Sacubitril-Valsartan for Prediabetes

Overseen By Joshua J Joseph, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Ohio State University

Must not be taking: Statins, β-Blockers, Antipsychotics, others

Disqualifiers: Type 2 diabetes, Hypertension, Heart failure, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 26 weeks

90 Participants Needed

Trial Summary

What is the purpose of this trial?

The primary objective is to examine the impact of the Renin-Angiotensin-Aldosterone System (RAAS) blockade with medications (valsartan) or RAAS and neprilysin inhibition (valsartan/sacubitril) vs. placebo on changes in blood sugar and insulin secretion from the pancreas over 26 weeks assessed with glucose clamp studies among African Americans (AAs) with impaired glucose tolerance. The investigators hypothesize that combined RAAS/neprilysin inhibition will lead to greater improvement in insulin release from the pancreas and improved blood sugar compared to RAAS inhibition alone among AAs with impaired glucose tolerance.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications. The trial excludes participants who are on anti-hypertensive medications, statins, β-Blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, renin inhibitors, mineralocorticoid antagonists, oral hypoglycemic medications, and antipsychotic medications.

What data supports the effectiveness of the drug Sacubitril-Valsartan for prediabetes?

Research suggests that Sacubitril-Valsartan, a drug used for heart failure, may improve blood sugar control in patients with type 2 diabetes, which could indicate potential benefits for prediabetes as well. ^{1 2 3 4 5}

Is sacubitril-valsartan safe for humans?

Sacubitril-valsartan has been approved by the U.S. Food and Drug Administration for treating heart failure, and studies show it does not affect heart rhythm even at high doses, indicating it is generally safe for human use. ^{5 6 7 8 9}

How is the drug sacubitril-valsartan unique for prediabetes treatment?

Sacubitril-valsartan is unique because it combines two actions: blocking a hormone system that raises blood pressure and inhibiting an enzyme that breaks down beneficial peptides, which may help improve blood sugar control. This dual action is different from other treatments for prediabetes, which typically focus only on blood sugar levels. ^{2 3 4 5 10}

Research Team

Joshua J Joseph, MD

Principal Investigator

Ohio State University

Eligibility Criteria

This trial is for African Americans aged 18-65 with prediabetes or risk factors like a family history of type 2 diabetes. It's not for those with type 2 diabetes, recent significant weight loss, certain heart conditions, abnormal kidney function, severe psychiatric disorders, pregnancy or specific medication use.

Inclusion Criteria

You have a specific level of high blood sugar after drinking a sugary drink.

I am African American, aged 18-65, with a history or risk factors for diabetes.

Exclusion Criteria

Your blood potassium level is higher than 5.0 milliequivalent/L.

My kidney function is below normal levels.

I have had heart problems or surgery in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either valsartan, sacubitril/valsartan, or placebo for 26 weeks to assess changes in blood sugar and insulin secretion

26 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Placebo Oral Tablet
• Sacubitril-Valsartan
• Valsartan

Trial Overview The study tests the effects of RAAS blockade (Valsartan) and combined RAAS/neprilysin inhibition (Sacubitril-Valsartan) versus placebo on blood sugar control and insulin release in African Americans with impaired glucose tolerance over a period of 26 weeks.

Participant Groups

Group I: Sacubitril/Valsartan Experimental Treatment 1 Intervention

Sacubitril/Valsartan (97/103 mg) twice daily for 26 weeks

Group II: Valsartan Active Control 1 Intervention

Valsartan 160 mg twice daily for 26 weeks

Group III: Placebo Placebo Group 1 Intervention

placebo (+/- amlodipine 2.5-5 mg twice daily if high blood pressure)

Who Is Running the Clinical Trial?

Ohio State University

Lead Sponsor

Trials

891

Recruited

2,659,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Findings from Research

In a retrospective study of 132 heart failure patients with reduced ejection fraction, those treated with sacubitril/valsartan showed significant improvements in both left ventricular ejection fraction (LVEF) and global left ventricular longitudinal strain (GLS) over an average of 14 months, indicating enhanced heart function.

Unlike the control group receiving conventional therapy, which only improved LVEF, the sacubitril/valsartan group demonstrated a notable increase in GLS, suggesting that this medication may offer additional benefits in heart remodeling beyond just improving ejection fraction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan improves left ventricular longitudinal deformation in heart failure patients with reduced ejection fraction. De Vecchis, R., Paccone, A., Di Maio, M.[2023]

In a study involving 36 healthy subjects, taking sacubitril/valsartan (LCZ696) with food significantly reduced the absorption rate of sacubitril and valsartan, with Cmax values decreasing by 42-54% and ~40%, respectively.

Despite the reduced absorption rates when taken with meals, LCZ696 was found to be safe and well tolerated, indicating that while food affects its bioavailability, it does not compromise the overall safety of the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of food on the oral bioavailability of the angiotensin receptor - neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects . Ayalasomayajula, S., Langenickel, TH., Chandra, P., et al.[2022]

In a study of 59 prediabetic patients with heart failure and reduced ejection fraction, treatment with sacubitril/valsartan for 24 weeks significantly improved metabolic parameters, including reductions in fasting plasma glucose, insulin levels, and hemoglobin A1c, indicating better glycemic control.

The treatment also led to significant improvements in heart function, as evidenced by reductions in left ventricular volumes and an increase in ejection fraction, suggesting that sacubitril/valsartan may enhance both metabolic control and cardiac function in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of sacubitril/valsartan on both metabolic parameters and insulin resistance in prediabetic non-obese patients with heart failure and reduced ejection fraction. Cloro, C., Zaffina, I., Sacchetta, L., et al.[2022]

Sacubitril-valsartan is projected to provide significant health benefits for patients with heart failure (HF) and an ejection fraction (EF) of 60% or less, adding 0.53 quality-adjusted life-years (QALYs) at an incremental cost of $40,892, resulting in an incremental cost-effectiveness ratio (ICER) of $76,852 per QALY compared to traditional renin-angiotensin system inhibitors (RASis).

The treatment is particularly cost-effective for patients with lower EFs (≤50%), with ICERs indicating high economic value, suggesting that sacubitril-valsartan could be a valuable treatment option for a broader range of HF patients, influencing clinical practice guidelines and insurance coverage decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health and Economic Evaluation of Sacubitril-Valsartan for Heart Failure Management. Bhatt, AS., Vaduganathan, M., Claggett, BL., et al.[2023]

In a study using a rabbit model of acute myocardial infarction, sacubitril/valsartan (SAC/VAL) significantly reduced infarct size and preserved left ventricular ejection fraction (LVEF) compared to placebo, demonstrating its acute infarct-sparing benefits.

SAC/VAL not only improved LVEF over time in heart failure treatment protocols but also significantly reduced left ventricular scar size after myocardial infarction, indicating its superior long-term protective effects compared to valsartan alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/Valsartan Averts Adverse Post-Infarction Ventricular Remodeling and Preserves Systolic Function in Rabbits. Torrado, J., Cain, C., Mauro, AG., et al.[2021]

In a study involving 84 healthy male subjects, both therapeutic (400 mg) and supratherapeutic (1200 mg) doses of sacubitril/valsartan (LCZ696) did not significantly affect cardiac repolarization, as indicated by QTcF intervals remaining within safe limits.

The study confirmed the safety of LCZ696, with no significant changes in ECG parameters or increased adverse events compared to placebo, supporting its use in patients with chronic heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single therapeutic and supratherapeutic doses of sacubitril/valsartan (LCZ696) do not affect cardiac repolarization. Langenickel, TH., Jordaan, P., Petruck, J., et al.[2021]

A study analyzing 80,316 reports from the FDA Adverse Event Reporting System found no significant increase in dementia-related adverse events associated with sacubitril/valsartan in heart failure patients, suggesting it is safe in this regard.

The statistical analysis showed that neither narrow nor broad dementia-related complications were over-reported in patients taking sacubitril/valsartan, indicating that long-term use may not adversely affect cognition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated insights on dementia-related risk of sacubitril/valsartan: A real-world pharmacovigilance analysis. Chen, C., Ding, L., Fu, F., et al.[2023]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan improves left ventricular longitudinal deformation in heart failure patients with reduced ejection fraction. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Effect of food on the oral bioavailability of the angiotensin receptor - neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects . [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Effects of sacubitril/valsartan on both metabolic parameters and insulin resistance in prediabetic non-obese patients with heart failure and reduced ejection fraction. [2022]

5. Canada pubmed.ncbi.nlm.nih.gov

Pharmacist- or Nurse Practitioner-Led Assessment and Titration of Sacubitril/Valsartan in a Heart Failure Clinic: A Cohort Study. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sacubitril valsartan in treating heart failure with midrange ejection fraction after acute myocardial infarction in diabetic patients. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Health and Economic Evaluation of Sacubitril-Valsartan for Heart Failure Management. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Sacubitril/Valsartan Averts Adverse Post-Infarction Ventricular Remodeling and Preserves Systolic Function in Rabbits. [2021]

9. Germany pubmed.ncbi.nlm.nih.gov

Single therapeutic and supratherapeutic doses of sacubitril/valsartan (LCZ696) do not affect cardiac repolarization. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Updated insights on dementia-related risk of sacubitril/valsartan: A real-world pharmacovigilance analysis. [2023]