODOLOGY: A multicentre retrospective cohort study was conducted using medical administrative databases from seven Canadian provinces and the UK Clinical Practice Research Datalink clinical database. The use of the three novel classes of antidiabetic drugs, dipeptidyl peptidase-4 (DPP-4) inhibitors, SGLT2 inhibitors and glucagon-like peptide-1 (GLP-1) agonists, is described for new users between 2016 and 2018. A methodological approach including both incident and prevalent new users was used to compare SGLT2 inhibitors with DPP-4 inhibitors in terms of the risk of cardiovascular events and the safety associated with their use. SGLT2 users were matched to DPP-4 users based on the nearest propensity score and a comparable level of diabetes treatment. The primary endpoint was MACE, defined as a composite of myocardial infarction, ischemic stroke, or cardiovascular death. The secondary endpoints included each of the individual MACE endpoints in addition to all-cause mortality and hospitalization for heart failure. The secondary endpoints for evaluating safety were urosepsis, diabetic ketoacidosis, and lower extremity amputation. A cohort was created for all the cardiovascular endpoints and for each of the three safety endpoints. The incidence of Fournier's gangrene was evaluated descriptively. A Cox proportional risk model was used to estimate the adjusted hazard ratios (aHRs) and their 95% confidence intervals (CIs) comparing the use of SGLT2 inhibitors with that of DPP-4 inhibitors using an as-treated approach. Analyses were performed for each endpoint and for each of the participating jurisdictions. The results from the seven Canadian provinces and those from the United Kingdom were then pooled using random-effects meta-analysis. RESULTS: A total of 2,175,815 antidiabetic users were identified for the period from January 1, 2016 to June 30, 2018, including 166,722 new SGLT2 inhibitor users and 194,070 new DPP-4 inhibitor users. Among SGLT2 users, 36.0% initiated treatment with empagliflozin, 33.4% with dapagliflozin and 30.6% with canagliflozin. The proportions of new DPP-4 and new SGLT2 users were generally similar across the jurisdictions. Certain differences in the new users' characteristics were observed between the three classes of antidiabetics na between the jurisdictions involved. In all, 209,867 new SGLT2 users were matched to 209,867 DPP-4 users. A decrease in the risk of MACE was observed in the patients receiving an SGLT2 inhibitor compared with those receiving a DPP-4 inhibitor (HR: 0.76; 95% CI: 0.69-0.84). A decreased risk was also observed for all-cause mortality (HR: 0.60; 95% CI: 0.54-0.67) and hospitalizations for heart failure (HR: 0.43; 95% CI: 0.37- 0.51). Comparable results were obtained for each of the individual MACE endpoints. A decreased risk of urosepsis was observed in patients receiving an SGLT2 inhibitor compared to those receiving a DPP-4 inhibitor (HR: 0.58; 95% CI: 0.42-0.80). The crude incidence rate of Fournier's gangrene was similar in the SGLT2 and DPP-4 users (0.08 versus 0.14 per 1,000 person-years). Additionally, the use of an SGLT2 inhibitor was associated with an increased risk of diabetic ketoacidosis compared to the use of a DPP4 inhibitor (HR: 2.85; 95% CI: 1.99-4.08). However, no difference between these two classes of drugs was observed for the risk of lower extremity amputation (HR: 0.88; 95% CI: 0.71-1.09). CONCLUSIONS: In this large, multicentre retrospective cohort study, the use of an SGLT2 inhibitor was associated with a decreased risk of MACE relative to the use of a DPP-4 inhibitor in patients with type 2 diabetes. Comparable results were observed for the individual MACE endpoints, all-cause mortality, and heart failure. The use of an SGLT2 inhibitor was also associated with a decreased risk of urosepsis but an increased risk of diabetic ketoacidosis. No significant differences were found between the SGLT2 users and DPP-4 users in terms of lower extremity amputations.

Real-world comparison of hospitalization costs for heart failure in type 2 diabetes mellitus patients with established cardiovascular disease treated with canagliflozin versus other antihyperglycemic agents.

Aims: This real-world study compared hospitalization for heart failure (HHF) costs and all-cause healthcare costs in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease treated with the sodium glucose co-transporter 2 inhibitor (SGLT2i) canagliflozin and non-SGLT2i antihyperglycemic agents (AHAs).Materials and methods: Propensity score-matched cohorts from a retrospective observational study (OBSERVE-4D) using the Truven MarketScan Commercial Claims and Encounters and Optum Clinformatics databases were analyzed. HHF and all-cause healthcare costs per-patient-per-month (PPPM) were compared for patients initiated on canagliflozin and non-SGLT2i AHAs in the on-treatment analysis.Results: Baseline characteristics were well balanced between matched cohorts that included new users of canagliflozin or non-SGLT2i AHAs in the Truven (13,954 and 45,101, respectively) and Optum (11,490 and 53,360, respectively) databases. The mean (95% CI) PPPM cost of HHF was lower for canagliflozin than for non-SGLT2i AHAs in analyses of both the Truven ($21.31 [$21.25, $21.37]) and Optum ($30.43 [$30.41, $30.45]) databases. The mean (95% CI) PPPM all-cause healthcare cost was also lower for canagliflozin than for non-SGLT2i AHAs in analyses of both the Truven ($321 [$280, $361]) and Optum ($449 [$402, $495]) databases.Limitations: This study is subject to the limitations inherent to observational research including potential for coding errors and biases and unobserved confounding. Because all patients were in commercially administered health plans, these findings cannot be easily generalized to uninsured or Medicaid populations. Patient costs were evaluated up to and including their first HHF event. Post-discharge costs such as the costs of subsequent rehospitalizations were not included in this analysis.Conclusions: For patients with T2DM and established cardiovascular disease in this real-world study, treatment with canagliflozin was associated with lower HHF costs and all-cause healthcare costs compared with treatment with non-SGLT2i AHAs.

Loop diuretic use among patients with heart failure and type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors.

AIMS: To compare loop diuretic use in patients with comorbid heart failure (HF) and type 2 diabetes (T2D) newly initiated on sodium glucose cotransporter-2 inhibitors (SGLT2Is) versus other oral anti-glycemic agents (AGAs). METHODS: This analysis used 2013-2015 MarketScan Medicare Supplemental claims data. HF and T2D patients were identified and SGLT2I users were propensity score matched to other AGA users. The mean daily dose of loop diuretics in furosemide equivalents was ascertained. For those not on baseline loop diuretics, new use was compared between cohorts. For those on baseline loop diuretics, we assessed patterns of use (increased dose, decreased dose, stable dose, no longer using) at 12-months. RESULTS: A total of 750 SGLT2I users were matched to 750 other AGA users. The distribution of loop diuretic use at mean doses of 0 mg (i.e., no use), ≤20 mg, >20 mg-40 mg, >40 mg-80 mg and >80 mg/day did not differ between cohorts at baseline or 12-months (p > 0.05 for both). SGLT2I use was associated with less new loop diuretic use (22.7% [79/348] vs. 34.0% [132/388]; p = 0.001). For those on loop diuretics at baseline (n = 764), patterns of use at 12-months did not differ between cohorts (p = 0.14). CONCLUSIONS: New loop diuretic use was less frequent among SGLT2I users; however, patterns of loop diuretic use did not differ between cohorts in those on loop diuretics at baseline.

Pharmacoeconomic evaluation of sodium-glucose transporter-2 (SGLT2) inhibitors for the treatment of type 2 diabetes.

INTRODUCTION: Clinicians have many safe and effective options for the treatment of type 2 diabetes that can improve glycemic control and effect other cardio-metabolic parameters. Sodium-glucose transporter-2 inhibitors (SGLT-2) are the most recent class of therapies, have a novel mechanism of action, and provide good glycemic efficacy and a favorable cardiovascular risk profile. Cost-effectiveness data can play an important role in assessing the benefits of this class of therapy in anti-diabetes treatment regimens. Areas covered: This review summarizes all the available evidence regarding the cost-effectiveness of SGLT-2 inhibitors. For the purposes of this article, the authors have performed a systematic review of pharmacoeconomic analyses through a non-restricted literature until June 2018. Expert opinion: The available analyses demonstrate that SGLT-2 inhibitors are a more cost-effective option compared to other oral anti-diabetes therapies and insulin in the treatment of individuals with uncontrolled type 2 diabetes. Future studies should examine populations with renal and liver disease and expand data of some SGLT-2 inhibitors to patients at high cardiovascular risk and hard endpoint data.

Replacement Effects and Budget Impacts of Insurance Coverage for Sodium-Glucose Co-Transporter-2 Inhibitors on Oral Antidiabetic Drug Utilization.

BACKGROUND AND OBJECTIVES: A new oral antidiabetic drug class, sodium-glucose co-transporter-2 inhibitors (SGLT-2 inhibitors), has been covered by national health insurance in Taiwan since May 2016. This study estimated the impacts of insurance coverage for SGLT-2 inhibitors on the replacement effects of antidiabetic drug use and the overall budget for antidiabetic drugs in Taiwan. METHODS: Antidiabetic drugs were divided into nine categories based on the American Diabetes Association guidelines. We retrieved claims data from 2015 to 2017 for all patients diagnosed with diabetes mellitus from the National Health Insurance Research Database. An interrupted time series design and segmented regression were used to estimate the budget impact of insurance coverage for SGLT-2 inhibitors. Three scenarios were designed for the prescribing pattern for SGLT-2 inhibitors: (1) monotherapy, (2) metformin-based (m-based) drug prescriptions, and (3) metformin and sulfonylurea-based (m-s-based) drug prescriptions. RESULTS: From May 2016 to April 2017, the prescription rate for m-based SGLT-2 inhibitors increased from 0.43 to 3.50%, and the expenditure rate increased from 0.82 to 6.58%. We found that the prescription rates of m-based and m-s-based dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) decreased by 6.23 and 11.51% following the initiation of insurance coverage for SGLT-2 inhibitors, respectively. Furthermore, there was a 5.95% increase in the overall budget impact of antidiabetic drugs 1 year following the initiation of insurance coverage for SGLT-2 inhibitors. CONCLUSIONS: Both the prescription rates and expenditure rates for SGLT-2 inhibitors have increased since they have been covered by national health insurance in Taiwan, which significantly reduced usage of DPP-4 inhibitors but caused the positive growth of overall antidiabetic drug expenditures.