HbA1c Fell in Diabetics on Sacubitril/Valsartan vs Enalapril in PARADIGM-HF

March 30, 2017

WASHINGTON, DC — Of patients in the PARADIGM-HF trial with known or newly diagnosed diabetes, those randomized to sacubitril/valsartan (Entresto, Novartis) showed significant reductions in HbA1c over 3 years compared with those assigned to the ACE inhibitor enalapril, according to a post hoc analysis[1].

Those taking the newer agent, classified as an angiotensin receptor-neprilysin inhibitor (ARNI), were also less likely to start taking insulin or other meds for glycemic control and showed better improvements in HDL cholesterol.

The significant improvement in HbA1c levels (P=0.0055) over 3 years in the sacubitril/valsartan group vs enalapril implies that heart-failure patients with diabetes who take the drug might benefit from and even require lower doses of any antidiabetic agents they may be taking, according to Dr Jelena P Seferovic (Brigham and Women's Hospital, Boston, MA).

It's also justification to update the drug's labeling for patients with heart failure to include improvement of dysglycemia, she said when presenting the PARADIGM-HF analysis here at the American College of Cardiology (ACC) 2017 Scientific Sessions . Seferovic is lead author on the report published online in Lancet Diabetes & Endocrinology at about the same time.

The observed reductions in HbA1c with the ARNI are especially striking, she said, given that the control group was on enalapril—ACE inhibitors and angiotensin-receptor blockers (ARBs) have previously been shown to improve glycemia vs placebo.

The findings "ought" to help sacubitril/valsartan, which has been slow to catch on in clinical practice despite showing superiority over enalapril in PARADIGM-HF, to be used more in patients with heart failure, according to Dr Scott D Solomon (Brigham and Women's Hospital), senior author on the post hoc analysis.

Based on current guidelines and going by the PARADIGM-HF primary outcomes, "any patient who can tolerate being on an ACE inhibitor or ARB who has heart failure with reduced ejection fraction should be switched to sacubitril/valsartan—but there's no question that if you have a patient who has diabetes or hyperglycemia, they will gain extra benefit from this, potentially, over an ACE inhibitor or ARB," Solomon said to heartwire from Medscape.

But also, "we think the patients will probably need lower doses of antidiabetic medications, including insulin, and that's something people ought to be aware of," he said.

Better HbA1c Is "Icing on the Cake"

"I think the story from the PARADIGM-HF trial gets more and more compelling to use sacubitril/valsartan," Dr Sripal Bangalore (New York University Langone Medical Center, NY), not connected with the trial, told heartwire . The agent is already indicated in place of ACE inhibitors or ARBs in patients with reduced-EF heart failure, and "to show better glycemic control than ACE inhibitors is icing on the cake."

He cautions that a post hoc analysis can be only hypothesis-generating, not evidence in the same league as prospectively defined outcomes. "But let's not forget that the effect of renin-angiotensin-system blockers on new-onset diabetes were all from such post hoc analyses in the past."

Also as an observer of the trial, Prof Michel Komajda (Groupe Hospitalier Pitié-Salpêtrière, Paris, France) agreed that the post hoc analysis should be interpreted with caution. "I do not think that these results modify the current indications of Entresto—that is, patients who are still symptomatic despite optimal therapy including ACE inhibitors or ARBs."

The analysis, he told heartwire by email, "simply highlights a potential added benefit in patients with both HF and diabetes, a situation that is known to be at very high CV risk. But the indications should remain based on HF status."

An editorial accompanying the published report points out that fewer antidiabetic meds to take could mean better treatment compliance in patients with heart failure, in whom compliance is already an issue.

But also, comment Dr Gregory Giamouzis (University of Thessaly, Larissa, Greece) and Dr Javed Butler (Stony Brook University, NY), some common antidiabetic agents have been associated with worsening heart failure or worsened HF prognosis, and there is evidence that beta-blockers and diuretics, mainstays in heart failure, might worsen dysglycemia.

"Thus, any heart-failure therapy that is protective against incident diabetes or worsening glycemic control is a welcome addition," they write.

Diabetes: Previously or Newly Diagnosed

The PARADIGM-HF post hoc analysis included 3778 patients with a diabetes diagnosis at study entry or who showed an HbA1c of at least 6.5% at baseline screening, from among the overall trial's 8442 patients with NYHA class 2–4 heart failure and an LVEF <40% who had been randomized to sacubitril/valsartan or enalapril on top of other HF meds.

As previously reported by heartwire , overall the hazard ratio for the primary outcome of CV death or HF hospitalization in the sacubitril/valsartan group over the median 27-month follow-up was 0.80 (P<0.001). There were similar reductions in all-cause and CV mortalities and HF hospitalization as individual end points (all P<0.001). Market approval for the ARNI soon followed in both the US and Europe.

In the current analysis, HbA1c levels at baseline were similar, at 7.41% in 1904 patients receiving sacubitril/valsartan and 7.48 in the 1874 taking enalapril (P=0.14), but over the follow-up they were persistently lower and fell significantly more for those taking the ARNI.

Mean HbA1c Levels (%) at Follow-up Visits in PARADIGM-HF Baseline Diabetics

Follow-up Sacubitril/Valsartan (n=1904) Enalapril (n=1874) P
1 y 7.09 7.30 0.0023
2 y 7.08 7.31 0.0040
3 y 6.97 7.16 0.072

Decreases in HbA1c measured longitudinally over the follow-up were significantly greater in the sacubitril/valsartan group compared with those on enalapril (P=0.0055).

Among the patients diabetic at baseline who had never before been on insulin, the rate of insulin initiation was an adjusted 29% lower among those in the sacubitril/valsartan group (P=0.0052). The corresponding adjusted rate of new use of oral glycemia-reducing agents trended lower, by 23% (P=0.073), in those receiving sacubitril/valsartan.

Rate of Insulin Initiation (Cumulative %) at Follow-up Visits in PARADIGM-HF in Diabetics Insulin-Naïve at Baseline

Follow-up Sacubitril/Valsartan (n=1550) Enalapril (n=1490) P
1 y 3.8 5.5 0.025
2 y 7.2 9.3 0.057
3 y 9.1 13.3 0.0037

Although there was no consistent pattern to differences in triglycerides over the follow-up, according to Seferovic, HDL-cholesterol levels increased significantly more (P=0.043) for those on sacubitril/valsartan compared with those randomized to enalapril.

In their editorial, Giamouzis and Butler observe that "there is an even stronger association between diabetes and heart failure with preserved ejection fraction" and that the PARAGON-HF trial, started in 2014 and scheduled to end in 2019, is exploring the efficacy of sacubitril/valsartan in preserved-EF heart failure.

That trial is randomizing an estimated 4600 patients to receive either the ARNI or the ARB valsartan, which had similarly been the comparator agent in the phase 2 PARAMOUNT study.

As reported by heartwire in 2012, PARAMOUNT had randomized about 300 patients with preserved-HF heart failure and found significant reductions in natriuretic peptides and left atrial size and improved NYHA functional class in those receiving sacubitril/valsartan compared with valsartan, with the effect greater in the subset of patients with diabetes.

Novartis funded the trial and "was involved in the PARADIGM-HF study design and protocol development, and data collection," according to the trial's primary publication. Seferovic discloses that she has no relevant financial relationships. Solomon reports receiving "either grant, personal, nonfinancial, or other support from Novartis." Bangalore reports honoraria from Daiichi-Sankyo, Pfizer, Abbott, Merck, Boehringer Ingelheim, Gilead, and Abbott Vascular. Disclosures for the coauthors are listed in the paper. Giamouzis discloses serving as a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Galenica, Menarini, MSD, Novartis, Pfizer, Sanofi, and Servier. Butler discloses serving as a consultant to Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiocell, CVRx, Luitpold, Novartis, Relypsa, and ZS Pharma.

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