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Novel Antihypertensive Lowers HbA1c in People with Diabetes

Combination ANRI sacubitril/valsartan (EntrestoR) showed significant reduction in risk for cardiovascular death and hospitalization for worsening heart failure.

In September 2014, The New England Journal of Medicine published the results of the PARADIGM-HF trial, which compared the effects of the novel angiotensin receptor/neprilysin inhibitor (ANRI) combination of sacubitril/valsartan (EntrestoR, Novartis) and enalapril on cardiovascular death and hospitalization rates of patients with reduced ejection fraction heart failure (NYHA class 2-4 heart failure and LVEF ≤ 40%).  The results were overwhelmingly in favor of sacubitril/valsartan, and the drug was approved by the FDA in July 2015.  Because of the cost associated with EntrestoR, and the lack of familiarity among practitioners, prescription numbers have been less than anticipated in spite of the benefits displayed in PARADIGM-HF. A recent post-hoc analysis of PARADIGM-HF has shown that sacubitril/valsartan displayed significant reductions in HbA1c in diabetes subjects when compared to people with diabetes in the enalapril control group.

Neprilysin is a naturally occurring endopeptide responsible for degradation of naturetic peptides and vasoactive peptides (angiotensin, bradykinin, and adrenomedulin).  Early efforts to inhibit neprilysin activity showed no effect on blood pressure, as the balance of vasoconstrictor and vasodilator peptides remained intact, even though serum levels increased. The notion of the addition of an angiotensin antagonist to allow increased overall vasodilatory activity to prevail eventually led to use of the ARB along with neprilysin, and the results were quite favorable in early trials. PARADIGM-HF demonstrated that the combination sacubitril/valsartan was superior to enalapril in reducing the risk of cardiovascular death or hospitalization for worsening heart failure with reduced ejection fraction (median 27-month follow up; HR 0.80; 95% CI 0.73-0.87, p<0.001). Similar reductions were seen in all-cause mortality, CV mortality, and heart failure admissions as individual endpoints.

In the recent issue of The Lancet Diabetes and Endocrinology, a post-hoc analysis of the 8,442 patients enrolled in PARADIGM-HF, 3,778 subjects had pre-established diagnosis of diabetes on record, or had a new diagnosis of diabetes evidenced by an HbA1c of at least 6.5% upon enrollment. Distribution of these pre-study diabetes patients was 1,904 in the ANRI group and 1,874 in the enalapril group. There was no difference in baseline characteristics except for lower triglycerides in the neprilysin/valsartan group. Of note, the incidence of pre-existing diabetes in both groups was the same (76% in enalapril, 77% in ARNI), while the mean HbA1c at baseline was 7.48% (SD 1.58) in enalapril and 7.41% (SD 1.51) in ARNI. Methods for statistical analysis included the Chi square test to compare categorical variables, t-test to compare continuous variables, linear regression to assess changes at annual visits, and the mixed effects longitudinal analysis model to assess overall changes.

Results of a three-year follow-up from enrollment (four visits including baseline) favored the ARNI sacubitril/valsartan over enalapril in reducing HbA1c in diabetes-diagnosed subjects. At the year 1 visit, the mean reduction in the ARNI group was to 7.09% vs enalapril at 7.30% (adjusted for screening values, between group reduction -0.31; 95% CI -0.22 to -0.05, p=0.0023), year 2: ANRI 7.08% vs enalapril 7.31% (-0.17; -0.28 to -0.05; p=0.004), and year 3: ARNI 6.97% vs enalapril 7.16%  (-0.15; -0.32 to 0.01; p=0.072, ns). Across the 3 years, the overall between-group reduction was -0.14 (-0.23 to -0.06; p=0.0055). It was recognized that the HbA1c benefit was only seen in patients with diabetes that was diagnosed at screening, but not in the patients with known diabetes. In addition, no connection was observed between the reduction of HbA1c and the primary outcomes of cardiovascular death, suggesting the benefits seen on heart failure and HbA1c are independent of each other.

While these findings do not necessarily support that diabetes should be an indication for EntrestoR, the potential benefits in people with diabetes who have heart failure support additional consideration for its use in this population. Currently under way is the PARAGON-HF trial, which will compare the efficacy of sacubitril/valsartan vs valsartan alone in heart failure with preserved ejection fraction. This study is expected to be completed in 2019. A smaller phase-2 study found that the ARNI showed similar effects as in PARADIGM-HF, with the difference being the subjects had preserved ejection fraction.  The positive effects were more prominent in the subset of patients with diabetes.

Practice Pearls:

  • Diabetes and components of its treatment carry an increased risk for development of heart failure.
  • The combination ANRI sacubitril/valsartan (EntrestoR) showed significant reduction in risk for cardiovascular death and hospitalization for worsening heart failure.
  • EntrestoR is associated with reductions in HbA1c in newly diagnosed patients with concomitant heart failure with reduced ejection fraction.


McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. Epub 2014/08/30. doi: 10.1056/NEJMoa1409077. PubMed PMID: 25176015.

Seferovic JP, Claggett B, Seidelmann SB, Seely EW, Packer M, Zile MR, et al. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol. 2017. Epub 2017/03/17. doi: 10.1016/S2213-8587(17)30087-6. PubMed PMID: 28330649.


Mark Lawrence, PharmD Candidate; University of Colorado-Denver; School of Pharmacy NTPD