RACELINES: Renal Actions of Combined Empagliflozin and LINagliptin in Type 2 diabetES
试验速览
- 阶段
- 4 期
- 发起方
- 入组人数
- 66
- 试验地点
- 1
- 主要终点
- GFR
研究概览
简要总结
The current study aims to explore the clinical effects and mechanistics of mono- and combination therapy with SGLT-2 inhibitor empagliflozin and DPP-4 inhibitor linagliptin on renal physiology and biomarkers in metformin-treated T2DM patients.
详细描述
Sodium-glucose linked transporters (SGLT-2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors are relatively novel glucose-lowering drugs for the treatment of T2DM. These agents seem to exert pleiotropic actions 'beyond glucose control'. SGLT-2 inhibitors decrease proximal sodium reabsorption and decrease glomerular pressure and albuminuria in rodents and type 1 diabetes patients. In addition, SGLT-2 inhibitors reduce, blood pressure and body weight. In rodents, SGLT-2 inhibitors also improved histopathological abnormalities associated with DKD. DPP-4 inhibitors are considered weight neutral, improve lipid profiles and slight reductions in blood pressure have been reported. To date, the potential renoprotective effects and mechanisms of SGLT-2 inhibitors and combination therapy with SGLT-2 inhibitors have not been sufficiently detailed in human type 2 diabetes. The current study aims to explore the clinical effects and mechanistics of mono- and combination therapy with an SGLT-2 inhibitor and a DPP-4 inhibitor on renal physiology and biomarkers in metformin-treated T2DM patients.
66 patients with type 2 diabetes will undergo a 16-week intervention period with 8-week empagliflozin (SGLT-2 inhibitor) monotherapy, followed by 8-week empagliflozin and linagliptin (DPP-4 inhibitor) combination therapy or 8-week linagliptin monotherapy, followed by 8-week linagliptin and empagliflozin combination therapy or 8-week gliclazide (SU derivative), followed by 8-week gliclazide intensification therapy in order to assess changes in the outcome parameters.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 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: 7.0 - 9.5% Diabetes Control and Complications Trial (DCCT) or 53 - 80 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 adverse 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
- •Estimated GFR <45 mL/min/1.73m2 (determined by the Modification of Diet in Renal Disease (MDRD) study equation)
- •Hemoglobin level < 7.0 mmol/L
- •Current urinary tract infection and active nephritis
- •History of unstable or rapidly progressing renal disease
- •Macroalbuminuria; defined as ACR of >300 mg/g.
- •Current/chronic use of the following medication: thiazolidinediones, sulfonylurea derivatives, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitor, oral glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MOAIs).
- •Patients on diuretics will only be excluded when these drugs cannot be stopped 3 months prior randomization and for the duration of the study.
- •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
- •Pregnancy
- •History of or actual severe mental disease
- •History of or actual severe somatic disease (e.g. systemic disease)
- •History of or actual malignancy (except basal cell carcinoma)
- •History of or actual pancreatic disease
- •(Unstable) thyroid disease
- •Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN)
- •Recent (<6 months) history of cardiovascular disease, including
- •Acute coronary syndrome
- •Stroke or transient ischemic neurologic disorder or chronic heart failure (NYHA grade II-IV)
- •Complaints compatible with or established neurogenic bladder and/or incomplete bladder emptying (as determined by ultrasonic bladder scan)
- •Substance abuse (alcohol: defined as >3 units alcohol/day)
- •History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g., emergency room visit and/or hospitalization) within 1 month prior to the Screening visit.
- •Recent blood donation (< 6 months)
- •Allergy to any of the agents used in the study
- •Inability to understand the protocol and/or give informed consent
- •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
研究组 & 干预措施
LINA/EMPA 5/10 mg QD (N=22)
8w LINA followed by LINA/EMPA 5/10 mg QD (N=22)
干预措施: EMPA/LINA 10/5 mg QD (n=22) (Drug)
EMPA/LINA 10/5 mg QD (n=22)
8w EMPA followed by 8w EMPA/LINA 10/5 mg QD (n=22)
干预措施: EMPA/LINA 10/5 mg QD (n=22) (Drug)
EMPA/LINA 10/5 mg QD (n=22)
8w EMPA followed by 8w EMPA/LINA 10/5 mg QD (n=22)
干预措施: LINA/EMPA 5/10 mg QD (N=22) (Drug)
LINA/EMPA 5/10 mg QD (N=22)
8w LINA followed by LINA/EMPA 5/10 mg QD (N=22)
干预措施: LINA/EMPA 5/10 mg QD (N=22) (Drug)
Gliclazide 30 mg QD/BID (N=22)
8w Gliclazide 30 mg QD, followed by 8w Gliclazide BID (N=22)
干预措施: Gliclazide 30 mg QD/BID (N=22) (Drug)
结局指标
主要结局
GFR
时间窗: 8 weeks
Changes from baseline following 8-week treatment on renal hemodynamics in both the fasting and postprandial state, measured as GFR (determined by the inulin-clearance technique)
次要结局
- Renal Damage(2 weeks)
- Renal tubular function(8 weeks)
- Heart Rate (Dinamap®)(2 weeks)
- Blood Pressure (Dinamap®)(2 weeks)
研究者
M.H.H. Kramer
Head of the Internal Medicine department
Amsterdam UMC, location VUmc