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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how two medications, sacubitril-valsartan and valsartan, affect blood sugar and insulin release in African Americans with prediabetes (a condition where blood sugar levels are elevated but not high enough for a diabetes diagnosis). Researchers compare these drugs to a placebo (a pill with no active treatment) to determine which is more effective at improving blood sugar and insulin levels. Suitable participants have a history of high blood sugar but not diabetes, along with risk factors such as a family history of type 2 diabetes or metabolic syndrome (a group of conditions that increase the risk of heart disease, stroke, and type 2 diabetes). As a Phase 4 trial, this research aims to understand how these FDA-approved treatments can benefit more patients.

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 is the safety track record for these treatments?

Research shows that sacubitril-valsartan is usually well-tolerated by patients, though some side effects can occur. Common issues include low blood pressure and occasional swelling, known as angioedema. Compared to some other treatments, there is a lower risk of kidney problems and high potassium levels, but these side effects are uncommon.

Valsartan has long been used to treat high blood pressure and heart failure. It is generally safe, with dizziness and tiredness as the most common side effects.

Both medicines have already been approved for other conditions, indicating they have passed several safety checks. Most people using these drugs do not experience serious problems, but discussing any concerns with a doctor is always advisable. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about Sacubitril-Valsartan for prediabetes because it combines two active ingredients, sacubitril and valsartan, which work together to not only manage blood pressure but also potentially impact glucose metabolism in a novel way. Unlike other treatments for prediabetes that typically focus on lifestyle changes or medications like metformin, Sacubitril-Valsartan targets the renin-angiotensin system while also increasing levels of natriuretic peptides, which may help improve insulin sensitivity. This dual action could offer a unique approach to managing prediabetes, with the potential to address both cardiovascular and metabolic aspects of the condition simultaneously.

What evidence suggests that this trial's treatments could be effective for prediabetes?

Research has shown that sacubitril-valsartan, a treatment under study in this trial, can help lower blood sugar levels. In studies, patients taking this medication experienced significant drops in fasting blood sugar, an important measure of blood sugar levels. One study found that sacubitril-valsartan reduced HbA1c levels, which indicate long-term blood sugar control, more effectively than valsartan alone, another treatment option in this trial. These results suggest that sacubitril-valsartan might help people with impaired glucose tolerance manage their blood sugar and insulin levels better. This is promising for those seeking more effective blood sugar control. ^{2 3 6 7 8}

Who Is on the Research Team?

Joshua J Joseph, MD

Principal Investigator

Ohio State University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10053359/

The impact of sacubitril/valsartan on outcome in patients ... Data have shown that the HbA1c levels in patients with diabetes mellitus could be impacted by sacubitril/valsartan. A possible positive effect in diabetes ...

2. novartis.com novartis.com/us-en/news/media-releases/new-analysis-shows-novartis-entresto-improves-glycemic-control-reduced-ejection-fraction-heart-failure-patients-diabetes

New analysis shows Novartis Entresto improves glycemic ... Over three years, HbA1c levels remained persistently lower in patients treated with Entresto compared to enalapril, with an overall reduction of 0.14% (95% CI [ ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9206286/

Effects of sacubitril/valsartan on glycemia in patients with ... We found that in patients with HFpEF and diabetes, sacubitril/valsartan significantly reduced HbA1c compared with valsartan, and that new use of ...

4. jamanetwork.com jamanetwork.com/journals/jamacardiology/fullarticle/2785700

Effect of Treatment With Sacubitril/Valsartan in Patients ... The results of the LIFE trial show there was no difference between sacubitril/valsartan and valsartan with respect to lowering NT-proBNP levels ...

5. frontiersin.org frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.940654/full

Effects of sacubitril/valsartan on both metabolic parameters ... Results: After 24-week of treatment with sac/val, a significant reduction in fasting plasma glucose (109 ± 9 vs 103 ± 8 mg/dl, p < 0.0001), ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/pmc/articles/PMC11357838

Safety Outcomes After Sacubitril/Valsartan Initiation in a ... Primary safety outcomes will include discontinuation of sacubitril/valsartan, incidence of angioedema, hyperkalemia, AKI, hypotension, and ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0167527323017035

The real-world safety of sacubitril / valsartan among older ... Sac/Val was associated with higher reporting of hypotension, lower reporting of acute kidney injury (AKI) and hyperkalemia, and similar reporting of angioedema.

8. researchgate.net researchgate.net/publication/382642372_Safety_Outcomes_After_SacubitrilValsartan_Initiation_in_a_Community_Teaching_Hospital_A_Retrospective_Observational_Study

(PDF) Safety Outcomes After Sacubitril/Valsartan Initiation ... Primary safety outcomes will include discontinuation of sacubitril/valsartan, incidence of angioedema, hyperkalemia, AKI, hypotension, and ...