Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial

doi:10.1016/S2213-8587(13)70084-6

The Lancet Diabetes & Endocrinology

Volume 1, Issue 3, November 2013, Pages 208-219

https://doi.org/10.1016/S2213-8587(13)70084-6 Get rights and content

Summary

Background

We aimed to investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium–glucose co-transporter 2, in patients with type 2 diabetes who had not received drug treatment in the preceding 12 weeks.

Methods

In our multicentre, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) who had not received oral or injected anti-diabetes treatment in the previous 12 weeks. Eligible patients had HbA_1c concentrations of 7–10%. We randomly allocated patients (1:1:1:1) with a computer-generated random sequence, stratified by region, HbA_1c, and estimated glomerular filtration rate at screening, to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily for 24 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA_1c at week 24 by ANCOVA in all randomly allocated patients who were treated with at least one dose of study drug and had a baseline HbA_1c value. This study is completed and registered with ClinicalTrials.gov, number NCT01177813.

Findings

Between Aug 12, 2010, and March 19, 2012, we randomly allocated 228 patients to receive placebo, 224 to receive empagliflozin 10 mg, 224 to receive empagliflozin 25 mg, and 223 to receive sitagliptin. Compared with placebo, adjusted mean differences in change from baseline HbA_1c at week 24 were −0·74% (95% CI −0·88 to −0·59; p<0·0001) for empagliflozin 10 mg, −0·85% (–0·99 to −0·71; p<0·0001) for empagliflozin 25 mg, and −0·73% (–0·88 to −0·59; p<0·0001) for sitagliptin. 140 (61%) patients in the placebo group reported adverse events (four [2%] severe and six [3%] serious), as did 123 (55%) patients in the empagliflozin 10 mg group (eight [4%] severe and eight [4%] serious), 135 (60%) patients in the empagliflozin 25 mg group (seven [3%] severe and five [2%] serious), and 119 (53%) patients in the sitagliptin group (five [2%] severe and six [3%] serious).

Interpretation

Empagliflozin provides a tolerable and efficacious strategy to reduce HbA_1c in patients with type 2 diabetes who had not previously received drug treatment.

Funding

Boehringer Ingelheim and Eli Lilly.

Introduction

Inhibition of the sodium–glucose co-transporter 2 (SGLT2) is an approach to reduce hyperglycaemia in patients with type 2 diabetes that does not directly target β-cell function or insulin resistance.¹ SGLT2 is located in the proximal tubule of the kidney and mediates about 90% of renal glucose reabsorption.¹ Inhibition of SGLT2 reduces such reabsorption, leading to increased urinary glucose excretion and improvement in glycaemic control with a low risk of hypoglycaemia.¹ Furthermore, urinary glucose excretion results in weight loss, possibly attributable to loss of calories,¹ and a reduction in blood pressure from osmotic diuresis.²

Empagliflozin is an oral, potent, and selective inhibitor of SGLT2 (half-maximum inhibitory concentration [IC₅₀] 3·1 nM, pIC₅₀ 8·5 [SE 0·02]), with a 2500-times higher selectivity for SGLT2 than SGLT1.³ In two phase 2 trials,4, 5 12 weeks' treatment with empagliflozin 5, 10, and 25 mg as monotherapy or empagliflozin 1, 5, 10, 25, and 50 mg as add-on to metformin in patients with type 2 diabetes was associated with improvements in glycaemic control, with a maximum placebo-corrected reduction in HbA_1c of 0·72%. In addition, placebo-corrected reductions in systolic blood pressure of up to 6 mm Hg and weight loss of about 1·5 kg were reported in patients treated with empagliflozin in these studies.4, 5

In our study, we aimed to assess the efficacy, safety, and tolerability of empagliflozin monotherapy compared with placebo and the dipeptidyl peptidase-4 (DPP4) inhibitor sitagliptin in previously untreated patients with type 2 diabetes, and to assess the efficacy and safety of open-label empagliflozin 25 mg in patients with poorly controlled diabetes (HbA_1c >10·0%).

Section snippets

Study design and participants

In our 24 week, double-blind, parallel-group, randomised phase 3 trial, we enrolled patients at 124 trial sites (academic medical centres, hospitals, and private practices) in nine countries, (Belgium, Canada, China, Germany, India, Ireland, Japan, Switzerland, and USA). We assessed eligibility of participants before and at the end of a 2 week open-label placebo run-in phase. Patients with previously untreated type 2 diabetes (no oral or injected anti-diabetes treatment for 12 weeks before

Results

Between Aug 12, 2010, and March 19, 2012, we randomly allocated 899 patients to treatment (table 1, figure 1). 803 (89%) of these patients completed the 24 week treatment period. We assigned 87 patients to open-label empagliflozin 25 mg, of whom 78 (90%) completed the 24 week treatment period. Figure 2 shows adjusted mean concentrations of HbA_1c over the 24 week treatment period. Reductions in HbA_1c at week 24 were greater with both doses of empagliflozin than they were with placebo (table 2,

Discussion

In our 24 week trial of previously untreated patients with type 2 diabetes and insufficient glycaemic control, treatment with empagliflozin 10 mg or 25 mg once daily as monotherapy led to significant and clinically meaningful improvements in HbA_1c, bodyweight, and systolic blood pressure, with a good tolerability profile (panel).

Although the reductions in HbA_1c we noted with empagliflozin were much the same as reductions with sitagliptin in patients with HbA_1c lower than 8·5% at baseline,

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Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors
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Efficacy and safety of empagliflozin, a sodium glucose cotransporter-2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycemia
Diabetes Obes Metab
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Empagliflozin as add-on to metformin for 24 weeks improves glycemic control in patients with type 2 diabetes (T2DM)
Diabetes
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Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week randomized, double-blind, placebo-controlled trial
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Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial
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Empagliflozin as add-on to basal insulin for 78 weeks improves glycemic control with weight loss in insulin-treated type 2 diabetes (T2DM)
Diabetes
(2013)

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Cited by (395)

Randomized Trial Comparing SGLT2 Inhibition and Hydrochlorothiazide on Sympathetic Traffic in Type 2 Diabetes
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Reductions in sympathetic nervous system activity may contribute to beneficial effects of sodium glucose cotransporter 2 (SGLT2) inhibition on cardiovascular outcomes. Therefore, we tested the hypothesis that SGLT2 inhibition with empagliflozin (Empa) lowers muscle sympathetic nerve activity (MSNA) in patients with type 2 diabetes mellitus (T2DM) compared with hydrochlorothiazide (HCT) to discern SGLT2-specific actions from responses to increased natriuresis.
We randomized patients with T2DM on metformin monotherapy to either 25 mg/d Empa (n = 20) or 25 mg/d HCT (n = 21) for 6 weeks in a parallel, double-blind fashion. We assessed MSNA by peroneal microneurography, blood pressure, cardiovascular and metabolic biomarkers at baseline and at the end of treatment.
Both drugs elicited volume depletion, as indicated by increased thoracic impedance. Compared with HCT, Empa caused 1.23 kg more body weight loss (P = 0.011) and improved glycemic control. Seated systolic blood pressure decreased with both treatments (P < 0.002). MSNA did not change significantly with either treatment; however, MSNA changes were negatively correlated with changes in body weight on Empa (P = 0.042) and on HCT(P = 0.001). The relationship was shifted to lower MSNA on Empa compared with HCT (P = 0.002).
Increased renal sodium excretion eliciting body weight loss may promote sympathetic activation. However, sympathetic excitation in the face of increased sodium loss may be attenuated by SGLT2 inhibitor-specific actions.
Glucometabolic control of once-weekly dulaglutide switched from DPP4 inhibitor versus daily empagliflozin add-on in patients with type 2 diabetes inadequately controlled with metformin, sulfonylurea, and DPP4 inhibitor: A randomised trial
2023, Diabetes Research and Clinical Practice
To compare the effectiveness and safety of empagliflozin and dulaglutide in patients with type 2 diabetes (T2D) inadequately controlled by oral triple therapy.
In this 24-week, multi-center, randomized trial, patients with T2D and HbA_1c level ≥7.5% (58 mmol/mol) on metformin, sulfonylurea, and dipeptidyl peptidase 4 inhibitor (DPP4-i) were randomly assigned into two groups: daily empagliflozin add-on or once-weekly dulaglutide switched from DPP4-i. The primary endpoint was changes from baseline HbA_1c at 24 weeks.
In total, 152 patients were recruited to the empagliflozin-added quadruple group (n = 76) or the switched-to-dulaglutide triple group (n = 76). At week 24, both groups showed significant reduction in HbA1c level from baseline with greater reduction with empagliflozin (the mean treatment difference: –0.27% [95% CI –0.50 to –0.04, p = 0.024]) (–2.88 mmol/mol [95% CI –5.37 to –0.39], p = 0.024). Empagliflozin significantly reduced body weight from baseline to week 24 (–1.72 kg [95% CI –1.98 to –0.59, p < 0.001]). No serious adverse events were reported with either empagliflozin or dulaglutide.
Empagliflozin, compared with once-weekly dulaglutide switched from DPP4-i, demonstrated greater HbA_1c reduction and weight loss in patients with T2D inadequately controlled with metformin, sulfonylurea, and DPP4-i.
Trial registration: cris.nih.go.kr (KCT0006157)
Empagliflozin in South Asians with type 2 diabetes: Real world data on effects on cardiometabolic parameters, safety and determinants of response to therapy from a diabetes practice in Sri Lanka
2023, Primary Care Diabetes
SGLT2 inhibitors provide cardiovascular and renal protection in people with type 2 diabetes (T2DM). Real-world data on their effect on improving glucose and cardiovascular risk factors, and adverse effects in South Asians are limited.
We retrospectively analyzed clinical, demographic, anthropometric and biochemical data among adults with T2DM, commenced on empagliflozin and followed up for at least one month in a diabetes clinic in Colombo.
Among 1523 participants (men 49.6 %, age 54.9 (± 10.8) years, diabetes duration 11.5 (± 7.6) years, body mass index 28.2 (± 4.5 kg/m²), over a median follow up of 12 months (range: 1–24 months), reduction in HbA1c, weight, systolic blood pressure (SBP) and urine albumin-creatinine ratio were evident within the first month. Benefits sustained up to two-years (mean changes from baseline: HbA1c − 0.31 (± 1.49), weight − 1.14 (± 4.17), SBP − 3.44 (± 21.75), UACR − 19.84 (± 108.22) follow up. eGFR declined by the third month, returned to baseline by 12th and remained stable over 24 months. Higher baseline HbA1c, weight and SBP predicted greater decline in HbA1c, weight and SBP respectively. Weight reduction independently predicted the SBP reduction. Eighteen participants per 100 patient-years discontinued therapy due to adverse effects: genital mycotic infections and features of hypovolaemia were the commonest. We observed only two events of diabetic ketoacidosis.
Empagliflozin effectively improves glucose, weight and SBP and retards progression of renal impairment in South Asians with T2D. Genital mycotic infections and hypovolaemia were the commonest reasons for discontinuation. Careful patient selection and advice can avoid other sinister complications.
Budget Impact Analysis of Empagliflozin in the Treatment of Patients With Type 2 Diabetes With Established Cardiovascular Disease in South Africa
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This study aimed to estimate the budget impact and affordability of empagliflozin added to usual care compared with usual care alone, in a diabetic population with established cardiovascular disease, from a private healthcare payer perspective in South Africa.
A budget impact model was adapted and localized. Epidemiological data were obtained from the South African Council for Medical Schemes. Clinical event rates were sourced from the EMPA-REG OUTCOME trial and drug costs from list prices. Clinical event costs were derived from a claims data analysis of the South African private healthcare sector and microcosting. Scenario analyses were performed on select inputs. The modeled outcomes included annual budget impact of empagliflozin, the incremental cost per life per month, cardiovascular deaths averted, and incremental cost per life saved, over 3 years.
A total of 9 503 patients were eligible for empagliflozin (year 1), 12 670 (year 2), and 16 947 (year 3). The incremental cost was $1 272 297, $1 764 705, and $2 455 235, for years 1 to 3, respectively. The incremental cost per beneficiary per month was calculated as $0.012 (year 1), $0.016 (year 2), and $0.023 (year 3). The model estimated a 38.6% reduction in cardiovascular deaths, 305 lives saved, and an incremental cost per life saved of $17 999.
Adding empagliflozin to usual care has a marginal budget implication and is highly affordable for private healthcare payers, with an acceptable incremental cost based on clinical outcomes.
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ArticlesEmpagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia

Diabetes Obes Metab

Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans

Kidney Int Suppl

Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors

Diabetes Obes Metab

A phase IIb, randomised, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes

Diabetes Obes Metab

Efficacy and safety of empagliflozin, a sodium glucose cotransporter-2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycemia

Diabetes Obes Metab

Empagliflozin as add-on to metformin for 24 weeks improves glycemic control in patients with type 2 diabetes (T2DM)

Diabetes

Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week randomized, double-blind, placebo-controlled trial

Diabetes Care

Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial

Diabetes Obes Metab

Empagliflozin as add-on to basal insulin for 78 weeks improves glycemic control with weight loss in insulin-treated type 2 diabetes (T2DM)

Diabetes

Articles
Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial