Canagliflozin for Heart Disease

(CANTORSING Trial)

Overseen By Kevin Boczar, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Ottawa Heart Institute Research Corporation

Must not be taking: Antibiotics, Prednisone, Methotrexate, others

Disqualifiers: Severe LV dysfunction, Decompensated heart failure, Active infection, Active inflammatory conditions, Pregnancy, Breastfeeding, GFR <50, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 6 months

24 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications, but you cannot participate if you are using certain medications like p-glycoprotein inhibitors or strong CYP3A4 inhibitors.

What evidence supports the effectiveness of the drug Canagliflozin for heart disease?

Research from the CANVAS Program shows that Canagliflozin, a drug used for type 2 diabetes, can lower the risk of heart-related problems like heart attacks and strokes in patients with high cardiovascular risk. This suggests it may be beneficial for heart disease. ^{1 2 3 4 5}

Is Canagliflozin safe for humans?

Canagliflozin, used for type 2 diabetes, has some serious side effects like severe ketoacidosis (a dangerous condition with high acid levels in the blood) and rare cases of acute pancreatitis (inflammation of the pancreas). It can also cause genital infections and, in some cases, low blood pressure, especially in older adults. ^{2 4 5 6 7}

How is the drug Canagliflozin unique for heart disease treatment?

Canagliflozin is unique because it works by blocking a protein in the kidneys that helps reabsorb sugar, which not only helps control blood sugar levels but also reduces hospitalizations for heart failure in people with type 2 diabetes. This dual benefit makes it different from many other heart disease treatments that do not address blood sugar control. ^{2 8 9 10 11}

What is the purpose of this trial?

CANTOR SING is a pilot single center double blinded randomized study. The investigators will compare the effect of canagliflozin (300 mg daily - intervention arm) vs. placebo (control group) on the FDG aortic uptake in patients with stable CAD (over 60 days post-myocardial infarction) after a 6-month period of treatment. The investigators plan to enroll 8 patients in each arm (total sample size: 16 patients). Primary endpoint is the change in FDG aortic uptake between baseline and 6 months in each arm.

Research Team

Kevin Boczar, MD

Principal Investigator

Ottawa Heart Institute Research Corporation

Eligibility Criteria

This trial is for people who have stable coronary artery disease (CAD) at least 60 days after a heart attack and also have type 2 diabetes. Participants must be willing to give informed consent.

Inclusion Criteria

I have diabetes.

Given informed consent

I had a heart attack over 2 months ago and my heart condition has been stable since.

Exclusion Criteria

I am unable to understand and give consent for treatment.

My heart's pumping ability is significantly reduced.

Pregnancy (all women of childbearing potential will have a negative BHCG test)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either canagliflozin 300 mg or placebo daily for 6 months

6 months

3 visits (in-person) every 3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including clinical evaluation and blood collection

6 months

2 visits (in-person) at baseline and 6 months

Treatment Details

Interventions

• Canagliflozin
• Placebo

Trial Overview The study compares Canagliflozin, a medication given daily, with a placebo over six months to see if it reduces inflammation in the blood vessels of patients with CAD and diabetes.

Participant Groups

Group I: Active Active Control 1 Intervention

Canagliflozin 300mg PO daily

Group II: Placebo Placebo Group 1 Intervention

Placebo PO daily

Canagliflozin is already approved in European Union, United States for the following indications:

Approved in European Union as Invokana for:

• Type 2 diabetes mellitus
• Cardiovascular risk reduction

Approved in United States as Invokana for:

• Type 2 diabetes mellitus
• Cardiovascular risk reduction
• Diabetic kidney disease

Who Is Running the Clinical Trial?

Ottawa Heart Institute Research Corporation

Lead Sponsor

Trials

200

Recruited

95,800+

Findings from Research

Canagliflozin, an SGLT2 inhibitor, effectively lowers blood glucose levels in patients with type 2 diabetes by increasing urinary glucose excretion, showing significant improvements in glycemic control over 26-52 week trials.

It has a low risk of causing hypoglycemia and is generally well tolerated, although it may lead to urinary tract infections and increased urination; its effects on cardiovascular risk are still being evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. Plosker, GL.[2021]

Canagliflozin, an SGLT2 inhibitor, effectively lowers blood sugar levels and HbA1c by promoting glucose excretion in urine, with an average HbA1c reduction of 0.75% when used alongside other diabetes treatments.

While canagliflozin is generally safe, it can cause genital infections and urinary tract infections, and caution is advised for elderly patients and those with renal insufficiency, as its efficacy decreases with lower kidney function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Canagliflozin (Invokana): kidney SGLT2 cotransporter inhibitor for treating type 2 diabetes]. Scheen, AJ.[2018]

Canagliflozin, an SGLT2 inhibitor, effectively lowers blood glucose, blood pressure, body weight, and albuminuria in patients with type 2 diabetes, while also significantly reducing the risk of serious cardiovascular events in high-risk patients, according to the CANVAS Program.

Despite its benefits, canagliflozin is associated with an increased risk of lower-limb amputation, highlighting the need for careful consideration of both its advantages and potential risks in diabetes treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The CANVAS Program: implications of canagliflozin on reducing cardiovascular risk in patients with type 2 diabetes mellitus. Carbone, S., Dixon, DL.[2020]

Canagliflozin, a sodium-glucose co-transporter 2 inhibitor for type 2 diabetes, can cause acute pancreatitis, a very rare side effect occurring in less than 1% of patients, as demonstrated in a case of a 50-year-old male who developed diabetic ketoacidosis after 4 days of treatment.

The case highlights the importance of monitoring for serious side effects like acute pancreatitis when prescribing canagliflozin, emphasizing the need for more detailed guidelines on patient selection for this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute pancreatitis in the use of canagliflozin: A rare side-effect of the novel therapy for type 2 diabetes mellitus. Srivali, N., Thongprayoon, C., Cheungpasitporn, W., et al.[2020]

Canagliflozin is effective in improving glycemic control in adults with type 2 diabetes, specifically by inhibiting SGLT2 to increase urinary glucose excretion, with a focus on patients having a baseline eGFR of 45 mL/min/1.73 m² or higher.

The safety analyses conducted during the clinical development of canagliflozin provided a comprehensive understanding of its impact on renal function, allowing for informed dosing recommendations in patients with renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Canagliflozin use in patients with renal impairment-Utility of quantitative clinical pharmacology analyses in dose optimization. Khurana, M., Vaidyanathan, J., Marathe, A., et al.[2022]

Canagliflozin, an SGLT-2 inhibitor introduced for type 2 diabetes, shows potential for type 1 diabetes treatment due to its insulin-independent mechanism of action.

However, it carries serious risks, including severe metabolic acidosis and euglycemic diabetic ketoacidosis, which require immediate recognition and treatment to prevent life-threatening complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe Ketoacidosis Associated with Canagliflozin (Invokana): A Safety Concern. Gelaye, A., Haidar, A., Kassab, C., et al.[2022]

In a large retrospective cohort study involving over 55,000 patients with type 2 diabetes, canagliflozin was associated with a significantly lower risk of hospital admission for heart failure compared to DPP-4 inhibitors, GLP-1 receptor agonists, and sulfonylureas.

Canagliflozin showed similar risks for major cardiovascular events (like heart attacks and strokes) when compared to these other diabetes medications, indicating its safety profile in terms of cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: population based cohort study. Patorno, E., Goldfine, AB., Schneeweiss, S., et al.[2022]

In a small study of 36 patients with type 2 diabetes and heart failure, canagliflozin showed improvements in lean peak oxygen consumption and ventilatory anaerobic threshold compared to sitagliptin, indicating potential benefits for cardiorespiratory fitness.

Although canagliflozin did not significantly improve the primary endpoints of peak oxygen consumption or VE/VCO2 slope, it did lead to a notable reduction in heart failure-related quality of life, suggesting it may still offer important benefits for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA-HF study. Carbone, S., Billingsley, HE., Canada, JM., et al.[2021]

In a study involving 10,194 patients with type 2 diabetes, canagliflozin was associated with a higher incidence of fractures (4.0%) compared to placebo (2.6%) in patients with cardiovascular risk, indicating a potential safety concern for this medication.

Overall, while the fracture risk was similar between canagliflozin and non-canagliflozin treatments in most patients, the increase in fractures was particularly noted in older patients with cardiovascular issues, suggesting that careful monitoring may be needed for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus. Watts, NB., Bilezikian, JP., Usiskin, K., et al.[2022]

In a study involving 716 older patients with type 2 diabetes, canagliflozin led to small but significant reductions in total hip bone mineral density (BMD) over 104 weeks, with decreases of -0.9% and -1.2% for the 100 mg and 300 mg doses, respectively.

The treatment was also associated with increases in bone turnover markers, indicating changes in bone formation and resorption, which were correlated with weight loss, but no significant changes in overall bone strength were observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Bone Mineral Density and Bone Biomarkers in Patients With Type 2 Diabetes Treated With Canagliflozin. Bilezikian, JP., Watts, NB., Usiskin, K., et al.[2022]

Canagliflozin, tested in 2313 patients over 26 weeks, was generally well tolerated and showed a similar incidence of adverse events compared to placebo, with low rates of serious adverse events and discontinuations.

While canagliflozin was associated with mild to moderate increases in genital infections and osmotic diuresis-related events, it also led to favorable changes in cholesterol levels, indicating its potential benefits alongside some manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of canagliflozin in patients with type 2 diabetes mellitus: pooled analysis of phase 3 study results. Usiskin, K., Kline, I., Fung, A., et al.[2018]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. [2021]

2. Belgium pubmed.ncbi.nlm.nih.gov

[Canagliflozin (Invokana): kidney SGLT2 cotransporter inhibitor for treating type 2 diabetes]. [2018]

3. England pubmed.ncbi.nlm.nih.gov

The CANVAS Program: implications of canagliflozin on reducing cardiovascular risk in patients with type 2 diabetes mellitus. [2020]

4. India pubmed.ncbi.nlm.nih.gov

Acute pancreatitis in the use of canagliflozin: A rare side-effect of the novel therapy for type 2 diabetes mellitus. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Canagliflozin use in patients with renal impairment-Utility of quantitative clinical pharmacology analyses in dose optimization. [2022]

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

Severe Ketoacidosis Associated with Canagliflozin (Invokana): A Safety Concern. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: population based cohort study. [2022]

8. England pubmed.ncbi.nlm.nih.gov

The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA-HF study. [2021]

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

Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus. [2022]

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

Evaluation of Bone Mineral Density and Bone Biomarkers in Patients With Type 2 Diabetes Treated With Canagliflozin. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Safety and tolerability of canagliflozin in patients with type 2 diabetes mellitus: pooled analysis of phase 3 study results. [2018]