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Empagliflozin + linagliptin

16 November 2015Sodium glucose co-transporter type 2 (SGLT-2) inhibitor
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New Medicines

JardianceChronic heart failure in patients with reduced ejection fraction, and with or without type 2 diabetes

Information

Jardiance
Licence extension / variation
Boehringer Ingelheim
Boehringer Ingelheim

Development and Regulatory status

Launched
Launched
Pre-registration (Filed)
July 2021
Jul 21Approved in EU [15].
Jul 21Licence extension approved by the MHRA. The new indication is use in adults for the treatment of symptomatic chronic heart failure with reduced ejection fraction [14].
May 21Recommended for EU approval by CHMP – the new indication is ‘Jardiance is indicated in adults for the treatment of symptomatic chronic heart failure with reduced ejection fraction’ [13].
Jan 21US FDA accepts a sNDA for empagliflozin to reduce risk of CV death and hospitalisation for heart failure in adults with chronic heart failure with reduced ejection fraction, including those with and without type 2 diabetes [12].
Aug 20Filings planned by end of 2020 [11].
Jun 19US FDA grants Fast Track designation [6].

Category

Sodium glucose co-transporter type 2 (SGLT-2) inhibitor
Prevalence of asymptomatic ventricular dysfunction is approximately 4%. 1-2% of the adult population in developed countries have heart failure, with the prevalence rising to 10% in patients 70 years of age or older. Community estimates of prevalence vary from 1.6 to 4.6 cases per 1,000 in men aged 45-74 years and from 0.9 to 2.2 cases per 1,000 in women [1].
Chronic heart failure in patients with reduced ejection fraction, and with or without type 2 diabetes
Oral

Further information

Yes

Trial or other data

Oct 20PIII EMPEROR-Reduced study is published; the RCT (n=3730, class II-IV heart failure, ejection fraction ≤40%) found empagliflozin in addition to standard treatments reduced risk & total number of inpatient and outpatient worsening heart failure events (415 vs 519 patients, respectively; HR 0.76, 95% CI,0.67-0.87;p<0.0001) [10].
Jul 20PIII EMPEROR-Reduced trial has met its primary endpoint, demonstrating that empagliflozin is superior to placebo at reducing CV death or heart failure-related hospitalisation when added to standard of care (composite outcome) [9].
Mar 20PIII EMPEROR-Reduced study has finished recruiting; collection of primary outcome data now expected to complete Jun 20 [8].
Sep 19Data from a real-world study presented at the European Association for the Study of Diabetes annual meeting reported empagliflozin reduced the risk of heart failure hospitalisations by 26% vs GLP-1s [7].
May 19Estimated study completion date for EMPEROR-Preserved and EMPEROR-Reduced now Dec 19 [5].
Mar 18Boehringer Ingelheim announce expansion of the heart failure clinical trial program for empagliflozin. Two PIII randomised, placebo-controlled trials will assess the effect of empagliflozin on heart failure symptoms as well as the ability of people with heart failure to perform daily exercise, by measuring change from baseline to week 12 in exercise capacity as measured by the distance walked in 6 minutes. EMPERIAL-preserved [NCT03448406] will enrol patients (n=300) with preserved ejection fraction and EMPERIAL-reduced [NCT03448419] will enrol patients (n=300) with reduced ejection fraction. The trials are due to complete H1 2019 [4].
Jul 17EMPEROR-Preserved and EMPEROR-Reduced are currently recruiting. Collection of primary outcome data is expected to complete in Jun 20 [3].
Mar 17Boehringer Ingelheim initiates the EMPEROR (EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure) HF trial programme to evaluate once daily empagliflozin in heart failure patients, both with and without type 2 diabetes receiving current standard of care. The programme comprises of the two PIII, randomised, double-blind trials which will assess heart failure in patients with preserved ejection fraction (EMPEROR-Preserved; NCT03057951) or patients with reduced ejection fraction (EMPEROR-Reduced; NCT03057977). EMPEROR-Preserved trial is designed to enrol 4,126 patients in the US and Colombia; EMPEROR-Reduced trial will enrol 2,850 patients. Primary endpoint is time to first event of adjudicated CV death or adjudicated hospitalisation for heart failure [2].

Evidence based evaluations

JardianceChronic heart failure in patients with preserved ejection fraction, and with or without type 2 diabetes

Information

Jardiance
Licence extension / variation
Boehringer Ingelheim
Boehringer Ingelheim

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Jan 21Jan 21: PIII EMPEROR-Preserved study is ongoing with estimated primary completion date of Mar 21 [9]

Category

Sodium glucose co-transporter type 2 (SGLT-2) inhibitor
Prevalence of asymptomatic ventricular dysfunction is approximately 4%. 1-2% of the adult population in developed countries have heart failure, with the prevalence rising to 10% in patients 70 years of age or older. Community estimates of prevalence vary from 1.6 to 4.6 cases per 1,000 in men aged 45-74 years and from 0.9 to 2.2 cases per 1,000 in women [1].
Chronic heart failure in patients with preserved ejection fraction, and with or without type 2 diabetes
Oral

Evidence based evaluations

JardianceAcute stabilised heart failure in patients with or without T2D

Information

Jardiance
Licence extension / variation
Boehringer Ingelheim
Boehringer Ingelheim

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

Selective sodium glucose co-transporter type 2 (SGLT2) inhibitor
Acute heart failure is a common cause of admission to hospital (over 67,000 admissions in England and Wales a year) and is the leading cause of hospital admission in people 65 years or older in the UK [2].
Acute stabilised heart failure in patients with or without T2D
Oral

JardianceChronic kidney disease in patients with or without type 2 diabetes

Information

Jardiance
Licence extension / variation
Boehringer Ingelheim
Boehringer Ingelheim

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

Sodium glucose co-transporter type 2 inhibitor. Mechanisms in kidney disease not yet full understood, but the EMPA-REG OUTCOME trial had positive results for patients with chronic kidney disease, including reduction in glomerular pressure [1].
Chronic kidney disease is highly prevalent in various parts of the world, affecting approx. 10-15% of the population [1].
Chronic kidney disease in patients with or without type 2 diabetes
Oral

JardianceType 1 diabetes mellitus - adjunct to insulin

Information

Jardiance
Licence extension / variation
Boehringer Ingelheim
Boehringer Ingelheim

Development and Regulatory status

Discontinued
Discontinued
Not approved
Apr 20Company no longer plans to file in the EU and has discontinued development [18].
Mar 20FDA issue a complete response letter rejecting the supplemental New Drug Application (sNDA) in its current form [17].
Nov 19FDA advisory panel vote 14-2 against approval of empagliflozin as an add-on to insulin therapy in patients with type 1 diabetes, saying available data did not show benefits outweigh risks and there was a need for at least one additional study, with a larger sample size, to determine safety [16].
May 19NDA seeking marketing approval for empagliflozin 2.5 mg once daily as an adjunct to insulin therapy to improve glycemic control in adults with T1DM is filed in US [15].
May 18Will be filed in EU using centralised procedure [9].
Jul 15PIII [1].

Category

Sodium glucose co-transporter type 2 inhibitor
Currently, 3.8 million people in the UK are diagnosed with diabetes. Up to 1 million people have type 2 diabetes that is yet to be diagnosed, so the total is estimated to be 4.7 million people at present. This represents 7% of the UK population (1 in every 15 people) having diabetes (diagnosed and undiagnosed). 10% have type 1 diabetes [12]. Incidence is increasing by about 4% each year, particularly in children under five, with a 5% increase each year in this age group [13].
Type 1 diabetes mellitus - adjunct to insulin
Oral

Further information

Yes
To be confirmed

Trial or other data

Dec 18Results of EASE studies published in Diabetes Care [14].
Oct 18Further data from the PIII EASE program. The PIII EASE-2 trial showed that empagliflozin 10mg or 25mg as adjunctive to inSulin therapy in type 1 diabetes met its primary efficacy endpoint of change in HbA1C vs. placebo after 52 weeks. Mean change in HbA1C at week 26 was -0.54% and -0.53% for empaglifozin 10 and 25 mg, respectively. In the EASE-3 trial, which studied the 2.5, 10 and 25 mg doses over 26 weeks, mean change in HbA1C at week 26 was -0.28%, -0.45%, and -0.52 %at vs. placebo respectively. Secondary endpoints were also met, which included reductions in weight, blood pressure and total daily insulin dose. The safety profiles of the drug are consistent with those from previous studies.[11]
Jun 18Boehringer Ingelheim and Lilly announce positive data from EASE PIII program for empagliflozin as adjunct to insulin in T1DM. Both RCTs met primary endpoint of placebo-corrected change from baseline in HBA1c after 26 weeks of treatment for all investigated doses of empagliflozin (2.5, 10 and 25 mg) [10].
Jan 18PIII NCT02580591 completed Sep 17 and NCT02414958 Oct 17 [8].
Jan 17Estimated primary completion date of PIII (EASE-3; NCT02580591) is now Sep 17 [7].
Feb 16The EMA has confirmed recommendations to minimise the risk of diabetic ketoacidosis in patients taking SGLT2 inhibitors (a class of type 2 diabetes medicines)[6].
Oct 15EASE-3 is expected to complete in Feb 17 [5].
Sep 15PIII (EASE-3; NCT02580591) study initiated to assess the efficacy, pharmacokinetics, safety and tolerability of empagliflozin tablets (2.5mg, 5mg, 10mg and 25mg once daily) as adjunctive to insulin therapy over 26 weeks in patients with type 1 diabetes. The primary endpoint is to determine the change in HbA1C from baseline up to week 26 [4].
Jun 15The PRAC of the EMA has started a review of the SGLT2 inhibitors with the aim of evaluating their risk of diabetic ketoacidosis. PRAC recommendation is expected in Feb 16 [3].
Jun 15Boehringer Ingelheim, in collaboration with Eli Lilly, initiate the PIII EASE-2 trial to assess empagliflozin as adjunctive therapy to insulin in patients with type-1 diabetes (NCT02414958). 720 patients will be recruited from USA, Belgium, Canada and Finland, Australia, Austria, Czech Republic, Denmark, France, Germany, Netherlands, Norway, Poland, Spain, Sweden, Taiwan and UK. The study is expected to complete collection of primary outcome data (change in HbA1c) in Sep 16 [2].
Apr 14PIIa trial comparing three doses (2.5mg, 10mg and 25mg) of oral empagliflozin over 28 days as an adjunctive treatment to insulin therapy in 75 patients with type 1 diabetes mellitus completes (EASE-2; NCT01969747). The study enrolled patients from Austria and Germany [2].