A Randomized, Double-blind, Comparator-controlled Trial to Assess the Effect of 12-week Treatment With Dapagliflozin Versus Gliclazide on Renal Physiology and Biomarkers in Metformin-treated Patients With Type 2 Diabetes Mellitus
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 44
- 试验地点
- 1
- 主要终点
- Effective Renal Plasma Flow (ERPF) in ml/Min
研究概览
简要总结
Background:
Worldwide, diabetic nephropathy or Diabetic Kidney Disease (DKD), is the most common cause of chronic and end-stage kidney disease. With the increasing rates of obesity and type 2 diabetes (T2DM), many more patients with DKD may be expected in the coming years. Large-sized prospective randomized clinical trials suggest that intensified glucose and blood pressure control, may halt the progression of DKD, both in type 1 diabetes and T2DM. However, despite the wide use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, a considerable amount of patients develop DKD during the course of diabetes, indicating an unmet need for renoprotective therapies. Sodium-glucose linked transporters (SGLT-2) inhibitors are novel glucose-lowering drugs for the treatment of T2DM. These agents seem to exert pleiotropic actions 'beyond glucose control', including reduction of blood pressure and body weight. In addition, SGLT-2 inhibitors decrease proximal sodium reabsorption and decrease glomerular pressure and albuminuria in rodents and type 1 diabetes patients. In rodents, SGLT-2 inhibitors also improved histopathological abnormalities associated with DKD. To date, the potential renoprotective effects and mechanisms of these agents have not been sufficiently detailed in human type 2 diabetes. The current study aims to explore the clinical effects and mechanistics of SGLT-2 inhibitors on renal physiology and biomarkers in metformin-treated T2DM patients with normal kidney function.
Study Design:
Randomized, double-blind, comparator-controlled, intervention trial
Study Endpoints:
Renal hemodynamics, i.e. measured glomerular filtration rate (GFR, ml/min) and effective renal plasma flow (ERPF, ml/min); 24-hour urinary solute excretion; markers of renal damage ; blood pressure; body anthropometrics; systemic hemodynamic variables (including stroke volume, cardiac output and total peripheral resistance); arterial stiffness will be assessed by applanation tonometry, (SphygmoCor®); insulin sensitivity and beta-cell function.
Expected results:
Treatment with the SGLT-2 inhibitor dapagliflozin, as compared to the sulfonylurea (SU) derivative gliclazide, may confer renoprotection by improving renal hemodynamics, and decreasing blood pressure and body weight in type 2 diabetes.
详细描述
Study design A phase 4, monocenter, randomized, double-blind, comparator-controlled, parallel-group, mechanistic intervention trial to assess the effect of 12-week treatment with the sodium-glucose linked transporters (SGLT)-2 inhibitor dapagliflozin versus the sulfonylurea (SU) derivative gliclazide on renal physiology and biomarkers in metformin-treated patients with type 2 diabetes mellitus (T2DM)
Recruitment Subjects will be recruited by researcher physicians involved in this trial using methods that are established practice for all human studies in the Diabetes Center, Vrije Universiteit (VU) University Medical Center (VUMC), via advertisements, use of a Diabetes Center database, through the Diabetes Center website.
Screening and eligibility After giving extensive oral and written information, a written informed consent form will be obtained from the subjects before screening. The screening procedure will consist of obtaining an extensive medical history, complete physical examination, blood analysis, urine screening, and a 12-lead electrocardiogram (ECG). Postvoid residual urine volume will be determined by ultrasonic bladder scan. After inclusion, participants will enroll in a 4-week run-in period to allow for study effects.
Baseline assessments Seven days prior to this visit, subjects will adhere to a 'normal-salt' (9 - 12 grams or 150 - 200 mmol per day) and protein (1.5 - 2.0 g/kg per day) diets, in order to minimize variation in renal physiology due to salt and protein intake. Participants will abstain from alcohol (24 hours), caffeine (12 hours) and nicotine (12 hours) and heavy exercise prior to and during visits 2. One day prior to the testing day, subjects will collect 24-hour urine.
Following an overnight fast, participants will be instructed to drink 500 mL of water, but to delay all morning-time medication (apart from metformin) until conclusion of the examination day. After taking subjects history, current weight and blood pressure, intravenous catheters will be placed in both forearms after which blood and urine will be collected. Thereupon the combined renal and clamp protocol will commence.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 35 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Caucasian*
- •Both genders (females must be post-menopausal; no menses >1 year; in case of doubt, Follicle-Stimulating Hormone (FSH) will be determined with cut-off defined as >31 U/L)
- •Age: 35 - 75 years
- •BMI: >25 kg/m2
- •HbA1c: 6.5 - 9.0% Diabetes Control and Complications Trial (DCCT) or 48 - 86 mmol/mol International Federation of Clinical Chemistry (IFCC)
- •Treatment with a stable dose of oral antihyperglycemic agents for at least 3 months prior to inclusion
- •Metformin monotherapy
- •Combination of metformin and low dose SU derivative**
- •Hypertension should be controlled, i.e. ≤140/90 mmHg, and treated with an ACE-I or ARB (unless prevented by side effect) for at least 3 months.
- •Albuminuria should be treated with a RAAS-interfering agent (ACE-I or ARB) for at least 3 months.
- •Written informed consent
- •In order to increase homogeneity ** In order to accelerate inclusion, patients using combined metformin/SU derivative will be considered. In these patients, a 12 week wash-out period of the SU derivative will be observed, only when combined use has led to a HbA1c <8% at screening. Subsequently, patients will be eligible to enter the study, now using metformin monotherapy, provided that HbA1c still meets inclusion criteria.
排除标准
- •History of unstable or rapidly progressing renal disease
- •Macroalbuminuria; defined as albumin-creatinine ratio of 300mg/g.
- •Estimated GFR <60 mL/min/1.73m2 (determined by the Modification of Diet in Renal Disease (MDRD) study equation)
- •Current/chronic use of the following medication: thiazolidinedione (TZD), SU derivative, Glucagon like peptide 1 receptor agonist (GLP-1RA), (dipeptidyl peptidase 4 inhibitor) DPP-4I, SGLT-2 inhibitors, glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Subjects on diuretics will only be excluded when these drugs cannot be stopped for the duration of the study.
- •Volume depleted patients. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status.
- •Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be allowed, unless used as incidental medication (1-2 tablets) for non-chronic indications (i.e. sports injury, head-ache or back ache). However, no such drugs can be taken within a time-frame of 2 weeks prior to renal-testing
- •History of diabetic ketoacidosis (DKA) requiring medical intervention (eg, emergency room visit and/or hospitalization) within 1 month prior to the Screening visit.
- •Current urinary tract infection and active nephritis
- •Recent (<6 months) history of cardiovascular disease, including:
- •Acute coronary syndrome
- •Chronic heart failure (New York Heart Association grade II-IV)
- •Stroke or transient ischemic neurologic disorder
- •Complaints compatible with neurogenic bladder and/or incomplete bladder emptying (as determined by ultrasonic bladder scan)
- •Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN
- •(Unstable) thyroid disease; defined as free thyroxine (fT4) outside of laboratory reference values or change in treatment within 3 months prior to screening visit
- •History of or actual malignancy (except basal cell carcinoma)
- •History of or actual severe mental disease
- •Substance abuse (alcohol: defined as >4 units/day)
- •Allergy to any of the agents used in the study
- •Individuals who are investigator site personnel, directly affiliated with the study, or are immediate (spouse, parent, child, or sibling, whether biological or legally adopted) family of investigator site personnel directly affiliated with the study
- •Inability to understand the study protocol or give informed consent
研究组 & 干预措施
Dapagliflozin 10mg once daily
Once daily treatment with oral dapagliflozin (forxiga) 10mg for 12 consecutive weeks.
干预措施: Dapagliflozin 10mg QD (Drug)
Gliclazide modified release 30mg once daily
Once daily treatment with oral gliclazide MR 30mg for 12 consecutive weeks.
干预措施: Gliclazide 30mg QD (Drug)
结局指标
主要结局
Effective Renal Plasma Flow (ERPF) in ml/Min
时间窗: 12 weeks
Calculated from urinary and plasma para-aminohippurate concentrations, ERPF in ml/min
Glomerular Filtration Rate (GFR) in ml/Min
时间窗: 12 weeks
Calculated from urinary and plasma inulin concentrations, GFR in ml/min
次要结局
- Fractional Excretion of Sodium in % of Filtered Sodium(12 weeks)
- Fractional Excretion of Potassium in % of Filtered Potassium(12 weeks)
- Fractional Excretion of Glucose in % of Filtered Glucose(12 weeks)
- Urinary Albumin-Creatinine Ratio in mg/mmol(12 weeks)
- Neutrophil Gelatinase-associated Lipocalin (NGAL)(12 weeks)
- Kidney Injury Molecule-1 (KIM-1) in ng/mmol(12 weeks)
研究者
M.H.H. Kramer
Head of the Internal Medicine department
Amsterdam UMC, location VUmc