Empagliflozin

Empagliflozin after Acute Myocardial Infarction

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Abstract

BACKGROUND

Empagliflozin improves cardiovascular outcomes in patients with heart failure, patients with type 2 diabetes who are at high cardiovascular risk, and patients with chronic kidney disease. The safety and efficacy of empagliflozin in patients who have had acute myocardial infarction are unknown.

METHODS

In this event-driven, double-blind, randomized, placebo-controlled trial, we assigned, in a 1:1 ratio, patients who had been hospitalized for acute myocardial infarction and were at risk for heart failure to receive empagliflozin at a dose of 10 mg daily or placebo in addition to standard care within 14 days after admission. The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis.

RESULTS

A total of 3260 patients were assigned to receive empagliflozin and 3262 to receive placebo. During a median follow-up of 17.9 months, a first hospitalization for heart failure or death from any cause occurred in 267 patients (8.2%) in the empagliflozin group and in 298 patients (9.1%) in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). With respect to the individual components of the primary end point, a first hospitalization for heart failure occurred in 118 patients (3.6%) in the empagliflozin group and in 153 patients (4.7%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98), and death from any cause occurred in 169 (5.2%) and 178 (5.5%), respectively (hazard ratio, 0.96; 95% CI, 0.78 to 1.19). Adverse events were consistent with the known safety profile of empagliflozin and were similar in the two trial groups.

CONCLUSIONS

Among patients at increased risk for heart failure after acute myocardial infarction, treatment with empagliflozin did not lead to a significantly lower risk of a first hospitalization for heart failure or death from any cause than placebo. (Funded by Boehringer Ingelheim and Eli Lilly; EMPACT-MI ClinicalTrials.gov number, NCT04509674.)

After acute myocardial infarction, patients are at increased risk for heart failure and death, particularly if they present with congestion or a decreased left ventricular ejection fraction.1-3 Treatment with sodium–glucose cotransporter 2 (SGLT2) inhibitors improves cardiovascular outcomes in high-risk patients with type 2 diabetes, those with chronic kidney disease, and those with heart failure with a reduced or preserved left ventricular ejection fraction.4 In the EMMY trial (Impact of Empagliflozin on Cardiac Function and Biomarkers of Heart Failure in Patients with Acute Myocardial Infarction), patients who received empagliflozin after an acute myocardial infarction had a reduced natriuretic peptide concentration, an increased left ventricular ejection fraction, and a decreased cardiac volume; however, this trial was not designed to assess clinical outcomes.5 The DAPA-MI trial (Dapagliflozin Effects on Cardiometabolic Outcomes in Patients with an Acute Heart Attack) was limited by the small number of clinical events during the trial and therefore was unable to assess the effects of SGLT2 inhibitor therapy after myocardial infarction on rates of death or hospitalizations for heart failure.6

Here, we report the results of the EMPACT-MI trial (Study to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction), in which empagliflozin was compared with placebo with respect to the risk of hospitalization for heart failure or death among patients with acute myocardial infarction and either a new reduction in left ventricular ejection fraction or signs or symptoms of congestion (or both).

Methods

TRIAL OVERSIGHT

The EMPACT-MI trial was an international, event-driven, double-blind, randomized, placebo-controlled trial. The trial design has been described previously.7 The trial was approved by the ethics committee at each trial site, and all the patients provided written informed consent. The trial sponsors were Boehringer Ingelheim and Eli Lilly. The trial protocol (available with the full text of this article at NEJM.org) was developed and amended by the executive and steering committees, which included employees of Boehringer Ingelheim (who represented the sponsors) and provided scientific oversight on the development of the statistical analysis plan (available with the protocol), patient recruitment and follow-up, and data analysis. An independent data monitoring committee reviewed the safety data. Statistical analyses were performed by employees of Boehringer Ingelheim with oversight by the executive committee, and key analyses were verified by an independent statistician. The first author prepared the first draft of the submitted manuscript, which was reviewed and edited by all the authors. The first and last authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol and the statistical analysis plan.

PATIENTS

Patients were men and women 18 years of age or older who had been hospitalized with an acute myocardial infarction within 14 days before randomization and had either evidence of a newly developed left ventricular ejection fraction of less than 45% or signs or symptoms of congestion that resulted in treatment during the index hospitalization (or both). Patients needed to have at least one additional enrichment factor (a clinical factor that was known to be associated with hospitalization for heart failure or death from any cause), including an age of 65 years or older; a newly developed ejection fraction of less than 35%; a history of myocardial infarction, atrial fibrillation, or type 2 diabetes; an estimated glomerular filtration rate (GFR) of less than 60 ml per minute per 1.73 m2 of body-surface area; an elevated natriuretic peptide or uric acid level; an elevated pulmonary artery or right ventricular systolic pressure; three-vessel coronary artery disease; peripheral artery disease; or no revascularization for the index myocardial infarction. Patients with a previous diagnosis of heart failure, as well as those who were taking or planning to take SGLT2 inhibitors, were excluded. A full list of eligibility criteria is provided in the Supplementary Appendix (available at NEJM.org) and was published previously.7

TRIAL DESIGN

Patients who met the eligibility criteria were randomly assigned in a 1:1 ratio to receive empagliflozin at a dose of 10 mg daily or placebo in addition to standard care. Randomization was performed with the use of interactive response technology and was stratified according to type 2 diabetes status and geographic region (North America, Latin America, Europe, or Asia). The EMPACT-MI trial had a streamlined design, with the collection of essential data only, including information about specific safety events, and mainly remote follow-up of patients (by means of a Web-based application or a telephone call) with only a few face-to-face visits; the trial assessed investigator-reported end-point events rather than centrally adjudicated end-point events.

After randomization, patients had a remote visit at 2 weeks, a face-to-face visit at 6 months, and remote visits every 6 months thereafter until the end of the trial, when a final telephone call was performed. During these visits, data on prespecified end points, safety events, and adherence to the trial regimen were collected. Data on all concomitant medications were collected for 6 months after randomization; thereafter, medication data were collected only on open-label initiation of treatment with SGLT2 inhibitors or combined treatment with SGLT1 and SGLT2 inhibitors. Because of the established safety profile of empagliflozin,8-10 we used focused safety reporting, in which the investigators reported only serious adverse events, adverse events that led to discontinuation of the trial regimen for at least 7 consecutive days, and adverse events of special interest. All the patients who underwent randomization were followed for the duration of the trial, regardless of whether they received empagliflozin or placebo.

TRIAL END POINTS

The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis. The key secondary end points in the prespecified hierarchical testing strategy were the total number of hospitalizations for heart failure or death from any cause, the total number of nonelective cardiovascular hospitalizations or death from any cause, the total number of nonelective hospitalizations for any cause or death from any cause, and the total number of hospitalizations for myocardial infarction or death from any cause. Additional prespecified end points are described in the Supplementary Appendix. In lieu of central adjudication, end-point events were reviewed and categorized according to prespecified definitions by investigators at the trial sites who were unaware of trial-group assignment and had received training in reviewing end-point events. Investigator-reported end-point events were verified according to the algorithm described in the Supplementary Appendix.

STATISTICAL ANALYSIS

In this event-driven trial, we estimated that 532 patients with a primary end-point event would provide the trial with 85% power to detect a 23% lower risk of an event in the empagliflozin group than in the placebo group, with a two-sided type I error of 0.05. The original protocol planned for the enrollment of 3312 patients, with an option to increase enrollment to 5000 patients if the accrual of events was slower than expected. The sample size was further increased to 6500. These decisions were made on the basis of blinded trial data, with no change to the target number of events or revisions to effect-size projections or power calculations. No interim efficacy analyses were performed.

The analyses of the primary composite end point and its components were performed according to the intention-to-treat principle and included all the patients who underwent randomization. The differences between the empagliflozin and placebo groups in the risk of a primary end-point event were assessed with the use of a Cox proportional-hazards model that included the baseline covariates of age, geographic region, estimated GFR (<45, 45 to <60, 60 to <90, or ≥90 ml per minute per 1.73 m2 according to the Chronic Kidney Disease Epidemiology Collaboration formula), left ventricular ejection fraction (<35% or ≥35%), type 2 diabetes status, persistent or permanent atrial fibrillation, previous myocardial infarction, peripheral artery disease, and smoking status. Data for patients who did not have a primary end-point event were censored on the last day they were known to have been free of the event, which may have been the last time point before the patient was lost to follow-up (under the assumption of noninformative censoring).

A prespecified hierarchical testing procedure was used, beginning with the primary end point and then proceeding to the set of key secondary end points. A Hochberg step-up procedure was used to assess the first and second key secondary end points at the same level of hierarchy, with the next two key secondary end points subsequently tested in a hierarchical manner.

All key secondary end points were analyzed with the use of a negative binomial regression model that included the same covariates as the primary model and the logarithm of time as an adjustment for observation time. The observation time started on the day of randomization and ended on the last day when information about end-point events was collected for an individual patient, which may have been the last time point before the patient was lost to follow-up. Post hoc sensitivity analyses that accounted for the competing risks of death from any cause and death from cardiovascular causes were performed with the use of Fine and Gray models for time to a first hospitalization for heart failure, time to death from cardiovascular causes, and time to a first hospitalization for heart failure or death from cardiovascular causes. Safety analyses included all the patients who received at least one dose of empagliflozin or placebo. The confidence intervals for the secondary and exploratory end points were not adjusted for multiplicity and should be interpreted as exploratory.

Results

PATIENTS

From December 2020 through March 2023, a total of 6610 patients at 451 sites in 22 countries were screened, of whom 6522 were randomly assigned to receive empagliflozin at a dose of 10 mg daily (3260 patients) or placebo (3262 patients). The median time from admission to randomization was 5 days (interquartile range, 3 to 8). The characteristics of the patients at baseline were similar in the two trial groups (Table 1).11 A total of 78.4% of the patients had a left ventricular ejection fraction of less than 45%, and 57.0% had signs or symptoms of congestion that resulted in treatment during the index hospitalization. Among the patients with signs or symptoms of congestion, 20.6% had a left ventricular ejection fraction of at least 45%. The most common enrichment factors included an age of 65 years or older (in 50.0% of the patients), type 2 diabetes (in 31.9%), and three-vessel coronary artery disease (in 31.0%); 70.5% of the patients had more than one enrichment factor (Table S1 in the Supplementary Appendix). Nearly 75% of the patients who underwent randomization presented with ST-segment elevation myocardial infarction (STEMI), and revascularization for the index myocardial infarction was performed in 89.3%.

TABLE 1

Characteristics of the Patients at Baseline.

The trial regimen was stopped prematurely for reasons other than death in 684 patients (21.2%) in the empagliflozin group and in 716 patients (22.2%) in the placebo group. A total of 436 patients (6.7%) started treatment with an open-label SGLT2 inhibitor during the trial, including 201 (6.2%) in the empagliflozin group and 235 (7.2%) in the placebo group. A total of 6328 patients (97.0%) were followed until the end of the trial for the occurrence of a primary end-point event, and 6467 patients (99.2%) had data on vital status available at the end of the trial (Fig. S1). The median duration of follow-up was 17.9 months, and the median duration of exposure to empagliflozin or placebo was similar in the two trial groups (Table S4). Adherence to the trial regimen is shown in Table S5.

END POINTS

A primary end-point event — a first hospitalization for heart failure or death from any cause — occurred in 267 of 3260 patients (8.2%) in the empagliflozin group and in 298 of 3262 patients (9.1%) in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). With respect to the individual components of the primary end point, a first hospitalization for heart failure occurred in 118 patients (3.6%) in the empagliflozin group and in 153 patients (4.7%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98), and death from any cause occurred in 169 (5.2%) and 178 (5.5%), respectively (hazard ratio, 0.96; 95% CI, 0.78 to 1.19) (Table 2 and Figure 1). Results for the primary end point, a first hospitalization for heart failure, and death from any cause were consistent across subgroups (Figure 2 and Figs. S2 and S3). Results for the primary end point were consistent across sensitivity analyses, which included additional categories of hospitalization for heart failure (Fig. S4). Causes of death are shown in Table S6.

FIGURE 1

Kaplan–Meier Estimates and Cumulative Incidence Function for the Composite Primary End Point and Its Components.

FIGURE 2

Composite Primary End Point, According to Prespecified Subgroups.

TABLE 2

Primary, Secondary, and Other End Points.

Results for key secondary end points are shown in Table 2. The rate ratio (empagliflozin vs. placebo) was 0.87 (95% CI, 0.68 to 1.10) for the total number of hospitalizations for heart failure or death from any cause, 0.92 (95% CI, 0.78 to 1.07) for the total number of nonelective cardiovascular hospitalizations or death from any cause, 0.87 (95% CI, 0.77 to 1.0) for the total number of nonelective hospitalizations for any cause or death from any cause, and 1.06 (95% CI, 0.83 to 1.35) for the total number of hospitalizations for myocardial infarction or death from any cause.

With respect to exploratory end points, death from cardiovascular causes occurred in 132 patients (4.0%) in the empagliflozin group and in 131 patients (4.0%) in the placebo group (hazard ratio, 1.03; 95% CI, 0.81 to 1.31). The time to death from cardiovascular causes and the time to a first hospitalization for heart failure or death from cardiovascular causes were similar in the two trial groups (Figs. S5 and S6). The total number of hospitalizations for heart failure was 148 in the empagliflozin group and 207 in the placebo group, with a rate of 2.4 and 3.6 events, respectively, per 100 patient-years (rate ratio, 0.67; 95% CI, 0.51 to 0.89). Results of sensitivity analyses that accounted for the competing risks of death from any cause or death from noncardiovascular causes were consistent with those from Cox regression models (data not shown).

SAFETY

A similar percentage of patients in the two trial groups had a serious adverse event (23.7% in the empagliflozin group and 24.7% in the placebo group) or an adverse event that resulted in permanent discontinuation of the trial regimen (3.8% in each group) (Table 3). Contrast-induced acute kidney injury occurred in 8 patients (0.2%) in the empagliflozin group and in 9 patients (0.3%) in the placebo group.

TABLE 3

Adverse Events in the Safety Population.

Discussion

In the EMPACT-MI trial, empagliflozin treatment did not lead to a significantly lower risk of a composite primary end-point event — a first hospitalization for heart failure or death from any cause — than placebo among patients presenting with an acute myocardial infarction and an increased risk of heart failure. The rates of prespecified key secondary end-point events did not differ substantially in the two trial groups.

Recently, the DAPA-MI trial, which excluded patients with diabetes, did not show a lower risk of death from cardiovascular causes or hospitalization for heart failure with dapagliflozin therapy than with placebo after acute myocardial infarction.6 The prespecified composite primary end point in the DAPA-MI trial was changed to a seven-level win ratio. The actual numbers of heart-failure events or deaths were too few to allow for any meaningful conclusion.12 The data from the EMPACT-MI trial help fill the gap in knowledge about the effect of SGLT2 inhibitors in patients after acute myocardial infarction.

Certain factors may have contributed to the lack of an effect of empagliflozin on the primary composite end point in the EMPACT-MI trial. Deaths from any cause composed 52% of the primary end-point events and occurred in a similar percentage of patients in the two trial groups. By design, we enrolled patients soon after acute myocardial infarction, a time when several mechanisms that may not be amenable to modification with SGLT2 inhibition, which include cardiac causes (e.g., stent thrombosis, recurrent myocardial infarction, mechanical complications, and scar-related ventricular arrhythmias) and noncardiac causes within the first 30 days, contribute to mortality.13

As in our trial, the sample size in the PARADISE-MI trial (Prospective ARNI versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events after Myocardial Infarction) was increased because of low rates of primary end-point events — 6.7 and 7.4 events per 100 patient-years in the valsartan–sacubitril and ramipril groups, respectively.14,15 These rates and the rates in our trial are lower than those observed in previous trials and observational studies.16,17 The reasons for this may be related to multiple factors, including the widespread use of medical therapies, timely access to revascularization after myocardial infarction, and the coronavirus disease 2019 (Covid-19) pandemic, as well as regional wars in the case of the EMPACT-MI trial.18

The number and percentage of heart-failure events that contributed to the primary end point may have been affected by several factors. Our trial was conducted during the Covid-19 pandemic, when the number of hospitalizations for heart failure decreased substantially.19 Patients with less severe symptoms may not have sought care or may have been treated in the outpatient setting. In addition, two of the regions where our trial was conducted were affected by war.20 Heart-failure events other than hospitalization were not included in the primary end point. In some other trials, outpatient heart-failure events have contributed meaningfully to the total burden of heart-failure events. For example, of the 4744 patients randomly assigned to receive dapagliflozin or placebo in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), 549 were hospitalized for heart failure, 33 had a heart-failure event that resulted in the receipt of intravenous diuretic therapy in the outpatient setting, and 604 had a worsening heart-failure event that resulted in the initiation or intensification of oral diuretic therapy in the outpatient setting.21 Whether the inclusion of a broader measure of the burden of heart failure in the primary end point would have affected the results of our trial is unclear.

In our trial, some of the patients with a lower left ventricular ejection fraction or congestion at the time of randomization may have had a stunned myocardium that was reversible; further improvement after revascularization is unlikely in this lower-risk population.3,22,23 This might be the case particularly in patients with STEMI, who composed nearly 75% of the patients in the EMPACT-MI trial, in which approximately 90% of the patients underwent early revascularization.

Previous trials involving patients with established heart failure or with type 2 diabetes and atherosclerotic cardiovascular disease have shown reductions of 29 to 35% in the relative risk of hospitalization for heart failure among patients treated with SGLT2 inhibitors as compared with patients who received placebo.8–10,24,25 The findings of our exploratory analyses of a first hospitalization for heart failure and the total number of hospitalizations for heart failure in the empagliflozin group as compared with the placebo group appear to be consistent with the results of these previous trials, and further study of the effects of SLGT2 inhibitors on heart-failure outcomes in high-risk patients after myocardial infarction may be warranted.

We did not observe evidence of increased rates of serious adverse events, adverse events that resulted in permanent discontinuation of the trial regimen, or adverse events of special interest. The data from EMPACT-MI trial further build on the safety profile of SGLT2 inhibitors in patients across the spectrum of cardiovascular risks and provide evidence for the safety of these agents in hospitalized patients.8,26,27

Our trial has limitations. The end-point events were not centrally adjudicated but were assessed by site investigators according to prespecified definitions. Outpatient heart-failure events were not analyzed as clinical end points. Despite our attempts to improve the representation of women, older adults, and historically underrepresented racial and ethnic minorities in this trial, their representation remained suboptimal. Some patients in these groups are at increased risk for heart failure after myocardial infarction, and further work is needed to improve their representation (Table S3).1,28 Only focused safety data were collected.

In the current trial, empagliflozin did not reduce the risk of the composite primary end-point event — a first hospitalization for heart failure or death from any cause — in patients with acute myocardial infarction who were at increased risk for heart failure.

One Class of Antidiabetic Linked With Lower Kidney Stone Risk

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Study compared SGLT2 inhibitors with GLP-1 agonists and DPP-4 inhibitors

A computer rendered cross section of kidneys with kidney stones

One class of glucose-lowering agent may help lower the risk of kidney stones in adults with type 2 diabetes, a cohort study suggested.

Adults who newly started on an SGLT2 inhibitor had a 31% lower risk of nephrolithiasis compared with those starting on a GLP-1 receptor agonist (HR 0.69, 95% CI 0.67-0.72), found Julie M. Paik, MD, ScD, MPH, of Brigham and Women’s Hospital in Boston, and colleagues. This equated to 14.9 versus 21.3 nephrolithiasis events per 1,000 person-years for new SGLT2 and GLP users over a median 192-day follow-up, respectively.

New SGLT2 users also had a significantly lower risk of nephrolithiasis when compared with new initiators of a DPP-4 inhibitor (HR 0.74, 95% CI 0.71-0.77), the group reported in JAMA Internal Medicineopens in a new tab or window. This equated to 14.6 versus 19.9 nephrolithiasis events per 1,000 person-years for SGLT and DPP-4 users, respectively.

These findings didn’t come as much of a surprise to the researchers, Paik told MedPage Today, given what is already known about SGLT2 inhibitors and their renoprotective benefits. According to the study, the reduced kidney stone risk with SGLT2 inhibitor use could be explained by the drugs’ ability to increase urinary citrate excretion or urinary bicarbonate excretion, their anti-inflammatory properties, or by increasing urine flow.

Currently, a few FDA-approved SGLT2 inhibitors have diabetes, kidney, and cardiovascular protection indications on their labels, including empagliflozin (Jardiance)opens in a new tab or window, dapagliflozin (Farxiga)opens in a new tab or window, and canagliflozin (Invokana).

“However, there had been no prior studies looking at the association between the use of this newer class of diabetes medication and the risk of kidney stones in a U.S. population receiving routine care,” she said. “The risk of kidney stones in a patient might be one additional consideration for a clinician to take into account when choosing among the different glucose-lowering agents for patients with type 2 diabetes.”

That being said, she pointed out that their study only included patients with type 2 diabetes and therefore it’s still unclear how this class of medications might modify risk in patients without type 2 diabetes but at risk for kidney stones.

In subgroup analyses, Paik’s group found that kidney stone risk was still significantly lower with SGLT2 inhibitors across various age groups, sex, race, and BMI. The only subgroup that didn’t have a lower nephrolithiasis risk were those falling into early chronic kidney disease (CKD) stages (1 to 2), but those in higher stages (3 to 4) had a significantly lower risk.

While all ages had significantly lower nephrolithiasis risk with SGLT2 inhibitors, the magnitude of the risk reduction was greater among those under 70 years.

The researchers pulled data on 716,406 adults with type 2 diabetes from Optum’s deidentified Clinformatics Data Mart Database (2013-2020), IBM MarketScan (2013-2019), and Medicare Fee-for-Service Parts A, B, and D (2013-2018). For inclusion, all patients had to be new adult users of an SGLT2 inhibitor, GLP-1 agonist, or DPP-4 inhibitor between 2013 and 2020. Those with a prior history of kidney or urinary tract stones were excluded. Nephrolithiasis was diagnosed by ICD codes in the inpatient or outpatient setting.

New SGLT2 users were propensity-score matched 1:1 to new users of GLP agonists and DPP-4 inhibitors.

Prior to matching, patients starting GLP agonists were more likely to be female and to have seen an endocrinologist or nephrologist; were more likely to have a higher combined comorbidity score, obesity, or CKD stage 3 to 4; and were more likely to be on insulin or a loop diuretic but less likely to be taking metformin.

The group initiating DPP-4 inhibitors were more likely to be older, to have seen a nephrologist, and to be taking a loop diuretic or an antihypertensive agent. They were also more likely to have a higher combined comorbidity score, CKD stage 3 to 4, heart failure, cerebrovascular disease, or a history of a urinary tract infection or acute kidney injury. This group was also less likely to have obesity, to be taking insulin, and to have seen an endocrinologist.

In the SGLT2- and GLP-matched cohort, the average age was 61 years, 51% were women, 71% were white, 40% had obesity, 7% had CKD stage 3 to 4, and 4% had a history of gout. In the cohort matched with DPP-4 inhibitors, the average age was 62 years, 47% were women, 62% were white, 34% had obesity, 6% had CKD stage 3 to 4, and 4% had a history of gout.

Because nephrolithiasis occurrence was measured with diagnostic codes, Paik’s group warned there was the potential for some outcome misclassification. Also, they couldn’t tell if kidney stones were new or recurrent, nor tell the composition of the stones.

Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the empa-kidney trial

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Summary

Background

Sodium–glucose co-transporter-2 (SGLT2) inhibitors reduce progression of chronic kidney disease and the risk of cardiovascular morbidity and mortality in a wide range of patients. However, their effects on kidney disease progression in some patients with chronic kidney disease are unclear because few clinical kidney outcomes occurred among such patients in the completed trials. In particular, some guidelines stratify their level of recommendation about who should be treated with SGLT2 inhibitors based on diabetes status and albuminuria. We aimed to assess the effects of empagliflozin on progression of chronic kidney disease both overall and among specific types of participants in the EMPA-KIDNEY trial.

Methods

EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA), and included individuals aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 20 to less than 45 mL/min per 1·73 m2, or with an eGFR of 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher. We explored the effects of 10 mg oral empagliflozin once daily versus placebo on the annualised rate of change in estimated glomerular filtration rate (eGFR slope), a tertiary outcome. We studied the acute slope (from randomisation to 2 months) and chronic slope (from 2 months onwards) separately, using shared parameter models to estimate the latter. Analyses were done in all randomly assigned participants by intention to treat. EMPA-KIDNEY is registered at ClinicalTrials.gov, NCT03594110.

Findings

Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and then followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroups of eGFR included 2282 (34·5%) participants with an eGFR of less than 30 mL/min per 1·73 m2, 2928 (44·3%) with an eGFR of 30 to less than 45 mL/min per 1·73 m2, and 1399 (21·2%) with an eGFR 45 mL/min per 1·73 m2 or higher. Prespecified subgroups of uACR included 1328 (20·1%) with a uACR of less than 30 mg/g, 1864 (28·2%) with a uACR of 30 to 300 mg/g, and 3417 (51·7%) with a uACR of more than 300 mg/g. Overall, allocation to empagliflozin caused an acute 2·12 mL/min per 1·73 m2 (95% CI 1·83–2·41) reduction in eGFR, equivalent to a 6% (5–6) dip in the first 2 months. After this, it halved the chronic slope from –2·75 to –1·37 mL/min per 1·73 m2 per year (relative difference 50%, 95% CI 42–58). The absolute and relative benefits of empagliflozin on the magnitude of the chronic slope varied significantly depending on diabetes status and baseline levels of eGFR and uACR. In particular, the absolute difference in chronic slopes was lower in patients with lower baseline uACR, but because this group progressed more slowly than those with higher uACR, this translated to a larger relative difference in chronic slopes in this group (86% [36–136] reduction in the chronic slope among those with baseline uACR <30 mg/g compared with a 29% [19–38] reduction for those with baseline uACR ≥2000 mg/g; ptrend<0·0001).

Interpretation

Empagliflozin slowed the rate of progression of chronic kidney disease among all types of participant in the EMPA-KIDNEY trial, including those with little albuminuria. Albuminuria alone should not be used to determine whether to treat with an SGLT2 inhibitor.

Discussion

Our analyses showed that, in this cohort of patients with chronic kidney disease at risk of progression, allocation to empagliflozin caused a small dip in kidney function of approximately 2 mL/min per 1·73 m2 (or 6%) and then halved the subsequent rate of long-term loss of kidney function. This overall result complements the 29% (95% CI 19–38) reduction in risk of kidney disease progression when assessed with the categorical composite outcome of end-stage kidney disease, a sustained decrease from baseline in eGFR of at least 40% or to less than 10 mL/min per 1·73 m2, or death from kidney failure. The beneficial effects of empagliflozin on the progression of chronic kidney disease varied by diabetes status and eGFR, but most prominently by albuminuria, where relative benefits might in fact be larger among participants with lower albuminuria. These findings are consistent with observations in other trials of SGLT2 inhibitors in chronic kidney disease, although these trials focused on patients with diabetes, significant levels of albuminuria, or both.

13

,  

14

 The broad range of patients included in the large EMPA-KIDNEY trial has allowed this to be explored in a more diverse population than those included in other large trials of SGLT2 inhibition in chronic kidney disease; in particular, EMPA-KIDNEY included participants with an eGFR of less than 25 mL/min per 1·73 m2 and with a uACR of less than 200 mg/g who were excluded from these previous trials.

The acute dip in eGFR when empagliflozin was initiated in EMPA-KIDNEY was modest (in all participant subgroups; it was on average ❤ mL/min per 1·73 m2 or <10% of baseline eGFR) and was largely reversible when treatment was discontinued. The acute effect was larger among participants with diabetes than in those without (on both absolute and relative scales), which might reflect the greater prevalence and degree of hyperfiltration in this group. The acute effect of SGLT2 inhibition on kidney function was recognised early in the development of this drug class (although not in all studies

23

) and is believed to be due to the acute reduction in intraglomerular pressure caused by afferent arteriolar vasoconstriction stimulated by increased sodium delivery to the macula densa.

24

,  

25

 The associated rapid reduction in albuminuria supports this hypothesis,

26

 and this reduction in intraglomerular pressure is one of the postulated mechanisms of the beneficial effects of SGLT2 inhibition on kidney function.

25

 Our exploratory analyses suggest that the reduction in albuminuria might be the most important measured determinant of the benefits observed in EMPA-KIDNEY, explaining a fifth of the effect on chronic slopes and two-fifths of the effect on the primary composite outcome of kidney disease progression, consistent with analyses from other trials in chronic kidney disease.

27

 These analyses need to be interpreted with some caution because they could have been subject to bias due to measurement error and residual mediator–outcome confounding. Whether this association is due to avoidance of direct toxic effects of albumin on tubular function, a reduction in intraglomerular pressure, or another unmeasured correlate of urinary albumin is not clear. However, these analyses also suggest that other mechanisms unrelated to albuminuria, blood pressure, or glycaemic control contribute to the benefit of SGTL2 inhibition on kidney function.

Our analyses focused on chronic slopes. Although effects on total slope correlate strongly with effects on clinical outcomes over short (2–3-year) follow-up periods,

8

 the chronic slope is likely to be more informative for longer time periods. When the magnitude of the acute dip correlates with the relative reduction in the chronic slope (which is plausible because they share causal mechanisms, such as reduced intraglomerular pressure), this reduces variation between subgroups in total slope when measured over 2–3 years. However, this would not be the case with longer follow-up (see appendix p 29 for an explanatory example). Clinicians seeking to delay or avoid kidney failure would usually consider such longer time periods for which the chronic slope is most relevant. Furthermore, the limited variation in total slopes between patient subgroups reduces the ability to explore any such differences in treatment effect that might exist between those subgroups. This is shown by the apparent consistency of treatment effect on total slope in EMPA-KIDNEY versus the evidence of effect modification when using chronic slopes.

When comparing chronic slopes, we have reported both the absolute and relative differences but have emphasised the latter. Absolute differences are determined by both the background annual rate of change in eGFR and the relative effect of treatment, so any heterogeneity observed could be due to either of these components. This is demonstrated in the analysis by baseline uACR: the absolute difference in the chronic slope among participants with a uACR of 2000 mg/g or higher was 1·82 mL/min per 1·73 m2 per year, whereas the background chronic slope among participants with a uACR of less than 30 mg/g was 0·88 mL/min per 1·73 m2 per year, so it was impossible for the absolute difference in the latter subgroup to be similar to that observed in the highest uACR subgroup. Indeed, the absolute difference in the chronic slope was positively associated with baseline uACR; however, the relative difference was inversely associated such that participants with the lowest baseline uACR had the largest relative reduction (86% [95% CI 36–136] in those with uACR <30 mg/g vs 29% [19–38] in those with uACR ≥2000 mg/g). There was no strong evidence that this association was importantly modified by the presence or absence of diabetes. Contrary to some international guidelines that only suggest (rather than recommend) using SGLT2 inhibitors in patients without diabetes and without significant albuminuria (uACR <200 mg/g),

28

 these analyses suggest that patients with low albuminuria (with or without diabetes) are likely to gain substantial benefit in terms of preservation of kidney function from SGLT2 inhibition, in addition to the other benefits of reductions in risk of acute kidney injury and cardiovascular disease.

29

 Given the short follow-up in EMPA-KIDNEY (median 2 years) it would be expected that a treatment that causes a 2 mL/min per 1·73 m2 acute dip in eGFR in the subgroup of patients with uACR <30 mg/g (progressing at only 1 mL/min per 1·73 m2 per year) would not demonstrate definitive benefits on the categorical outcome (by contrast with subgroups with higher uACR progressing faster than 2 mL/min per 1·73 m2 per year). These analyses of the chronic slope suggest that important benefits would likely emerge with longer treatment (see appendix p 29 for an example).

These analyses are limited by the characteristics of patients included in EMPA-KIDNEY.

11

 Few patients with type 1 diabetes were included, and patients with autosomal dominant polycystic kidney disease or with a kidney transplant were not eligible for the trial. In a companion paper, we assess whether the effects of allocation empagliflozin vary in different types of kidney disease.

12

 The trial deliberately excluded patients at low risk of chronic kidney disease progression (ie, those with an eGFR of ≥45 mL/min per 1·73 m2 and uACR <200 mg/g), but demonstrated that the relative benefit on the chronic slope was inversely proportional to predicted risk of kidney failure. Participants only received study treatment for 2 years on average because the trial was stopped earlier than planned owing to clear evidence of benefit. A further 2 years of off-treatment follow-up is underway to assess the longer-term effects of an average of 2 years of treatment.

In summary, in EMPA-KIDNEY, allocation to empagliflozin compared with placebo caused a modest acute dip in eGFR, and then substantially slowed the longer-term progression of chronic kidney disease. The longer-term benefits varied by diabetes status, eGFR, and most prominently uACR (and related characteristics such as predicted risk of kidney failure). Although the trial stopped early because of clear benefits emerging based on results in patients at highest risk, these analyses show that patients at lower risk such as those with lower levels of albuminuria—many of whom in their lifetime would otherwise develop kidney failure—could benefit in terms of preservation of kidney function, in addition to other proven cardiovascular and mortality benefits.

29

 If widely implemented, use of SGLT2 inhibitors could have a substantial effect on the public health impacts of chronic kidney disease.

Empagliflozin as adjunctive therapy improves time in range in type 1 diabetes

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Adults with type 1 diabetes spent more time in range with empagliflozin 2.5 mg or 5 mg as an adjunctive therapy to hybrid closed-loop insulin therapy compared with placebo, according to a speaker.

“We look at large trials assessing hybrid closed-loop therapy in type 1 diabetes and 34% to 69% of the participants do not actually achieve the target HbA1c post-intervention,” Melissa-Rosina Pasqua, MD, an endocrinologist and PhD candidate at the McGill University Health Center Research Institute in Montreal, said during a presentation at the International Conference on Advanced Technologies & Treatments for Diabetes. “When we look at other ways to reduce HbA1c, SGLT2 inhibitors as an adjunct to insulin therapy have been shown to reduce HbA1c in type 1 diabetes. The caveat is there is risk for diabetic ketoacidosis, particularly euglycemic. … The objective of our study was to assess the effect of low-dose empagliflozin on glucose control in adults with type 1 diabetes on a hybrid closed-loop system who did not otherwise get the target time in range of 70% or more.”

Empagliflozin 2.5 mg and 5 mg linked to higher time in range than placebo.
Data were derived from Pasqua MR, et al. OP 027. Presented at: International Conference on Advanced Technologies & Treatments for Diabetes; Feb. 22-25, 2023; Berlin (hybrid meeting).

Researchers conducted a double-blind, crossover, randomized controlled trial enrolling 24 adults with type 1 diabetes and a baseline HbA1c between 7% and 10.5% (50% men; mean age, 33 years). The trial consisted of three 14-day intervention periods in which participants received empagliflozin 2.5 mg (Jardiance, Boehringer Ingelheim/Eli Lilly), empagliflozin 5 mg or placebo as an adjunct to hybrid closed-loop insulin therapy. The order of therapies was randomly sequenced. Continuous glucose monitoring outcomes were obtained during the last 10 days of each intervention period. Morning ketone levels were collected daily.

At the conclusion of the study, adults had a 71.6% time in range with empagliflozin 2.5 mg and a 70.2% time in range with empagliflozin 5 mg compared with a 59% time in range with placebo (P < .0001). The associations were not affected by time of day, as adults had a higher time in range with either empagliflozin dose compared with placebo during both daytime and nighttime.

Time in hypoglycemia did not differ between those receiving empagliflozin 2.5 mg and placebo. Adults had a higher time in hypoglycemia with empagliflozin 5 mg than placebo (1.5% vs. 1%; P = .0051). However, the association of higher time in hypoglycemia with empagliflozin 5 mg compared with placebo was only significant during daytime hours (1.1% vs. 0.7%; P = .0065).

Participants used 54 insulin U per day with empagliflozin 2.5 mg and 52.9 U with empagliflozin 5 mg compared with 59.2 U with placebo. Morning ketone levels were similar with both empagliflozin doses and placebo.

No serious adverse events were reported during the study and there were no episodes of DKA or severe hypoglycemia.

“There were some limitations,” Pasqua said. “It was a short, small study. We powered for time in range, we didn’t power necessarily for ketone data.”

In addition, Pasqua noted the cohort had a mean BMI of 28.8 kg/m2 and insulin requirements that suggested they were mostly low-risk participants. She said studies are being planned to further explore the impact of empagliflozin on time in range in a larger cohort of adults with type 1 diabetes.

Empagliflozin in Chronic Kidney Disease

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Did empagliflozin reduce the risk of progression of kidney disease or death from cardiovascular causes as compared with placebo in this trial?

The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY Collaborative Group conducted a randomized, placebo-controlled trial that evaluated the effects of treatment with empagliflozin on kidney disease and cardiovascular outcomes in a wide range of patients with chronic kidney disease (CKD). Read the NEJM Original Article here.

Clinical Pearls

Q: What are the key risk factors for the development of kidney failure in patients with CKD?

A: CKD is often progressive, with a decreased glomerular filtration rate (GFR) and the presence of albuminuria representing key risk factors for the subsequent development of kidney failure. Slowing CKD progression and avoiding dialysis or kidney transplantation is highly desirable, given the effects of dialysis and kidney transplantation on quality of life and cardiovascular morbidity and mortality, as well as the substantial costs associated with kidney-replacement therapy.

Q: What gaps in our knowledge regarding the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors for chronic kidney disease did this trial aim to fill?

A: There is geographic variation, but worldwide, the majority of people with CKD have low levels of albuminuria (i.e., a urinary albumin-to-creatinine ratio [with albumin measured in milligrams and creatinine measured in grams] of <300) and do not have diabetes. Therefore, studying a wide range of patients with CKD has particular importance for public health. The results of a prespecified subgroup analysis from a trial of the SGLT2 inhibitor dapagliflozin in patients with CKD and a urinary albumin-to-creatinine ratio of at least 200 showed that benefits with respect to kidney failure extended to patients without diabetes, but there were limited data regarding patients with an estimated GFR (eGFR) of less than 30 ml per minute per 1.73 m2 of body-surface area and how these benefits might vary among the wider population of patients with CKD.

Morning Report Questions 

Q: Did empagliflozin reduce the risk of progression of kidney disease or death from cardiovascular causes as compared with placebo in this trial?

A: In this population of patients with a wide range of GFRs, levels of albuminuria, and causes of CKD, empagliflozin led to a risk of progression of kidney disease or death from cardiovascular causes that was 28% lower than that with placebo, with no major safety concerns. Progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P<0.001). Treatment with empagliflozin was effective regardless of diabetes status and was effective in patients with a broad range of eGFRs, down to approximately 20 ml per minute per 1.73 m2.

Q: What were some of the other findings of the trial?

A: The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P = 0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups.

SGLT-2 Inhibitors

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Photo credit: Ikris Pharma Network

SGLT-2 inhibitors are a class of diabetes drugs used to treat type 2 diabetes and, often off-label, type 1 diabetes. These drugs work by preventing your body from re-absorbing sugar into your bloodstream and instead flush it out when you urinate. SGLT-2 medications are taken orally, typically daily.

This drug has an interesting history. The compound was first discovered in the 1800s when someone noticed that if dogs urinate at the bark of a certain tree, ants would be attracted to that dog’s urine. The dog’s urine was sweet. One and a half centuries later, we have a new diabetes treatment!

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a relatively new class of prescription drugs which are FDA approved for type 2 diabetes to use in combination with diet and exercise to help lower blood sugar levels.

Medications in this class include:

  • canagliflozin (Invokana)
  • dapagliflozin (Farxiga)
  • empagliflozin (Jardiance)

These are available as single-ingredient drugs or in combination with other diabetes medications. The combinations currently available are:

  • canagliflozin and metformin (Invokamet)
  • dapagliflozin and metformin extended-release (Xigduo XR)
  • empagliflozin and linagliptin (Glyxambi)

How do SGLT2 Inhibitors Work?

SGLT2 is a protein humans have which helps glucose reabsorb in the kidneys. The SGLT2 protein is responsible for 90% of the glucose reabsorption in the proximal renal tube.

An SGLT2 inhibitor stops the reabsorption of glucose in the kidneys and the extra sugar is excreted into the urine. This helps to lower blood sugar levels. Below is a graphic that shows an SGLT2 inhibitor does this:

International Diabetes Association

Side Effects of SGLT2 Inhibitors

The FDA states that “The safety and efficacy of SGLT2 inhibitors have not been established in patients with type 1 diabetes, and FDA has not approved them for use in these patients.” Studies have been indicating patients with type 1 diabetes may be able to use SGLT2 inhibitors safely, however.

Side effects of SGLT2 inhibitors, as reported by the FDA include:

  • acidosis
  • dehydration
  • kidney problems
  • low blood sugar when combined with other diabetes medications
  • elevated blood cholesterol
  • yeast infections in men and women

Warnings from the FDA

The FDA has issued a strengthened warning for canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). The warning is for acute kidney injury and they add the following recommendations to help lower this risk:

“Patients should seek medical attention immediately if they experience signs and symptoms of acute kidney injury. This is a serious condition in which the kidneys suddenly stop working, causing dangerous levels of wastes to build up in the body. Signs and symptoms of acute kidney injury may include decreased urine or swelling in the legs or feet. Patients should not stop taking their medicine without first talking to their health care professionals. Doing so can lead to uncontrolled blood sugar levels that can be harmful.”

The FDA has also issued a warning for any SGTL2 inhibitor stating it may lead to diabetic ketoacidosis (DKA).

It is especially helpful when taking a medication to keep a journal of when you take something and how much you took. Include your symptoms and blood sugar readings in order to be able to help you and your healthcare provider decide whether or not a medication is working safely for you.

If you live in the USA and have experienced a serious side effect, you or your doctor may send a report to the FDA’s MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

SLGT-2 Inhibitors for Type 1 Diabetes

diaTribe shares the following advice from Dr. Anne Peters, who helped author the study that led to the warning on SGLT-2 inhibitors.

In individuals with type 1 diabetes who are using the drug off-label, it is best to work out a plan for safe use of the medication with a health care provider. Dr. Peters has patients temporarily hold the drug if unusual activity will be occurring during the day (e.g., travel, increased exercise, or a person feels unwell). Her patients with type 1 diabetes test ketones a week or two before starting the SGLT-2 inhibitor to obtain a baseline ketone level, then test urine ketones every morning while on the drug. If ketone levels are moderate to large, Dr. Peters recommends stopping use of the drug that day until the ketones clear. Finally, her patients with type 1 or type 2 diabetes stop the drug for three days before any elective surgery.

glycemic diabetic ketoacidosis.”

Comparative analysis of cardiovascular outcomes between Dapagliflozin and Empagliflozin in Patients with Type 2 Diabetes

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Type 2 diabetes is considered to be one of the major predisposing factors for microvascular and macrovascular diseases. In recent years, the treatment for diabetes has broadened from glycaemic control and has become a more patient-centred approach, in which the hazard of heart failure and atherosclerotic cardiovascular disease is taken into consideration.

Oral diabetic drugs known as inhibitors of sodium-glucose cotransporter-2 (SGLT2) promote the excretion of glucose by impeding the glucose reabsorption by the renal proximal tubules, thereby reducing plasma glucose levels. Based on current recommendations, SGLT2 inhibitors need to be considered as a second-line treatment after Metformin in patients with type 2 diabetes.

Several randomised control trials have manifested that SGLT2 inhibitors can improve cardiovascular outcomes in patients having diabetes. 

Sodium diuresis and sodium excretion effects of Dapagliflozin last longer and are more stable compared to those of Empagliflozin. Thus, Dapagliflozin has been found to decrease the 24-hour fluctuation in blood pressure. This, in turn, is associated with a lower risk for cardiovascular diseases.

Currently, studies have reported that SGLT2 inhibitors have beneficial impacts on cardiovascular outcomes, but the effect differs among individual SGLT2 inhibitors. 

Dapagliflozin did not enhance plasma noradrenaline and aldosterone levels compared to Empagliflozin, which could be beneficial for the prevention of heart failure. 

The recommended dose at which Dapagliflozin must be started is 5 mg once a day, and the dosage can be escalated to 10 mg once daily in patients who require additional glycaemic control. Empagliflozin is recommended at a starting dosage of 10 mg daily.

A clinical study compared the effects of Dapagliflozin and Empagliflozin on cardiovascular outcomes in patients with type 2 diabetes. It was inferred that the risks of developing stroke, heart failure, myocardial infarction, and cardiac-related death were not significantly different among the patients receiving Dapagliflozin or Empagliflozin. It is suggested that SGLT2 inhibitors can decrease the risk of cardiovascular diseases, but the study did not find any significant difference in the effectivity of Dapagliflozin and Empagliflozin

Empagliflozin Slows Progression of Renal Disease in Diabetes

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New data from the EMPA-REG OUTCOME trial with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) show that the drug significantly reduced the incidence of worsening nephropathy by 39% in the population of type 2 diabetes patients studied (ie, those who were at high cardiovascular risk).

The results were received to spontaneous applause here today at the American Diabetes Association (ADA) 2016 Scientific Sessions when presented by nephrologist Christoph Wanner, MD, of the Würzberg University Clinic, Germany; they were also simultaneously published in New England Journal of Medicine with Dr Wanner as lead author.

The assessment of renal outcomes in EMPA-REG was a prespecified outcome of the trial, Dr Wanner noted, and he added that the beneficial effects on the kidney observed in the trial “were there early and continued for the whole of the study.” Moreover, these effects were observed with both doses of empagliflozin employed (10 mg and 25 mg once daily).

“Empagliflozin reduced clinically relevant renal events when added to standard of care in patients with type 2 diabetes and high cardiovascular risk,” he announced, adding that this effect was primarily driven by a reduction in new-onset macroalbuminuria (hazard ratio [HR], 0.62 for those treated with empagliflozin compared with placebo; P < .001).

He pointed out that kidney disease is “a growing concern” in patients with type 2 diabetes, with 35% of patients eventually developing it, and noted that almost half (44%) of the renal-dialysis population at any current time is made up of those with diabetes, primarily type 2.

“In the placebo group you see the natural progression of kidney disease [as would be expected in type 2 diabetes] whereas the [estimated glomerular filtration rate] eGFR in the empagliflozin group remained stable,” he observed.

Important Addition to Original Findings, but More Work Needed

Dr Wanner noted, however, that the EMPA-REG trial lasted only 3 years, “so we are certainly looking to the future for more on this.”

And both he and discussant of the findings at ADA, endocrinologist and epidemiologist, William Herman, MD, MPH, of the University of Michigan, Ann Arbor, stressed that the results are applicable only “to the population studied in the EMPA-REG trial” (ie, older patients with type 2 diabetes at high cardiovascular risk).

Currently, about a third of the population of type 2 diabetes fall into that category, Dr Herman said.

Nevertheless, Dr Wanner observed in his presentation: “There have been no new diabetic kidney-disease–specific treatments in the past 15 years, until today.”
And he hinted that the agent may well be used in those who don’t yet have overt cardiovascular disease (CVD). “Nephrologists are waiting for this drug for patients with albuminuria,” he told Medscape Medical News.

They and endocrinologists “maybe will not wait until the patient has survived a myocardial infarction — there are some patients without cardiovascular disease but already with nephropathy, so I think we are all going to use this drug in the nephropathy patients with albuminuria.”

But Dr Herman pointed out in his talk that “the absolute differences are relatively small” in EMPA-REG and the number needed to treat with empagliflozin to achieve the renal benefits was 200.

In addition, it’s possible that the findings “had to do with medications not administered,” he said. “So it may not be a benefit of empagliflozin but the fact that those in the empagliflozin group did not receive medications causing harm [as patients in the trial were also allowed certain other standard therapies for diabetes].”

Overall, as well as the demonstrated renal effects, empagliflozin is “moderately effective” at lowering HbA1c and results in a 2- to 3-kg reduction in body weight, with no issue with hypoglycemia, although it does increase the risk of genitourinary infections, Dr Herman surmised.

He concluded that empagliflozin is “a reasonable therapy, but we still don’t know its exact role or exact mechanisms of action.”

Chair of the session in which the EMPA-REG renal findings were presented at ADA, Matthew Riddle, MD, from Oregon Health & Science University, Portland, said the renal outcomes from EMPA-REF are “an important addition to the original findings,” which nevertheless require further analysis.

Cost Is a Huge Issue

Of key importance, said both Drs Herman and Riddle, is the fact that empagliflozin and other SGLT2 inhibitors — like the other newer agents for type 2 diabetes (dipeptidyl peptidase-4 [DPP-4] inhibitors, glucagonlike peptide-1 [GLP-1] agonists, and insulin analogues) —are expensive, costing, in the US, in the region of $500 per month, as compared with a few dollars for metformin, the recommended first-line agent for type 2 diabetes and some other generically available drugs, such as sulfonylureas and pioglitazone.

Another trial with one of these newer agents, the GLP-1 agonist liraglutide (Victoza, Novo Nordisk), stole the headlines here yesterday with the results of the LEADER trial indicating that it significantly reduced the rates of major adverse cardiovascular events in a patient population similar to those in EMPA-REG, type 2 diabetes patients at elevated cardiovascular risk. This has prompted some experts to predict “a new era” in the management of type 2 diabetes.

Dr Riddle, however, believes this is a premature conclusion to draw: “I don’t think the regulatory agencies’ and the professional societies’ recommendations are going to change immediately; we are going to have to digest these findings,” he told Medscape Medical News.

And, he added, “The cost [of newer diabetes drugs] is a huge issue in the US. It’s one of the things I’m very interested in and very disturbed by.

“The range of cost between a generic established evidence-based oral therapy like metformin, the sulfonylureas, and now pioglitazone and the new agents is 100-fold. That is a big increase for, in some cases, a modest theoretical or practical advantage. So it’s a problem for physicians and patients in the US.”

Drilling Down Into Renal Outcomes

In the overall EMPA-REG trial, first reported last September to much acclaim, more than 6000 patients with type 2 diabetes at high risk of cardiovascular events were randomly assigned to one of two doses of empagliflozin or placebo on top of standard therapy. Empagliflozin reduced the risk of major adverse cardiovascular events by 38% relative to placebo.

 In this new analysis of microvascular outcomes, incident or worsening nephropathy occurred in 525 of 4124 patients taking empagliflozin and 388 of 2061 in the placebo group (12.7% vs 18.8%; HR, 0.61; P< .001).

This renal end point consisted of a combination of progression to macroalbuminuria, a doubling of serum creatinine, the start of renal-replacement therapy, or renal death.

However, the benefit was primarily driven by the reduction in new-onset albuminuria, which occurred in 459 of 4091 patients taking empagliflozin compared with 330 of 2033 patients on placebo (11.2% vs 16.2%; HR, 0.62; P < .001).

 Kidney dialysis was also reduced by more than half among those taking empagliflozin, although the absolute numbers affected were small (HR, 0.45; P = .0409).

In an editorial accompanying the renal findings in the published paper, Julie R Ingelfinger, MD, from Massachusetts General Hospital, Boston, Massachusetts, and Clifford J Rosen, MD, from the Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, say: “This new report indicates that empagliflozin was associated with a slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care in [type 2 diabetes] patients at high cardiovascular risk.”

And commenting on both EMPA-REG overall and LEADER, “We are left with differences that are encouraging yet are not a home run with regard to the management of diabetes,” they point out.

Is Empagliflozin a Renal Drug?

There was also some discussion at the ADA meeting about the mechanism of action of empagliflozin, both in lowering cardiovascular risk and now with regard to these renal benefits.

Most newer agent for diabetes will require dose adjustment in diabetic kidney disease because the majority are renally excreted; this includes DPP-4 inhibitors other than linagliptin, most GLP-1 agonists with the exception of liraglutide, and the SGLT2 inhibitors.

The latter, including empagliflozin, have required dose adjustment in patients with diabetic kidney disease. The current licenses for most SGLT-2 inhibitors precludes their use in patients with renal failure (eGFR < 60 mL/min/1.73 m2 in some cases or < 45 mL/min/1.73 m2 in others).

Dr Wanner said that 25% of the patients in EMPA-REG had eGFR < 60 mL/min/1.73 m2, more than a third already had albuminuria, and almost a third already had prevalent kidney damage.

Yet, paradoxically, they seem to provide some renal protection. These newest findings from EMPA-REG bolster excitement about the potential for SGLT2 inhibitors to provide a renoprotective effect, despite being metabolized by the kidney.

“The effect of empagliflozin on renal outcomes was there early and continued for the whole of the study, with both doses showing an effect. Empagliflozin works at lower stages of kidney function too,” Dr Wanner stressed.

Silvio Inzucchi, MD, of Yale University, New Haven, Connecticut, the lead investigator of EMPA-REG, added also that, regarding the overall cardiovascular benefit of empagliflozin seen in the trial, “there was no heterogeneity of effect based on eGFR; cardiovascular disease was reduced even in stage 3b renal-disease [eGFR 30–45 mL/min/1.73 m2] patients.”

Another SGLT2 inhibitor, canagliflozin (Invokana, Janssen) is being specifically tested in a diabetic kidney-disease population in the large multicenter randomized Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial.

This will enroll 3000 patients with stage 2 or 3 chronic kidney disease and macroalbuminuria already receiving standard of care. They will be randomized to canagliflozin 100 mg daily or placebo for 5 years, and results are not expected until 2019.

It is not known whether the latest caution from the Food and Drug Administration, strengthening the warning regarding acute kidney injury for canagliflozin and dapagliflozin, will affect this trial. This states that healthcare providers should consider factors that might predispose patients to acute kidney injury prior to starting them on canagliflozin or dapagliflozin.

 

Diabetes Drug to Be Studied in Heart Failure

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Boehringer Ingelheim and Eli Lilly announced on Wednesday that they were planning two separate outcomes trials to test the effect of the diabetes drug empagliflozin (Jardiance) in patients with chronic heart failure.

The trials herald a remarkable shift in emphasis, as there have been repeated concerns that some classes of diabetes drugs might actually worsen or increase the risk of developing heart failure. Only earlier this month the FDA added a new heart failure warning to the labels of the diabetes drugs saxagliptin (Onglyza) and alogliptin (Nesina).

The new hope for empagliflozin is based on the highly positive results of last year’s EMPA-REG OUTCOME trial, which found a significant reduction in cardiovascular events in patients with type 2 diabetes taking the drug, which is an SGLT2 inhibitor. A second paper examining the heart failure outcomes was published in January in theEuropean Heart Journal. The trial investigators reported “consistent reductions” in hospitalization for heart failure and cardiovascular death in patients with heart failure at baseline or who were taking heart failure medications. Patients in the empagliflozin group were also less likely to need loop diuretics.

Heart failure hospitalization or cardiovascular death was reduced by 34% from 8.5% in the placebo group to 5.7% in the empagliflozin group. The authors calculated a number needed to treat of 35 to prevent one heart failure hospitalization or cardiovascular death over 3 years.

The cardiovascular benefit “was observed very early and was sustained throughout the trial,” according to the researchers. “This suggests that the benefit was not driven by an effect on atherosclerosis.” Although the precise mechanism of benefit is unknown, they speculated about several possible mechanisms, including “osmotic diuresis, effects on plasma volume and sodium retention with modulation of the cardio-renal axis, reductions in arterial stiffness and the rate pressure product, indicating diminished left ventricular afterload, reductions in weight and blood pressure without increases in sympathetic nervous activity, reductions in hyperglycemia with concomitant reductions in insulin levels, and reductions in uric acid.”

Boehringer Ingelheim and Lilly said they would conduct two trials in patients with chronic heart failure, one in patients with type 2 diabetes and one without diabetes.

Diabetes and heart failure are urgent and growing problems, perhaps inevitable results of an aging and increasingly obese population. And they are closely related. Sanjay Kaul, MD, of Cedars-Sinai Heart Institute in Los Angeles, pointed out that “diabetes is prevalent in 25% to 40% of patients with heart failure. Diabetes increases the risk of developing heart failure by two- to five-fold. In patients with established heart failure, diabetes is associated with a 60% to 80% increased risk of cardiovascular and all-cause mortality.”

Kaul said that “the heart failure findings in the EMPA-REG OUTCOME trial were clinically meaningful and statistically persuasive. However, they were not systematically evaluated, in part because they were not highly anticipated. Logically these findings need to be replicated in heart failure patients with and without diabetes. Simultaneously, studies need to be conducted to understand the mechanism(s) of benefit. The planned studies, if positive, will expand the portfolio of evidence in favor of the cardioprotective effects of empagliflozin.”

Milton Packer, MD, of Baylor University in Dallas, also supported the studies. “It makes a great deal of sense to study empagliflozin in heart failure, even in those without diabetes. The mechanisms by which the drug may reduce hospitalizations for heart failure in diabetics are not likely to be specific to diabetics.”

“The real question,” Packer wondered, “is what type of heart failure? The best decision here would be to study empagliflozin in patients with heart failure with a PRESERVED ejection fraction. There are reasons to believe that such patients are likely to have been the type that showed particular benefit in the EMPA-REG trial.”

Empagliflozin reduced CV deaths in T2D patients

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According to the recently published findings of the EMPA-REG OUTCOME trial, empagliflozin caused a relative reduction of 38 percent in cardiovascular (CV) death in type 2 diabetes (T2D) patients who are at high risk for CV events. [N Eng J Med 2015;Doi:10.1056/NEJMoa1504720]

The trial also showed a relative risk reduction of more than 30 percent for both hospitalization due to heart failure and all-cause mortality, said lead investigator, Dr. Bernard Zinman, director of the Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Canada. Additionally, empagliflozin—a sodium glucose cotransporter-2 (SGLT-2) inhibitor—reduced the risk for non-fatal myocardial infarction (MI), non-fatal stroke and CV death by 14 percent, he said.

The mechanism behind the reduction in CV death and all-cause mortality is unclear, but Zinman suggested it could be due to empagliflozin’s haemodynamic effects. This is because the benefit of mortality risk reduction occurred very early in the study and generally, atherosclerosis- or hyperglycaemia-related mortality risk reduction does not appear that early, he explained.

Similar to the findings of antecedent studies, the trial found empagliflozin to be safe for long-term use, said Zinman. The incidence of genital infections, a known side effect of empagliflozin, was higher compared to the control group but there was no increase in other adverse events such as diabetic ketoacidosis, acute renal failure and bone fracture.

A total of 7,020 T2D patients from 42 countries participated in the study. All the participants had established CV disease and their CV risk factors were well treated using pharmacological agents. In the study, they were randomized to receive either 10 mg or 25 mg of empagliflozin once daily, or placebo, on top of standard care.

Diabetes is a major risk factor for CV disease and the concurrent existence of both T2D and CV disease increases mortality risk. As diabetic patients have to undergo lifelong treatment with antidiabetic drugs, it is vital to understand the CV safety profile of the drugs. Thus, in 2008, the USA Food and Drug Administration (FDA) issued a new recommendation for novel antidiabetic drugs to undergo CV safety studies. Prior to the EMPA-REG Outcome study, no antidiabetic drug had been found to be able to reduce the risk of CV events.