dapagliflozin (Farxiga)

Effect of Dapagliflozin on Total Heart Failure Events in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction

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Key Points

Question  Does dapagliflozin reduce the risk of total episodes of worsening heart failure (HF; defined as hospitalization for HF or urgent HF visit requiring intravenous HF therapies) and cardiovascular death in patients with mildly reduced or preserved ejection fraction heart failure?

Findings  In this prespecified analysis of the DELIVER trial including 6263 patients, dapagliflozin reduced the risk of total HF events and cardiovascular death by 23%, and this was consistent across a range of subgroups, including across the spectrum of ejection fraction.

Meaning  In this study, dapagliflozin demonstrated no reduction in efficacy in reducing second or subsequent HF events.

Abstract

Importance  In the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, dapagliflozin reduced the risk of time to first worsening heart failure (HF) event or cardiovascular death in patients with HF with mildly reduced or preserved ejection fraction (EF).

Objective  To evaluate the effect of dapagliflozin on total (ie, first and recurrent) HF events and cardiovascular death in this population.

Design, Setting, and Participants  In this prespecified analysis of the DELIVER trial, the proportional rates approach of Lin, Wei, Yang, and Ying (LWYY) and a joint frailty model were used to examine the effect of dapagliflozin on total HF events and cardiovascular death. Several subgroups were examined to test for heterogeneity in the effect of dapagliflozin, including left ventricular EF. Participants were enrolled from August 2018 to December 2020, and data were analyzed from August to October 2022.

Interventions  Dapagliflozin, 10 mg, once daily or matching placebo.

Main Outcomes and Measures  The outcome was total episodes of worsening HF (hospitalization for HF or urgent HF visit requiring intravenous HF therapies) and cardiovascular death.

Results  Of 6263 included patients, 2747 (43.9%) were women, and the mean (SD) age was 71.7 (9.6) years. There were 1057 HF events and cardiovascular deaths in the placebo group compared with 815 in the dapagliflozin group. Patients with more HF events had features of more severe HF, such as higher N-terminal pro–B-type natriuretic peptide level, worse kidney function, more prior HF hospitalizations, and longer duration of HF, although EF was similar to those with no HF events. In the LWYY model, the rate ratio for total HF events and cardiovascular death for dapagliflozin compared with placebo was 0.77 (95% CI, 0.67-0.89; P < .001) compared with a hazard ratio of 0.82 (95% CI, 0.73-0.92; P < .001) in a traditional time to first event analysis. In the joint frailty model, the rate ratio was 0.72 (95% CI, 0.65-0.81; P < .001) for total HF events and 0.87 (95% CI, 0.72-1.05; P = .14) for cardiovascular death. The results were similar for total HF hospitalizations (without urgent HF visits) and cardiovascular death and in all subgroups, including those defined by EF.

Conclusions and Relevance  In the DELIVER trial, dapagliflozin reduced the rate of total HF events (first and subsequent HF hospitalizations and urgent HF visits) and cardiovascular death regardless of patient characteristics, including EF.

Introduction

Patients with heart failure (HF) are frequently hospitalized for decompensation of HF. While the risk of death declines as ejection fraction (EF) increases, the risk of hospitalization for HF remains relatively static across the spectrum of EF.1 Therefore, repeated hospitalizations account for a greater proportion of the burden of disease in patients with HF with mildly reduced EF (HFmrEF) or HF with preserved EF (HFpEF) compared with HF with reduced EF (HFrEF). These repeated hospitalizations are the major driver of the burden of HF on patients and health care systems. In HFmrEF and HFpEF, as with HFrEF, these repeated hospitalizations are also associated with a higher subsequent risk of death.2 The gradient of risk is linear; as the number of repeated hospitalizations increases, the subsequent risk of both cardiovascular and all-cause mortality also increases.3

Recognizing the importance of repeated hospitalizations in patients with HF, analysis of repeated or total hospitalizations for HF was the primary outcome in a trial of sacubitril/valsartan in patients with HFmrEF or HFpEF.4 More recently, there has also been a recognition that urgent visits for treatment for HF are associated with worse outcomes, and these events have been incorporated into time to first event composites along with HF hospitalizations.5–7 Trials of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin were designed with a primary outcome of time to first worsening HF event (first hospitalization for HF or urgent HF visit) or cardiovascular death, in recognition of the prognostic impact of both of these nonfatal events.8,9 However, to our knowledge, the trials of SGLT2 inhibitors in HF still only examine the total number of hospitalizations for HF as a secondary outcome7,10–12 and not the effect of treatment on the total burden of this condition reflected by the full spectrum of HF events from urgent visits through to cardiovascular death. In this prespecified analysis, we describe in detail the efficacy of dapagliflozin on total HF events, ie, first and subsequent HF hospitalizations or urgent visits for HF and cardiovascular deaths, in the population with HFmrEF or HFpEF enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial.

Discussion

In patients with HFmrEF or HFpEF, dapagliflozin reduced the risk of total HF events, ie, repeated in addition to first events. This benefit was observed in all the prespecified DELIVER subgroups and across the spectrum of EF. The characteristics associated with multiple HF events in this population with HFmrEF or HFpEF were similar to those in patients with HFrEF experiencing multiple hospitalizations.18

The reduction in burden of total HF events with dapagliflozin was evident regardless of the method used to analyze the total events and whether we examined total HF events including urgent HF visits or HF hospitalizations without urgent visits. The point estimates were more favorable to that obtained in the time to first event analysis, which was the primary outcome of the DELIVER trial,10 ie, dapagliflozin demonstrated no reduction in efficacy in reducing second or subsequent events. The estimates were also consistent with other trials of SLGT2 inhibitors in patients with HFmrEF HFpEF. In the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trial,12 the SGLT2 inhibitor empagliflozin reduced the rate of total HF hospitalizations by 27% (rate ratio, 0.73; 95% CI, 0.61-0.88; P < .001) using the joint frailty approach (compared with 0.71 [95% CI, 0.63-0.80; P < .001] using the same outcome and model in the DELIVER trial).10 In a separate analysis of the DELIVER trial, we also examined if this reduction in total HF events was also observed for all-cause hospitalizations and found that there was a similar but smaller relative risk reduction of 11%.19 The observation that the benefits of dapagliflozin were consistent across the range of EF is important, as an earlier pooled analysis of total HF hospitalizations in the EMPEROR-Reduced and EMPEROR-Preserved trials reported that the effect of empagliflozin on total HF hospitalizations appeared to diminish at higher EFs.20 We did not see any evidence of an attenuation of the benefit of dapagliflozin on total HF events at higher EFs in this analysis or for total HF hospitalizations in our pooled analysis.21 We also found that the elevated risk for subsequent death in a patient whose first event was an urgent HF visit, compared with a patient who did not have any worsening HF event, was elevated, in keeping with reports from HFrEF trials.5,22 Furthermore, we found that although urgent HF visits were associated with a higher risk of death, the excess risk was not as high as in patients in whom the first event experienced during follow-up was an HF hospitalization, in keeping with the findings of a similar analysis in the Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial.6

As most prior trials enrolling patients with an EF greater than 40% have been neutral, there are few data with which to compare the relative efficacy of SGLT2 inhibitors in reducing total HF events. A post hoc analysis of the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity–Preserved (CHARM-Preserved) trial, which enrolled patients with an EF greater than 40%, suggested that candesartan reduced total HF hospitalizations and cardiovascular death using a negative binomial model.23 In that analysis, candesartan reduced total HF hospitalizations by 25%, ie, the rate ratio for total HF hospitalizations and cardiovascular death was 0.75 (95% CI, 0.62-0.91; P = .003). This post hoc analysis appeared to provide enough power to detect a treatment effect that was not evident in a time to first event analysis. In theory, total events should require a smaller sample size to demonstrate a treatment effect, as not only are subsequent nonfatal HF events counted but cardiovascular deaths that occur after these events are also counted (whereas both are ignored after a first HF event in a traditional time to first event analysis). In our trial, these repeated events contributed a further 193 deaths and 557 HF events that would otherwise have been ignored. Consequently, power calculations in the setting of total events are more complex, and factors such as heterogeneity of patient risk have to be incorporated, which is not currently part of routine sample size estimation strategies.24 However, use of total HF events as a primary outcome may result in a smaller sample size than is needed for a time to first event primary end point (or provide more power for secondary total events end points in trials powered for a time to first event primary outcome).

One attraction of recurrent or total events analysis is that they describe the full burden of disease and are potentially more meaningful to patients, representing the full disease experience. Therefore, describing reductions in total events may be helpful to explain treatment effects to patients. Explaining treatment efficacy is difficult in a clinical setting, and it is well known that relative risks are poorly understood by patients and by some clinicians. Other methods of expressing treatment benefits, such as the number needed to treat, are equally, if not more difficult, in the setting of total events.25 We reported that the AUC ratio for dapagliflozin vs placebo was 0.72, not dissimilar to the estimates from the conventional model-based approaches that we had prespecified. Although the relative risk reduction can be described as a ratio, perhaps more usefully the absolute risk reduction of 2.2 months over a 3-year period is easily explained to clinicians and patients, ie, a gain of 2.2 months of event-free survival. This absolute risk reduction with the accompanying time scale is a directly interpretably into clinically relevant terms for the patient. Simulation studies of power calculations using this approach suggest that sample sizes based on time to first events may be 20% larger than samples based on an AUC.17 The results that we observed using the AUC method (which is an extension of the restricted mean survival time used in multiple disease areas26–29) were consistent with the more traditional model-based approaches to analyzing total events. The technique may be useful in situations where model assumptions are not met, as the approach does not require a statistical model to be constructed and could be used in addition to other metrics, such as days alive and out of hospital.

Conclusions

In summary, among patients with HFmrEF or HFpEF, dapagliflozin reduced the risk of total (first and recurrent) HF events or cardiovascular deaths compared with placebo. HF events are common and preventable, and the efficacy of dapagliflozin in reducing the number of these events is consistent across a broad range of subgroups and across the spectrum of EF.

Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

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Abstract

BACKGROUND

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain.

METHODS

We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis.

RESULTS

Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups.

CONCLUSIONS

Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction.

Discussion

In this randomized, placebo-controlled trial involving patients with heart failure and a mildly reduced or preserved ejection fraction, dapagliflozin resulted in a lower risk of the primary composite outcome, worsening heart failure or cardiovascular death, than placebo, with no appreciable difference in benefit among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, or in other subgroups. Each of the three components of this composite outcome was less common in the dapagliflozin group than in the placebo group. In addition, dapagliflozin resulted in fewer total worsening heart failure events and cardiovascular deaths and a lower symptom burden than placebo. The incidence of adverse events was similar to that in the placebo group.

In a previous trial (DAPA-HF; Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), dapagliflozin reduced the risk of worsening heart failure or cardiovascular death among patients with heart failure and a left ventricular ejection fraction of 40% or less.1 The results of the DELIVER trial extend those of the DAPA-HF trial to patients with heart failure and a left ventricular ejection fraction of more than 40% and are consistent with the overall results of the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction), which assessed the effects of empagliflozin in patients with a left ventricular ejection fraction of more than 40%.10 The rationale for the dual primary analyses in our trial (i.e., evaluation of the primary outcome in patients with a left ventricular ejection fraction of less than 60% in addition to the overall patient population) was based on concern about a potential declining benefit in patients with an ejection fraction in the normal range that had been observed in several previous trials of neurohormonal modulators.6,15 Although the EMPEROR-Preserved trial suggested some potential attenuation of benefit in the highest part of the range of ejection fraction,8 we observed no evidence of heterogeneity with respect to left ventricular ejection fraction in the DELIVER trial, with similar overall treatment effects among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%. This finding suggests that the benefit of SGLT2 inhibition is likely to extend throughout the full range of ejection fraction.

The DELIVER trial was designed with broader inclusion criteria than those used in previous trials involving similar populations in that we enrolled patients who were hospitalized or recently hospitalized, for whom evidence-based therapy is limited, as well as those with heart failure and a left ventricular ejection fraction that had improved to more than 40% at the time of enrollment.4 Our data suggest that these understudied groups also benefit from dapagliflozin.

The most recent guidelines of the American Heart Association, American College of Cardiology, and Heart Failure Society of America designated SGLT2 inhibitors as class IIA, level B, for the treatment of heart failure with a mildly reduced or preserved left ventricular ejection fraction.4 The results of the DELIVER trial may inform future guidelines and provide further guidance for their broader use in clinical practice. Although the risk of cardiovascular death was not significantly lower with dapagliflozin than with placebo, the rate of cardiovascular death among patients who received placebo was substantially lower among patients with a left ventricular ejection fraction of more than 40% than among those in the DAPA-HF trial with a reduced ejection fraction (3.8 events per 100 patient-years in DELIVER vs. 7.9 events per 100 patient-years in DAPA-HF), and DELIVER was not powered to assess the effect of dapagliflozin on cardiovascular death alone. Trials in higher-risk populations, or of longer duration, or pooled analyses of several trials would be needed for robust evaluation of benefits with respect to mortality.

This trial has some limitations. The use of specific inclusion and exclusion criteria may have limited the generalizability of our findings. Less than 5% of the patients enrolled were Black, although this percentage was proportional to the population percentage on a regional basis (Table S8). Owing to the Covid-19 pandemic, assessment of symptom burden was limited to patients for whom an 8-month assessment was planned or performed before March 11, 2020, although results were similar in all patients for whom data were available. Because all the subgroups in the DELIVER trial were underpowered, within-subgroup results should be interpreted cautiously.

Among patients with heart failure and a mildly reduced or preserved ejection fraction, dapagliflozin resulted in a lower risk of the primary composite outcome (worsening heart failure or cardiovascular death), in fewer worsening heart failure events and cardiovascular deaths, and in a lower symptom burden, with no excess of adverse events. Findings were consistent across prespecified subgroups, including those defined according to left ventricular ejection fraction. These data provide further evidence to support the use of an SGLT2 inhibitor as essential therapy in patients with heart failure, regardless of the presence or absence of type 2 diabetes mellitus or left ventricular ejection fraction.

SOURCE: NEJM

SGLT2 Inhibitors Should Be Considered for All Patients With Heart Failure

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Introduction

It is highly improbable and incredibly fortuitous for a therapy to work across an entire syndrome. As luck would have it, that syndrome is heart failure—perhaps the most common cause of suffering and mortality across the world—and the therapy is sodium-glucose cotransporter-2 (SGLT2) inhibitors, whose glycosuric mechanism cannot fully explain its ability to reduce adverse clinical events and improve quality of life across large phenotypic swaths of heart failure.1 Randomized controlled trials of SGLT2 inhibitors in all iterations of heart failure, ranging from acute to chronic, across the spectrum of left ventricular ejection fraction, with and without type 2 diabetes and chronic kidney disease, have consistently showed significant reductions in both surrogate and clinical endpoints. Especially given the safety and tolerability of these medications, absent rare contraindications, SGLT2 inhibitors should be considered for all patients with heart failure.

In this issue of the Journal of the American College of Cardiology, Cunningham et al2 further bolster the evidence in support of near universal benefit of SGLT2 inhibitors in heart failure and address a key question: when should these medications be initiated? In a secondary analysis of the DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trial that randomized 6,263 patients with heart failure and LVEF >40% to dapagliflozin or placebo, the authors examined whether the benefits of the therapy were present in patients who were randomized during their index hospitalization or within 30 days of discharge. Approximately 10% of the patients (n = 654) met this criterion; as expected, they were sicker at baseline and had higher event rates than more stable outpatients with heart failure. Notably, only 90 patients were enrolled while hospitalized, with an additional 167 subjects randomized within the 7 days of discharge. Unfortunately, the authors do not provide information on the proportion of patients who had never been hospitalized or the median time from a prior hospitalization in the no recent hospitalization group. Nonetheless, the relative reductions in the primary outcome of worsening heart failure or cardiovascular death were consistent across these strata of patient risk: dapagliflozin reduced the primary outcome by 22% in the “perihospitalized” population (18% in all others) and had a consistent benefit in improving quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Total Symptom Score. Most importantly, because of the increased absolute risk of the perihospitalized population compared with those enrolled without a recent hospitalization, the absolute risk reduction in the primary outcome with dapagliflozin vs placebo was nearly 3 times greater (4.4 events vs 1.5 events per 100 patient-years) corresponding to a substantial difference in the number needed to treat with dapagliflozin vs placebo in those recently hospitalized (28 patient-years) compared with those enrolled without recent hospitalization (65 patient-years). Similarly, serious adverse events or drug discontinuation did not differ.

These data extend prior findings from EMPULSE (A Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure), which demonstrated that in-hospital initiation of empagliflozin, compared with placebo, led to a significant clinical benefit (a broad composite of death, heart failure events, and change in symptom burden) among individuals hospitalized with acute heart failure, regardless of ejection fraction.3 Additionally, SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) showed that in patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo.4

Given the results of the DELIVER trial overall and the prior published data, there is now a vast body of evidence to support a foundational role of SGLT2 inhibitors in heart failure, and this is reflected in the recent guidelines from the American College of Cardiology/American Heart Association.5 The data from Cunningham et al2 coupled with insights from EMPULSE and SOLOIST provide important practical evidence (efficacy and safety) to substantiate initiation of SGLT2 inhibitors during or right after a hospitalization for heart failure. Indeed, given the obvious improvements in hospitalization metrics and the greater absolute risk reduction achieved in the recently hospitalized group, one might predict that health care systems, insurance companies, and clinicians would be clamoring to promote widespread prescriptions, especially in their highest-risk patients—those currently or recently hospitalized. Unfortunately, this is not the case, and the sobering gap between clinical evidence and clinical practice persists, revealing the important work that lies ahead if we are to achieve high-quality, cost-effective heart failure care. We believe that there is an urgent need for a multifaceted approach to close the implementation gap in heart failure, and the ongoing experience with SGLT2 inhibitors can serve as an exemplar for the pathways needed for success. The following approaches should be considered in order to make substantial progress in closing these gaps.

Leveraging the Electronic Health Record

Health care delivery in the United States has moved toward integrated systems of care that are linked by a shared electronic health record backbone. This allows for a move toward data-driven population health, where clinicians can be nudged to prescribe evidence-based therapies, and real-time monitoring of patient treatment can allow for rapid evaluations of any interventions.6 For example, we recently demonstrated in PROMPT-HF (A Cluster Randomized PRagmatic Trial Aimed At ImprOving Use Of Guideline Directed Medical Therapy In OutPatienTs With Heart Failure) that a personalized electronic health record–based alert to clinicians seeing outpatients with heart failure dramatically improved prescription rates of guideline-directed medical therapies.7 A parallel study in the inpatient setting is ongoing, and efforts are well underway to expand this low-cost and easily scalable intervention to health care systems across the world.

Improving Affordability

Despite widespread recognition of the importance of quadruple therapy for heart failure with reduced ejection fraction and now the emergence of evidence-based therapies for heart failure with preserved ejection fraction, there are major access and financial barriers that impede and undermine patient adoption. Broadly speaking, about 1 in 6 patients with heart failure report forgoing or delaying care primarily because of financial causes.8 More specifically, we have seen that while payer access to evidence-based medical therapy for heart failure has improved, cost barriers persist. In fact, in a recent analysis of Medicare Advantage and stand-alone Medicare Part D prescription drug plans, 99% required at least tier 3 cost-sharing. For an entire year of quadruple therapy, the median out-of-pocket price was U.S. $2,271, which included $976 for the angiotensin receptor-neprilysin inhibitor and $939 for the SGLT2 inhibitor.9 This degree of cost-sharing undermines adherence to highly effective therapies and must be examined as part of any comprehensive strategy to improve heart failure care.

Reassessing Heart Failure Quality Improvement Efforts

Current strategies at improving heart failure quality are beset by fragmentation and an excessive focus on evidence agnostic metrics. For example, health care systems invest enormously in resource intensive translational care programs that are assembled around concepts such as fluid and salt restriction that have a limited likelihood to improve patient outcomes.10 Furthermore, emerging evidence suggests that existing readmission prevention programs could even harm patients.11 A more effective approach might be to refocus efforts on increasing prescription of evidence-based therapies across the spectrum of heart failure patients; ongoing data continues to show that the majority of eligible patients remain untreated. This approach would be truly value-dominant, resulting in substantial improvements in patient quality of life, cardio-reno-metabolic outcomes, and reductions in health care utilization.

In conclusion, the data clearly shows that SGLT2 inhibitors should be considered for all patients with heart failure. Their lackluster implementation at the bedside uncovers an ongoing and much needed shift in heart failure care delivery: away from fee-for-service to value-based models. The current system has contributed to suboptimal quality, marked variation in outcomes and performance, spiraling costs, and glaring inequities. As health systems and other providers expand participation in alternative payment models and hold financial risk for the patients and populations they are caring for, we will have better alignment of incentives and could finally deliver on the promise of optimal heart failure care for all. All evidence suggests that SGLT inhibitors should be integral to this new and improved ecosystem.

Three Diabetes Drugs Linked to Ketoacidosis, FDA Warns

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Three type 2 diabetes drugs — canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) — may lead to ketoacidosis, the FDA warned today.

The sodium-glucose co-transporter-2 (SGLT2) inhibitors are designed to lower blood sugar in patients with diabetes, but the FDA is investigating a connection between the drugs and dangerously high acid levels in the blood. They are also looking at whether changes will need to be made to the prescribing information, they said in the warning, which is posted online.

At least two studies presented here at the annual meeting of the American Association of Clinical Endocrinologists have found a connection between the SGLT2 inhibitors and diabetic ketoacidosis (DKA).

“Healthcare professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or symptoms,” the FDA said. “Discontinue SGLT2 inhibitors if acidosis is confirmed, and take appropriate measures to correct the acidosis and monitor sugar levels.” The signs and symptoms listed included difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness.

The FDA is issuing the warning after they searched their database of adverse event complaints, they said in an announcement. From March 2013 to June 2014 there were 20 cases of DKA reported, most of them with type 2 diabetes as the indication. Hospitalization was required in all of the cases, and the median time to onset was 2 weeks after starting the drug.

“I would encourage that these cases be studied so we can learn the scenarios behind them so they can be broadcast,” said Farhad Zangeneh, MD, medical director of Endocrine, Diabetes and Osteoporosis Clinic, in an interview with MedPage Today. “The important thing here it is good to know as much info as available.”

But he added that we should look at the background before issuing a general warning against the class. He manages hundreds of patients with the three SGLT2 inhibitors, he said, and has never had any problems. He suggested starting with low doses and making sure that patients are always well hydrated, have no renal problems, and get their lab work done.

Many doctors prescribe SGLT2 inhibitors off-label to type 1 diabetes patients, said Zangeneh, but in that case, the patients should at least be “super-patients” — they should be well controlled, hand-picked, excellent carb-counters.

“Certainly this report warrants a closer look at these cases to find out the exact details of the individual scenarios,” he added.

In one of the studies presented here, researchers led by Foiqa Chaudhry, MD, an endocrinology fellow at the University of Florida, described two cases of DKA that developed after the patients were taking SGLT2 inhibitors. An 18-year-old female presented with persistent vomiting and abdominal pain for the last 24 hours. She’d had type 2 diabetes since she was 8, but had never had ketoacidosis.

She had started taking metformin and canagliflozin 3 weeks earlier, and her primary care physician increased the dosage from 100 mg to 300 mg one week earlier. She was treated for diabetic ketoacidosis with an insulin drip and an IVF, and was eventually discharged.

In the other case, a 55-year-old man presented with dizziness. It was found that he had recently started taking glipizide and dapagliflozin. He was treated for mild DKA and sent home. The authors of the paper said that the safety of SGLT2 therapy warrants further study.

“In the cases presented, given the degree of poor baseline glycemic control, it is concerning if these agents propagated the state of dehydration thus accelerating the development of DKA,” they wrote. “As such, it is suggested that more specific counseling be given to patients regarding hydration status when being started on this class of medications.”

In an email to MedPage Today, Chaudhry said, “Though causality cannot be established with case reports alone, in our care of two patients with type 2 DM [diabetes mellitus] who developed hyperglycemic DKA — which happened to be temporally related to the use of SGLT2 inhibitor therapy — one must at least be vigilant about monitoring the volume status in these patients to avoid the potential complication of DKA.”

And in a late-breaking trial of 10 type 1 diabetes patients on insulin, liraglutide, and dapagliflozin, one of the patients developed DKA, according to the researchers, who were led by Nitesh Kuhadiya, MD, at the University of Buffalo.

“This is the first study demonstrating that the addition of dapagliflozin to insulin and liraglutide in patients with T1D results in a significant improvement in glycemia,” they wrote. “However, care would have to be exercised in terms of the reduction in insulin dose and thus the occurrence of euglycemic DKA.”

The FDA said that the cases they analyzed were atypical because glucose levels were only mildly elevated at less than 200 mg/dL in some reports. With type 1 diabetes patients who have DKA, these levels are usually greater than 250 mg/dL, they noted.

They added that, in most of the cases, a high anion gap metabolic acidosis was accompanied by higher blood or urine ketones. “Potential DKA-triggering factors that were identified in some cases included acute illness or recent significant changes such as infection, urosepsis, trauma, reduced caloric or fluid intake, and reduced insulin dose,” they wrote. “Potential factors, other than hypoinsulinemia, contributing to the development of a high anion gap metabolic acidosis identified in the cases included hypovolemia, acute renal impairment, hypoxemia, reduced oral intake, and a history of alcohol use.”

But they noted that for half of the cases, there was no triggering factor that was listed.

One other late-breaking study found that dapagliflozin improved beta-cell function and insulin sensitivity in 24 patients with type 2 diabetes. Lead author Carolina Solis-Herrera, MD, a resident at the University of Texas Health Science Center at San Antonio, said that there was no evidence of DKA in their trial.

“We did not find that in our study, but it’s definitely something that should be looked into,” she told MedPage Today.

The FDA asked healthcare professionals to report adverse events and side effects from these products to their MedWatch program.