Incretin and Treatment With Inhibition of Sodium-glucose Cotransporter-2 Combination Insights Into Mechanisms Implicated in Congestive Heart Failure: "NATRIURETIC" Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Proximal tubular natriuresis
研究概览
简要总结
This study aims to provide essential mechanistic insights into natriuretic and hemodynamic effects of SGLT2i and GLP-1RA agents in T2D patients. Ultimately, by obtaining physiological data in T2D patients without HF, our aims are to gain insight into how the use of this combined therapy may be used in T2D with HF in future work.
详细描述
Type 2 diabetes (T2D) is an epidemic that afflicts more than 350 million people world-wide. Despite the use of existing medical therapies, T2D continues to cause significant morbidity and mortality, leading to large societal and financial costs to Canadians.
Newer agents called sodium glucose co-transporter-2 inhibitors (SGLT2i) have been developed to improve glycemic control and lower hemoglobin A1c by increasing glycosuria. SGLT2i also reduce blood pressure and albuminuria in T2D - possibly through natriuresis. Importantly, a landmark trial "EMPA-REG OUTCOME" demonstrated that the SGLT2i empagliflozin is the first anti- hyperglycemic agent to reduce mortality and heart failure (HF) risk, and also to decrease the risk of progressive diabetic nephropathy.
Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is a subcutaneous drug, used for treating T2D patients. Recently, this drug was also able to reduce cardiovascular endpoints in the LEADER trial. Furthermore, liraglutide attenuated the risk of progressive albuminuria as well. GLP-1RAs induce natriuretic effects, but have not been shown to reduce HF risk. Their positive cardiovascular effects are probably due to reduction in atherosclerotic events.
T2D patients are at high risk for development of both HF and atherosclerotic diseases. Given that SGLT2i and GLP-1RA seem to reduce cardiovascular outcomes via different approaches, combining these two agents in the treatment of T2D is an appealing new strategy. In this project, we aim to combine GLP-1RA and SGLT2i therapies in T2D patients without HF and compare renal and cardiovascular physiological measures in these patients, such as renal function, neurohormonal activation, blood pressure, arterial stiffness, and systemic vascular resistance. This could give a better understanding on the action of the combination therapy in T2D, support future mechanist trials with patients with HF, and give support to the development of large clinical trials on this topic.
Study design: Open-label, exploratory, randomized (with randomization concealment), pilot mechanistic trial, with two groups and 2 sequential treatments within each group.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women diagnosed with T2D ≥6 months prior to informed consent;
- •eGFR ≥30 mL/min/1.73m2;
- •Age >18 years;
- •HbA1c 7.0%-12.0%;
- •Body Mass Index (BMI) 18.5-40.0 kg/m2;
- •Stable HbA1c, measured 2-12 months prior to screening, within 5% of baseline value;
- •Blood pressure ≤160/100 mmHg at screening, >90/60 mmHg;
- •Stable on dose of ACE inhibitor, angiotensin receptor blocker or renin inhibitor for at least 2 weeks.
排除标准
- •Type 1 Diabetes;
- •Leukocyte and/or nitrite positive urinalysis that is untreated;
- •Severe hypoglycaemia within 2 months prior to screening;
- •History of hypoglycaemia unawareness based on investigator judgement;
- •Unstable coronary artery disease with acute coronary syndrome, percutaneous intervention or bypass surgery within 3 months;
- •Clinically significant valvular disease subject to PI/Sub PI's discretion;
- •Congestive heart failure subject to PI/Sub PI's discretion;
- •Bariatric surgery or other surgeries that induce chronic malabsorption within one year;
- •Anti-obesity drugs or diet regimen and unstable body weight three months prior to screening;
- •Treatment with systemic corticosteroids;
- •Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells;
- •Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control;
- •Participation in another trial with an investigational drug within 30 days of informed consent;
- •Alcohol or drug abuse within three months prior to informed consent that would interfere with trial participation or any ongoing clinical condition that would jeopardize subject safety or study compliance based on investigator judgement;
- •Liver disease, defined by serum levels of alanine transaminase, aspartate transaminase, or alkaline phosphatase >3 x upper limit of normal as determined during screening;
- •Medical history of cancer or treatment for cancer in the last five years prior to screening;
- •History of pancreatitis;
- •Personal of family history of medullary thyroid cancer or MEN2B;
- •Tachycardia, HR >100;
- •Use of SGLT2i, GLP-1RA or DPP-4i within the past 1 month (1-month minimum washout is allowed);
- •History of gastroparesis;
- •Known intolerance to SGLT2i or GLP-1RA;
- •Allergy to iodine-based substances if receiving iohexol for GFR measures.
研究组 & 干预措施
Liraglutide
Liraglutide Subcutaneous Total Dose 1.8mg daily for 6 weeks
干预措施: Empagliflozin 25 MG + Liraglutide 1.8 MG (Drug)
Liraglutide
Liraglutide Subcutaneous Total Dose 1.8mg daily for 6 weeks
干预措施: Liraglutide 1.8 MG + Empagliflozin 25 MG (Drug)
Empagliflozin
Empagliflozin Tablets Total Dose 25mg daily for 6 weeks
干预措施: Empagliflozin 25 MG + Liraglutide 1.8 MG (Drug)
Empagliflozin
Empagliflozin Tablets Total Dose 25mg daily for 6 weeks
干预措施: Liraglutide 1.8 MG + Empagliflozin 25 MG (Drug)
结局指标
主要结局
Proximal tubular natriuresis
时间窗: up to 12 weeks
Measured by fractional excretion of sodium
次要结局
- Glomerular Filtration Rate(Glomerular Filtration Rate (GFR, based on plasma iohexol clearance) will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks))
- Systolic blood pressure(Systolic blood pressure (SBP) will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks))
- Body weight(Body weight will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks))
- Arterial stiffness(Arterial stiffness will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks))
- Systemic vascular resistance(Systemic vascular resistance will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks))
- Urinary concentration of the renin-angiotensin aldosterone system (RAAS) markers(Outcome will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks))
- Urinary EGF,FGF2,Eotaxin,TGFa,G-CSF,Flt-3L,GM-CSF,Fractalkine,IFNa2,IFNy,GRO,IL10,MCP-3,IL-12P40,MDC,IL-12P70,PDGF-AA,IL-13,PDGF-BB,IL-15,sCD40L,IL-17A,IL-1RA,IL1a,IL9,IL1B,IL2,IL3,IL4,IL5,IL6,IL7,IL8,IL10,MCP-1,MIP-1a,MIP-1B,RANTES,TNFalpha,TNFB,VEGF(Outcome will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks))
研究者
David Z.I. Cherney
Associate Professor of Medicine, Clinician Scientist
University Health Network, Toronto