Colchicine for Cardiovascular Disease in Diabetes (CADENCE Trial)
Palo Alto (17 mi)Overseen byRob S Beanlands, MD
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Ottawa Heart Institute Research Corporation
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 1 jurisdiction
Trial Summary
What is the purpose of this trial?This trial tests colchicine to see if it can reduce inflammation in blood vessel plaques in high-risk patients with diabetes or pre-diabetes who recently had a heart attack or stroke. The goal is to prevent future cardiovascular events by reducing plaque inflammation. Colchicine is an ancient drug with anti-inflammatory effects, historically used for conditions like gout and familial Mediterranean fever, and has shown promise in reducing cardiovascular events by targeting inflammation in blood vessel plaques.
Is the drug Colchicine a promising treatment for heart disease in people with diabetes?Yes, Colchicine is a promising drug for heart disease in people with diabetes. It has been shown to reduce the risk of heart problems in people with chronic coronary artery disease and diabetes. It also helps lower the risk of major heart events in people with type 1 diabetes by reducing inflammation, which is a key factor in heart disease.89111213
What data supports the idea that Colchicine for Cardiovascular Disease in Diabetes is an effective drug?The available research shows that colchicine can be effective in reducing cardiovascular risk in patients with diabetes. The LoDoCo2 trial demonstrated that colchicine reduces cardiovascular risk in patients with chronic coronary artery disease and diabetes. Additionally, in type 1 diabetes, colchicine reduced the risk of major adverse cardiovascular events by 25% in trials focused on preventing atherosclerotic cardiovascular disease. This suggests that colchicine can be a promising option for lowering cardiovascular risk in people with diabetes.1341213
What safety data exists for colchicine in treating cardiovascular disease in diabetes?The provided research does not contain specific safety data for colchicine or its brand names (Colcrys, Mitigare, Gloperba, Lodoco) in the context of treating cardiovascular disease in diabetes. The studies focus on other drugs like aliskiren, liraglutide, and various anti-diabetic medications, assessing their cardiovascular safety. To find relevant safety data for colchicine, further research specifically targeting colchicine's effects in diabetic patients with cardiovascular disease is needed.256710
Do I need to stop my current medications for this trial?The trial protocol does not specify if you need to stop your current medications. However, you cannot participate if you are using potent p-glycoprotein inhibitors or strong CYP3A4 inhibitors like cyclosporine, clarithromycin, or ketoconazole.
Eligibility Criteria
This trial is for adults over 18 with Type 2 Diabetes or pre-diabetes who've recently had a cardiovascular event like a heart attack or stroke. They must have stable symptoms and not be severely ill from other conditions. Pregnant women, those with severe liver, heart, or kidney issues, active infections, immune compromise, certain cancers within the last 3 years are excluded.Inclusion Criteria
I am 18 years old or older.
I have Type 2 Diabetes or pre-diabetes and may be on medication or insulin.
Exclusion Criteria
I need treatment for a serious heart valve problem.
I have severe liver issues or my ALT levels are more than three times the normal limit.
I am not willing to use two forms of birth control during the study.
I have chronic diarrhea.
My heart failure is severe and not well-controlled.
I have an active inflammatory condition or am on systemic anti-inflammatory therapy.
I am allergic to dyes or my kidney function is low, so I will have a PET/CT instead of a CTA.
My kidney function is reduced with a GFR less than 50.
I am currently taking strong medication that affects how drugs are processed in my body.
My heart's pumping ability is severely reduced.
I have atrial fibrillation and have had a stroke or TIA.
I currently have an active infection and am taking antibiotics.
I often get infections due to a weak immune system.
I am unable to understand and give consent for treatment.
Treatment Details
The study tests if Colchicine can reduce inflammation in blood vessel plaques in high-risk patients using FDG PET imaging. Participants will either receive Colchicine or a placebo to see if there's an effect on plaque inflammation which contributes to cardiovascular events.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: ColchicineExperimental Treatment1 Intervention
Colchicine: 0.6 mg colchicine capsule to be taken once a day.
Group II: PlaceboPlacebo Group1 Intervention
Placebo: Sugar pill manufactured to mimic colchicine 0.6 mg capsule. Placebo to be taken once a day.
Colchicine is already approved in United States for the following indications:
🇺🇸 Approved in United States as Colcrys for:
- Gout
- Familial Mediterranean Fever
Find a clinic near you
Research locations nearbySelect from list below to view details:
Mazankowski Alberta Heart InstituteEdmonton, Canada
University of Ottawa Heart InstituteOttawa, Canada
Loading ...
Who is running the clinical trial?
Ottawa Heart Institute Research CorporationLead Sponsor
Canadian Institutes of Health Research (CIHR)Collaborator
References
The effect of glycemic control on the incidence of macrovascular complications of type 2 diabetes. [2019]Of all the complications of diabetes mellitus, macrovascular complications, ie, large-vessel atherosclerosis, account for the largest share of morbidity, mortality, and health care expenditures. Whereas there is now highly persuasive evidence that glycemic control reduces the risk of microvascular complications in type 1 diabetes, and probably in type 2 diabetes as well, such evidence is unavailable for macrovascular complications. Prospective epidemiologic studies, however, indicate that poor glycemic control enhances cardiovascular risk, and a number of biochemical mechanisms have been advanced to explain this phenomenon. However, data from animal studies, in vitro studies, and prospective epidemiologic studies suggest that endogenous insulin or insulin resistance may be atherogenic. Thus, a dilemma exists for insulin treatment, although the weight of evidence still favors its aggressive use. For persons whose glycemia can be adequately controlled with oral agents, the use of agents such as metformin and troglitazone--which do not raise, and may even lower, insulin concentrations--may offer an advantage. Definitive clinical trials on the benefits and risks of insulin therapy related to macrovascular complications are lacking and urgently needed.
[Should the occurrence of a first coronary event change the management of diabetes?]. [2022]The coronary morbi-mortality is particularly high in type 2 diabetes, which represents the vast majority of all diabetes. Hyperglycemia is an independent vascular risk factor in the short and long-term. The relationship between the degree of hyperglycemia and vascular risk is linear with no threshold effect. The occurrence of a first coronary event is an occasion, though late, to review the management of all risk factors in diabetic patients. In these patients, intensive insulin therapy administered in the acute phase of infarction reduces cardiovascular mortality by 30% at 1 and 3 years. There are no specific studies of secondary prevention by optimal therapy of diabetes, but, in the UKPDS, the treatment of hyperglycemia with sulfonylurea or insulin only marginally reduced the number of cardiovascular events. On the other hand, treatment of obese patients with metformin significantly reduced the incidence of myocardial infarction and of mortality diabetes related. These results, though observed with the same level of glycemic control as in the other treatment groups, suggest a cardio-protective effect of metformin itself. These beneficial effects should be weighed up against the potential risk of lactic acidosis which still limits the widespread use of metformin in with coronary heart disease patients. Follow-up studies show that diabetic with coronary heart disease patients do not receive all effective therapeutic inventions in secondary prevention and that the treatment of hyperglycemia is often neglected. Close collaboration between cardiologists and diabetologists is necessary to improve the management of type 2 diabetes.
Clinical trial evidence for cardiovascular risk reduction in type 2 diabetes. [2019]Major clinical trials have shown that excellent glycemic control, sustained over time, can prevent or delay the microvascular complications of diabetes, including retinopathy, nephropathy, and neuropathy. No prospective trial has clearly shown that glycemic intervention can prevent the macrovascular complications of diabetes, such as myocardial infarction, cerebrovascular accident, and amputation. However, a number of landmark clinical trials have shown the efficacy of control of blood pressure and lipids and use of antiplatelet agents (mainly aspirin) in protecting the macrovasculature of individuals with diabetes. In this article, glycemic, blood pressure, lipid, and antiplatelet trials relevant to the treatment of people with type 2 diabetes are reviewed.
Cardiovascular disease in type 2 diabetes mellitus: current management guidelines. [2019]Cardiovascular disease is the most prevalent and detrimental complication of diabetes mellitus. The incidence of cardiovascular mortality in diabetic subjects without a clinical history of previous cardiac events is as high as the incidence in nondiabetic subjects with a history of myocardial infarction. This inordinate increase in the risk of coronary events in diabetic patients is attributed to multiple factors, including glycation and oxidation of proteins and increased prevalence of classic risk factors of coronary disease, such as hypertension, obesity, and dyslipidemia. Despite advances in the management of cardiovascular disease, a large proportion of diabetic subjects continue to have uncontrolled hyperglycemia, hypertension, and dyslipidemia. In addition, certain medical interventions with established efficacy in the general population do not appear to be appropriate for diabetic subjects. Recently published clinical trials of managing coronary risk factors indicate that more stringent goals of therapy should be set for diabetic patients. In this communication, some of these landmark studies are reviewed and some practical guidelines of management are suggested.
Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2: 3 liraglutide clinical development studies. [2022]We assessed the cardiovascular safety of liraglutide, a glucagon-like peptide-1 receptor agonist, using existing clinical data. Patient-level results from all completed phase 2 and 3 studies from the liraglutide clinical development programme were pooled to determine rates of major adverse cardiovascular events (MACE): cardiovascular death, myocardial infarction, stroke. MACE were identified by querying the study database using Medical Dictionary for Regulatory Activities (MedDRA) terms combined with serious adverse events recorded by study investigators. Broad, narrow, and custom groups of MedDRA queries were used. Candidate events from each query were independently adjudicated post hoc. In 15 studies (6638 patients; 4257 liraglutide treated), there were 114 patients with MACE identified using the broad MedDRA query. Of these, 44 were classified as serious adverse events and 39 were adjudicated as MACE. The incidence ratio for adjudicated broad/serious MACE associated with liraglutide was 0.73 (95% CI 0.38-1.41) versus all comparator drugs (metformin, glimepiride, rosiglitazone, insulin glargine, placebo), within cardiovascular safety limits defined by the United States Food & Drug Administration for diabetes therapies under current investigation.
[Cardiovascular safety of non-insulin anti-diabetic drugs. Scientific position statement of SEMERGEN]. [2016]Diabetes increases the risk of both microvascular and macrovascular complications. Although reducing plasma glucose levels to recommended targets decreases the risk of microvascular outcomes, the effects of anti-diabetic drugs on macrovascular complications and cardiovascular death are of concern. In fact, it has been suggested that some anti-diabetic agents could even be harmful for cardiovascular outcomes. In this context, several health care regulatory agencies have established the need for performing clinical trials specifically designed to assess the cardiovascular safety of anti-diabetic drugs. The results of 2 clinical trials have recently been published that provide important information on the cardiovascular safety of dipeptidyl peptidase 4 (DPP-4) inhibitors. The aim of this document was to review the available evidence on the cardiovascular safety of non-insulin anti-diabetic drugs and provide practical recommendations on their use in this context.
Effects of aliskiren in diabetic and non-diabetic patients with coronary artery disease: Insights from AQUARIUS. [2016]Aliskiren previously was found to have potentially harmful effects in diabetic individuals prescribed concomitant angiotensin converting enzyme inhibitors (ACEI) or angiotenisn receptor antagonists (ARB). We explored potential effects of aliskiren on coronary atheroma progression and major adverse cardiovascular events (MACE: death/non-fatal MI/non-fatal stroke/hospitalization for heart failure/hospitalization for ACS/arterial revascularization) in patients with and without diabetes mellitus (DM).
Increased Calcific Aortic Valve Disease in response to a diabetogenic, procalcific diet in the LDLr-/-ApoB100/100 mouse model. [2020]Label="OBJECTIVE" NlmCategory="OBJECTIVE">Calcific aortic valve disease (CAVD) is a major cause of aortic stenosis (AS) and cardiac insufficiency. Patients with type II diabetes mellitus (T2DM) are at heightened risk for CAVD, and their valves have greater calcification than nondiabetic valves. No drugs to prevent or treat CAVD exist, and animal models that might help identify therapeutic targets are sorely lacking. To develop an animal model mimicking the structural and functional features of CAVD in people with T2DM, we tested a diabetogenic, procalcific diet and its effect on the incidence and severity of CAVD and AS in the, LDLr-/-ApoB100/100 mouse model.
Type-2 diabetes mellitus and cardiovascular disease. [2019]The global prevalence of diabetes has risen in adults from 4.7% in 1980 to 8.5% in 2014. 90-95% of adults with diabetes have Type 2 diabetes (T2D). This paper focuses on the diagnosis and treatment of T2D patients who have or are at risk for cardiovascular disease. Hyperglycemia, insulin resistance and excess fatty acids increase oxidative stress, disrupt protein kinase C signaling and increase advanced glycation end-products that result in vascular inflammation, vasoconstriction, thrombosis and atherogenesis. Intensive T2D treatment produces a ≥10% risk reduction in major macrovascular and microvascular events. Glucose-lowering therapies must be individualized. Metformin is an optimal drug for monotherapy. If hemoglobin A1c is not at goal, a sodium-glucose cotransporter-2 inhibitor or a dipeptidyl peptidase-4 inhibitor should be considered for therapy with metformin. Coronary angioplasty/stenting is recommended for diabetic patients with acute myocardial infarctions. Coronary artery bypass grafting is recommended for symptomatic diabetic patients with multivessel disease.
The Association Between Baseline Insulin Treatment and Cardiovascular Events: A Meta-Analysis. [2023]We conducted a meta-analysis to compare major adverse cardiovascular events (MACEs) in recent diabetes type 2 drugs cardiovascular outcome trials (CVOTs) in the subgroups that used insulin at baseline to the subgroups that did not.
Aortic valve disease in diabetes: Molecular mechanisms and novel therapies. [2022]Valve disease and particularly calcific aortic valve disease (CAVD) and diabetes (DM) are progressive diseases constituting a global health burden for all aging societies (Progress in Cardiovascular Diseases. 2014;56(6):565: Circulation Research. 2021;128(9):1344). Compared to non-diabetic individuals (The Lancet. 2008;371(9626):1800: The American Journal of Cardiology. 1983;51(3):403: Journal of the American College of Cardiology. 2017;69(12):1523), the diabetic patients have a significantly greater propensity for cardiovascular disorders and faster degeneration of implanted bioprosthetic aortic valves. Previously, using an original experimental model, the diabetic-hyperlipemic hamsters, we have shown that the earliest alterations induced by these conditions occur at the level of the aortic valves and, with time these changes lead to calcifications and CAVD. However, there are no pharmacological treatments available to reverse or retard the progression of aortic valve disease in diabetes, despite the significant advances in the field. Therefore, it is critical to uncover the mechanisms of valve disease progression, find biomarkers for diagnosis and new targets for therapies. This review aims at presenting an update on the basic research in CAVD in the context of diabetes. We provide an insight into the accumulated data including our results on diabetes-induced progressive cell and molecular alterations in the aortic valve, new potential biomarkers to assess the evolution and therapy of the disease, advancement in targeted nanotherapies, tissue engineering and the potential use of circulating endothelial progenitor cells in CAVD.
The potential of colchicine for lowering the risk of cardiovascular events in type 1 diabetes. [2023]In type 1 diabetes, average life expectancy is reduced by ˃10 years as compared with outside of diabetes. Residual cardiovascular risk defines high cardiovascular event rate despite modern, guideline-recommended standard of care of established risk factors like hypertension, dyslipidaemia, and glycaemic control, and it adds importantly to these lost years of life in type 1 diabetes due to atherosclerotic cardiovascular diseases like myocardial infarction and ischaemic stroke. With a growing understanding of inflammation as an important driver of atherosclerotic cardiovascular disease, residual inflammatory risk is a novel and common risk factor and a promising target for lowering residual cardiovascular risk in type 1 diabetes. Interestingly, the inexpensive anti-inflammatory agent colchicine reduced the risk of major adverse cardiovascular events by 25% in cardiovascular outcome trials in the secondary prevention of atherosclerotic cardiovascular disease. Here, we summarize the role of inflammation as a driver of atherosclerosis and review current evidence linking inflammation and atherosclerotic cardiovascular disease in type 1 diabetes. Also, we provide an overview of the evidence base for targeting residual inflammatory risk with colchicine for lowering residual cardiovascular risk in type 1 diabetes.
Colchicine and diabetes in patients with chronic coronary artery disease: insights from the LoDoCo2 randomized controlled trial. [2023]Despite optimal treatment, patients with chronic coronary artery disease (CAD) and diabetes mellitus (DM) are at high risk of cardiovascular events, emphasizing the need for new treatment options. The Low-Dose Colchicine 2 (LoDoCo2) trial demonstrated that colchicine reduces cardiovascular risk in patients with chronic CAD. This analysis determines the efficacy of colchicine in patients with chronic CAD and DM as well as the effect of colchicine on the development of new-onset type 2 diabetes mellitus (T2DM).