Dapagliflozin

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.

Dapagliflozin’s HFpEF Benefit Tied to Lower Filling Pressure

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Treatment of patients with heart failure with preserved ejection fraction (HFpEF) with the SGLT2 inhibitor dapagliflozin (Farxiga) for 24 weeks produced significant and beneficial reductions in left-heart filling pressures in a mechanistic, randomized clinical study.

The findings “provide new insight into the mechanisms underlying the favorable clinical effects of dapagliflozin in patients with HFpEF,” Barry A. Borlaug, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. “Elevations in left heart filling pressures at rest and during exercise are fundamental pathophysiologic features of HFpEF,” he noted.

Results from prior studies documented the benefit of dapagliflozin for improving clinical outcomes in patients with HFpEF in the DELIVER trial, and for the related sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) in the EMPEROR-Preserved trial. The new findings presented by Dr. Borlaug provide evidence from a placebo-controlled, prospective study for one way by which these SGLT2 inhibitors exert this benefit in patients with HFpEF.

The results of his single-center study showed that, in patients with HFpEF who also exhibited “severe” elevations in pulmonary capillary wedge pressure (PCWP) during exercise, 24 weeks of treatment with dapagliflozin led to a significant reduction in PCWP during exercise. The treatment produced an average 6.1–mm Hg drop from baseline compared with control patients who received placebo. A similar pattern occurred when these patients were at rest, when dapagliflozin treatment linked with a significant average reduction in PCWP from baseline of 3.5 mm Hg compared with controls.

Improving a ‘specific and fundamental’ feature of HFpEF

“This fantastic study looked at one of the fundamental aspects of HFpEF,” said John R. Teerlink, MD, designated discussant for the study. “You’ve shown that dapagliflozin targets a specific and fundamental” manifestation of HFpEF by lowering PCWP, said Dr. Teerlink, director of Heart Failure at the San Francisco Veterans Affairs Medical Center.

However, Dr. Teerlink added, the study did not directly address the related question of what physiologic action of dapagliflozin produces this notable drop in PCWP.

“We’re just starting to look at that,” replied Dr. Borlaug, a cardiologist and professor at the Mayo Clinic in Rochester, Minn.

He reported finding an intriguing correlate in the current study linked to the cut in PCWP with dapagliflozin treatment. The SGLT2 inhibitor at a standard daily 10-mg dose produced an average 3.5-kg drop in body weight in the dapagliflozin-treated patients that significantly linked with the changes in PCWP both at rest and during exercise. Dapagliflozin-treated patients also showed a significant reduction from their baseline plasma volume compared with placebo-treated patients, but this “poorly correlated” with the dapagliflozin-linked cuts in PCWP, Dr. Borlaug said.

“I don’t think this means weight loss is the cause of the hemodynamic benefit, but maybe it’s an indicator. When patients [with HFpEF] lose weight, they are in a metabolic state that leads to good changes in hemodynamics,” he suggested. “My guess is that there is probably a combination of many different little things [caused by dapagliflozin treatment of patients with HFpEF] that together result in the 20%-25% relative improvement we see in filling pressure.”

An ‘obese, cardiometabolic’ HFpEF phenotype

The study enrolled patients with HFpEF and a left ventricular ejection fraction of at least 50%, a New York Heart Association functional class of 2 or 3, and a PCWP during exercise of at least 25 mm Hg. Of the 37 evaluable patients, about two-thirds of the patients were women, more than two-thirds were in functional class 3, about 70% were obese, and their average ejection fraction was about 62%. The study excluded patients with HFpEF who also had type 1 diabetes, cardiomyopathy, pericardial disease, or other causes of dyspnea or heart failure.

Dr. Teerlink asked about the generalizability of the findings, as the study cohort seemed to differ in certain respects from the patients enrolled in the DELIVER trial, and because of the many apparently distinct patient phenotypes that exist within the scope of HFpEF.

An “obese, cardiometabolic phenotype” predominated the study cohort, Dr. Borlaug said. “The patients we enrolled look like the HFpEF patients seen in U.S. clinics.” However, he added that “in reality, many [HFpEF phenotypes] coexist in one patient. It’s not that simple,” that every patient with HFpEF can be categorized into a single HFpEF phenotype.

The researchers monitored PCWP invasively with high-fidelity micromanometer catheters.

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

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

Dapagliflozin in Patients Recently Hospitalized With Heart Failure and Mildly Reduced or Preserved Ejection Fraction

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Abstract

Background

Patients recently hospitalized for heart failure (HF) are at high risk for rehospitalization and death.

Objectives

The purpose of this study was to investigate clinical outcomes and response to dapagliflozin in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF) who were enrolled during or following hospitalization.

Methods

The DELIVER (Dapagliflozin Evaluation to Improve the LIVES of Patients With PReserved Ejection Fraction Heart Failure) trial randomized patients with HF and LVEF >40% to dapagliflozin or placebo. DELIVER permitted randomization during or shortly after hospitalization for HF in clinically stable patients off intravenous HF therapies. This prespecified analysis investigated whether recent HF hospitalization modified risk of clinical events or response to dapagliflozin. The primary outcome was worsening HF event or cardiovascular death.

Results

Of 6,263 patients in DELIVER, 654 (10.4%) were randomized during HF hospitalization or within 30 days of discharge. Recent HF hospitalization was associated with greater risk of the primary outcome after multivariable adjustment (HR: 1.88; 95% CI: 1.60-2.21; P < 0.001). Dapagliflozin reduced the primary outcome by 22% in recently hospitalized patients (HR: 0.78; 95% CI: 0.60-1.03) and 18% in patients without recent hospitalization (HR: 0.82; 95% CI: 0.72-0.94; Pinteraction = 0.71). Rates of adverse events, including volume depletion, diabetic ketoacidosis, or renal events, were similar with dapagliflozin and placebo in recently hospitalized patients.

Conclusions

Dapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without history of recent HF hospitalization. Starting dapagliflozin during or shortly after HF hospitalization in patients with mildly reduced or preserved LVEF appears safe and effective. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure

Dapagliflozin Safe and Effective for Heart Failure With Frailty.

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https://jamanetwork.com/journals/jama/fullarticle/2792619?guestAccessKey=6a21f1dd-e6d8-410c-9f53-a44874d5443d&utm_source=linkedin_company&utm_medium=social_jama&utm_term=7015535364&utm_campaign=article_alert&linkId=166468762

Relationship of Dapagliflozin With Serum Sodium: Findings From the DAPA-HF Trial

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Clinical Research

Abstract

Objectives

This study aimed to assess the prognostic importance of hyponatremia and the effects of dapagliflozin on serum sodium in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial.

Background

Hyponatremia is common and prognostically important in hospitalized patients with heart failure with reduced ejection fraction, but its prevalence and importance in ambulatory patients are uncertain.

Methods

We calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) and secondary outcomes according to sodium category (≤135 and >135 mmol/L). Additionally, we assessed: 1) whether baseline serum sodium modified the treatment effect of dapagliflozin; and 2) the effect of dapagliflozin on serum sodium.

Results

Of 4,740 participants with a baseline measurement, 398 (8.4%) had sodium ≤135 mmol/L. Participants with hyponatremia were more likely to have diabetes, be treated with diuretics, and have lower systolic blood pressure, left ventricular ejection fraction, and estimated glomerular filtration rate. Hyponatremia was associated with worse outcomes even after adjustment for predictive variables (adjusted HRs for the primary outcome 1.50 [95% CI: 1.23-1.84] and all-cause death 1.59 [95% CI: 1.26-2.01]). The benefits of dapagliflozin were similar in patients with and without hyponatremia (HR for primary endpoint: 0.83 [95% CI: 0.57-1.19] and 0.73 [95% CI: 0.63-0.84], respectively, P for interaction = 0.54; HR for all-cause death: 0.85 [95% CI: 0.56-1.29] and 0.83 [95% CI: 0.70-0.98], respectively, P for interaction = 0.96). Between baseline and day 14, more patients on dapagliflozin developed hyponatremia (11.3% vs 9.4%; P = 0.04); thereafter, this pattern reversed and at 12 months fewer patients on dapagliflozin had hyponatremia (4.6% vs 6.7%; P = 0.003).

Conclusions

Baseline serum sodium concentration was prognostically important, but did not modify the benefits of dapagliflozin on morbidity and mortality in heart failure with reduced ejection fraction. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]: NCT03036124)

Discussion

In a contemporary, well-treated ambulatory cohort of patients with HFrEF, most of whom had mild symptoms, the prevalence of hyponatremia was low (8.4%) and there were few cases of severe hyponatremia (0.06%). However, hyponatremia remained an independent predictor of outcomes despite adjustment for other prognostic variables, including NT-proBNP. The benefit of dapagliflozin was consistent across the range of sodium concentrations measured at baseline. Dapagliflozin had a small biphasic effect on serum sodium concentration. Initially, compared with placebo, dapagliflozin led to a small, although statistically significant, decrease in sodium. However, after 2 weeks, the opposite pattern was observed.

Although hyponatremia is recognized as the most common electrolyte disorder among hospitalized patients with HF, there are few reports of the prevalence of hyponatremia in ambulatory patients with HFrEF and none in patients comprehensively managed with contemporary guideline-recommended medical therapy.9-11 Even accounting for different definitions, the prevalence of hyponatremia in our outpatient cohort (8.4%) was less than half that reported in hospitalized patients (generally 20% to 25%).1-4

Although most cases of hyponatremia in the DAPA-HF trial were mild, low sodium still predicted worse outcomes. This excess risk persisted despite adjustment for other recognized prognostic variables, many of which showed an imbalance between patients with and without hyponatremia. Indeed, we know of no prior study where such extensive adjustment was made, including for natriuretic peptide level, in ambulatory patients. 9-11 Moreover, most studies to date have only reported the association between hyponatremia and all-cause mortality, whereas we have also shown that low sodium was independently predictive of worsening HF events (principally HF hospitalization) and symptoms.16,17

The prognostic importance of a single sodium measurement was remarkable given the rapid and frequent resolution of hyponatremia on rechecking blood chemistry. In the placebo group, almost half of cases of hyponatremia had resolved at the 2-week measurement after randomization and about two-thirds of cases had resolved by 8 months. This substantial recategorization occurred because the initial measurement was only slightly below normal in many patients. However, almost as many people in the placebo group developed new hyponatremia at each timepoint during follow-up as showed resolution of hyponatremia. Dapagliflozin had a surprising, previously unrecognized, biphasic effect on new hyponatremia. The incidence of hyponatremia was increased during the first 14 days after randomization but was decreased thereafter in patients treated with dapagliflozin compared to placebo. The explanation for this pattern is uncertain. The initial osmotic and natriuretic diuresis induced by SGLT2 inhibitors causes an increase in vasopressin secretion and a reduction in free-water clearance, experimentally and clinically, which might account for the early transient reduction in serum sodium concentration.18-21 The subsequent effects on serum sodium concentration are harder to predict given the direct effects of SGLT2 inhibitors and the compensatory responses to these. The diuresis induced by SGLT2 inhibitors is believed to lead to a reduction in intravascular volume and blood pressure, and the increased delivery of sodium to the distal nephron results in a decline in eGFR by inducing tubuloglomerular feedback.22-25 However, it has been hypothesized that SGLT2 inhibitors reduce blood volume less than conventional diuretics.26 Although the initial decrease in sodium mirrors the early decline in eGFR after starting dapagliflozin, subsequently, serum sodium concentration increased more in the dapagliflozin group than the placebo group, to the extent that the mean concentration was eventually significantly higher in the dapagliflozin group. Although the initial decrease in eGFR also partially recovers, eGFR does not recover back to the same level as in the placebo group (as is also observed in other trials and real-world data over the same period) and eGFR does not crossover as for sodium.27,28 So, it seems unlikely that the effect of SGLT2 inhibitors of eGFR alone explain the early effect on sodium, although it might explain the longer-term effect if there is a relative increase in free-water clearance with these agents (as seems likely) and sodium excretion is maintained (and sodium retention does not occur), which may be the case if eGFR is maintained. The complexity of these effects is reflected in the seeming paradox of the early decline in serum sodium concentration occurring contemporaneously with an increase in hematocrit, questioning whether the latter can be wholly explained by volume contraction. Although detailed analyses of change in hemoglobin have been reported in other trials, the effect of other SGLT2 inhibitors on serum sodium has not been reported.29 Irrespective of the possible mechanisms, the important overarching finding was that after 14 days, patients treated with dapagliflozin were less likely to develop new hyponatremia and more likely to show resolution of existing hyponatremia than individuals treated with placebo, which may be a favorable effect of SGLT2 inhibition in HF. The benefits of dapagliflozin on the primary and secondary cardiovascular outcomes were consistent in patients with and without hyponatremia (and across the range of serum sodium concentration at baseline), despite the initial transient small decline in serum sodium concentration. Indeed, the absolute risk reduction with dapagliflozin was 1.5- to 2.0-fold greater in patients with hyponatremia than in those without. Similarly, dapagliflozin was also well-tolerated in patients with hyponatremia, and the safety of dapagliflozin was similar in patients with and without hyponatremia.

Source: JACC

SGLT2 Inhibitors: Is This the Start of a New Era?

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antihyperglycemic agents that lower blood glucose by enhancing urinary excretion of glucose.[1] This mechanism of action, along with the relatively modest HbA1c reduction when used as a second-line agent, left some clinicians underwhelmed.

Beginning in 2015, however, cardiovascular outcomes trials designed to demonstrate safety began reporting cardiovascular benefits—especially in heart failure—as well as reductions in albuminuria and increases in estimated glomerular filtration rate (eGFR).[2]

The American Heart Association (AHA) 2018 Scientific Sessions included reviews of existing data and exciting new clinical trial results on the benefits of SGLT2 inhibitors.

The Metabolic Face of Heart Failure

The Sunday afternoon symposium, “The Metabolic Face of Heart Failure,” was presented by experts who reviewed what is currently known about SGLT2 inhibitors as well as the other newer classes of antihypeglycemics—dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists.

Dr Eugene Braunwald led with an overview of the positive effects of SGLT2 inhibitors on diabetes, heart failure, and renal dysfunction. The EMPA-REG OUTCOME trial was the first to report cardiovascular benefits, achieving a 14% risk reduction in the primary composite outcome with empagliflozin.[3] The result was driven by a 38% reduction in death from cardiovascular causes, with no significant differences in nonfatal myocardial infarction or stroke. The other key finding was a 35% reduction in risk for hospitalization for heart failure.

A subsequent pooled analysis of phase 3 trials of empagliflozin demonstrated a significant reduction in urine albumin-to-creatinine ratio (UACR).[4] Two years later, the CANVAS Program reported a 14% reduction in the same primary outcome with canagliflozin, along with a 33% reduction in hospitalization for heart failure and a 27% lower risk for progression of albuminuria. Risk for the composite outcome of a 40% reduction in eGFR, renal replacement therapy, or death from renal causes was reduced by 40%.[5]

A later report from CANVAS suggested a slowing of eGFR decline among those who were randomly assigned to canagliflozin.[6] Both EMPA-REG and CANVAS were conducted among patients with diabetes who had established atherosclerotic disease or were otherwise at high risk for cardiovascular disease.

Dr Subodh Verma further reviewed cardiovascular outcomes trials of SGLT2 inhibitors, as well as those for DPP-4 inhibitors and GLP-1 receptor agonists. Overall, DPP-4 inhibitors did not provide a cardiovascular benefit and produced mixed results on heart failure.

GLP-1 receptor agonists may provide some cardiovascular benefit, although Verma pointed out that the benefit may be limited to analogues of human GLP-1 rather than exendin-based or DPP-4–resistant analogues. He also noted that the reduction in major cardiovascular events with SGLT2 inhibitors was limited to patients with diabetes who had established cardiovascular disease.

Indeed, the DECLARE-TIMI 58 cardiovascular outcomes trial of dapagliflozin, which included patients who were at risk but did not have established cardiovascular disease, reported no benefit (or harm) in the risk for major cardiovascular events.[7] However, like EMPA-REG and CANVAS, DECLARE-TIMI 58 demonstrated a significant reduction in risk for hospitalization for heart failure (27%) and risk for the renal composite (24%). A meta-analysis of these three trials was published simultaneously with the 2018 AHA Scientific Sessions.[2]

EMPA-HEART Explains the Benefits

Although blood-pressure lowering and weight loss were seen in the treatment arms of the three SGLT2 inhibitor outcomes trials, they were not enough to account for the results. Thus, the mechanism by which these studies achieved their heart failure and mortality benefits has not been clear.

In a late-breaking clinical trials session, the EMPA-HEART study[8] was presented to a packed house. The goal of the randomized controlled trial was to examine the effects of empagliflozin (n = 49) versus placebo (n = 48) on left ventricular remodeling over 6 months among patients with type 2 diabetes, with or without prior heart failure. All participants had established cardiovascular disease (ie, prior coronary revascularization or history of myocardial infarction), normal kidney function (eGFR ≥ 60 mL/min/1.73 m2), and left ventricular (LV) ejection fraction (EF) of at least 30%. Most of the participants were men (93%).

The primary outcome was change in LV mass index from baseline. After statistical adjustment, the empagliflozin group attained a 2.6 g/m2 reduction in LV mass index versus -0.01 g/m2 with placebo (P = .01), with the greatest improvement occurring among those with baseline LV mass index > 60 g/m2.

In addition, the treatment group had a change in systolic blood pressure of -7.9 mm Hg versus -0.7 mm Hg (P = .003), an increase in hematocrit (2.4% vs 0.4%, P = .006), and an improvement in LVEF, though not significant (2.2% vs -0.01%, P = .07).

It is remarkable that these effects were observed over a follow-up of only 6 months. On the other hand, the short follow-up begs the question of whether the effects could be sustained or whether they would continue to separate over longer periods.

In any case, the study provided the first mechanistic explanation for the favorable heart failure and cardiovascular death benefits seen in the EMPA-REG OUTCOME, CANVAS Program, and DECLARE-TIMI 58 cardiovascular outcomes trials.

Other important studies of SGLT2 inhibitors are underway. In particular, whether these agents can reduce heart failure hospitalizations and cardiovascular deaths in patients without diabetes with preserved or reduced ejection fraction will be reported in 2020. Another large trial studying the renal benefits of SGLT2 inhibitors in patients both with and without diabetes has also been announced. The era of SGLT2 inhibitors may indeed be upon us.

Dapagliflozin drives HbA1c, SBP, and weight down in DERIVE

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Dr Siew-Pheng Chan.

The use of the sodium/glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin in patients with type 2 diabetes (T2D) and moderate renal impairment provides benefits beyond glucose lowering, with no new safety signals, in the phase III DERIVE* study.

At 6 months, the primary endpoint of mean reduction in HbA1c level was greater by 0.34 percent in patients treated with dapagliflozin vs placebo (p< 0.001). There were also greater reductions in systolic blood pressure (SBP, 3.1 mm Hg; p<0.05) and mean body weight (1.25 percent, p< 0.001) with dapagliflozin. (APSC 2018, abstract S105-01)

“Dapagliflozin induces glycosuria and lowers blood glucose. However, the glycaemic efficacy of dapagliflozin is attenuated in patients with moderate renal impairment, for example in stage 3 CKD, because less glucose is cleared in the kidney in this group,” said Dr Siew-Pheng Chan, consultant endocrinologist at Subang Jaya Medical Centre in Subang Jaya, Malaysia, who is unaffiliated with the study.

Researchers led by Dr Paola Fioretto of the University of Padova in Padua, Italy conducted the DERIVE study to compare the efficacy and safety of dapagliflozin vs placebo in 321 patients with T2D (HbA1c of 7 –11 percent) and moderate renal impairment (stage 3A chronic kidney disease (CKD), estimated glomerular filtration rate (eGFR), 45 to <60 mL/min/1.73m2). Patients were randomized to either dapagliflozin 10 mg (n=160) or placebo (n=161) over 6 months. Randomization was stratified by background glucose-lowering medication. Both groups had similar baseline characteristics.

At 6 months, treatment with dapagliflozin resulted in a significant reduction in mean HbA1c (-0.37 percent vs -0.03 percent for placebo) and mean body weight (-3.17 vs -1.92 kg, respectively) from baseline. The mean fasting plasma glucose was also significantly reduced with dapagliflozin (-21.46 vs -4.87 mg/dL for placebo) as was mean SBP (-4.8 vs -1.7 mm Hg, respectively) from baseline to 6 months.

In terms of safety, mean eGFR was reduced with dapagliflozin (-3.23 mL/min/1.73m2) vs placebo (-0.63 mL/min/1.73m2). Urinary tract infection and genital infection were the most common adverse events of interest reported. Overall, the safety profile of dapagliflozin was consistent with previous reports seen for T2D. No bone fractures or amputations were reported.

Dapagliflozin is currently indicated as an adjunct to diet and exercise to improve glycaemic control in adults with T2D. Dapagliflozin remains contraindicated in patients with an eGFR <30 mL/min/1.73 m².

 

*DERIVE: Study to Evaluate the Effect of Dapagliflozin on Blood Glucose Level and Renal Safety in Patients With Type 2 Diabetes.
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