PDF(Pubmed)
Abstract：
The insulin-like growth factors (IGF) play a crucial role in regulating cellular proliferation, apoptosis, and key metabolic pathways. The ratio of IGF-1 to IGF binding protein-3 (IGFBP-3) is an important factor in determining IGF-1 bioactivity. We sought to investigate the association of IGF-1 and IGFBP-3 with cardio-renal outcomes among persons with type 2 diabetes.
Samples were available from 2627 individuals with type 2 diabetes and chronic kidney disease that were randomized to receive canagliflozin or placebo and were followed up for incident cardio-renal events. Primary outcome was defined as a composite of end-stage kidney disease, doubling of the serum creatinine level, or renal/cardiovascular death. IGF-1 and IGFBP-3 were measured at baseline, Year-1 and Year-3. Elevated IGF-1 level was defined according to age-specific cutoffs. Cox proportional hazard regression was used to investigate the association between IGF-1 level, IGFBP-3, and the ratio of IGF-1/IGFBP-3 with clinical outcomes.
Elevated IGF-1 was associated with lower glomerular filtration rate at baseline. Treatment with canagliflozin did not significantly change IGF-1 and IGFBP-3 concentrations by 3 years (p-value > 0.05). In multivariable models, elevated IGF-1 (above vs below age-specific cutoffs) was associated with the primary composite outcome (incidence rate:17.8% vs. 12.7% with a hazard ratio [HR]: 1.52; 95% confidence interval CI 1.09-2.13;P: 0.01), renal composite outcome (HR: 1.65; 95% CI 1.14-2.41; P: 0.01), and all-cause mortality (HR: 1.52; 95% CI 1.00-2.32; P; 0.05). Elevations in log IGFBP-3 did not associate with any clinical outcomes. Increase in log IGF-1/IGFBP-3 ratio was also associated with a higher risk of the primary composite outcome (HR per unit increase: 1.57; 95% CI 1.09-2.26; P; 0.01).
These results further suggest potential importance of IGF biology in the risk for cardio-renal outcomes in type 2 diabetes. SGLT2 inhibition has no impact on the biology of IGF despite its significant influence on outcomes.
CREDENCE; ClinicalTrials.gov Identifier: NCT02065791.
Samples were available from 2627 individuals with type 2 diabetes and chronic kidney disease that were randomized to receive canagliflozin or placebo and were followed up for incident cardio-renal events. Primary outcome was defined as a composite of end-stage kidney disease, doubling of the serum creatinine level, or renal/cardiovascular death. IGF-1 and IGFBP-3 were measured at baseline, Year-1 and Year-3. Elevated IGF-1 level was defined according to age-specific cutoffs. Cox proportional hazard regression was used to investigate the association between IGF-1 level, IGFBP-3, and the ratio of IGF-1/IGFBP-3 with clinical outcomes.
Elevated IGF-1 was associated with lower glomerular filtration rate at baseline. Treatment with canagliflozin did not significantly change IGF-1 and IGFBP-3 concentrations by 3 years (p-value > 0.05). In multivariable models, elevated IGF-1 (above vs below age-specific cutoffs) was associated with the primary composite outcome (incidence rate:17.8% vs. 12.7% with a hazard ratio [HR]: 1.52; 95% confidence interval CI 1.09-2.13;P: 0.01), renal composite outcome (HR: 1.65; 95% CI 1.14-2.41; P: 0.01), and all-cause mortality (HR: 1.52; 95% CI 1.00-2.32; P; 0.05). Elevations in log IGFBP-3 did not associate with any clinical outcomes. Increase in log IGF-1/IGFBP-3 ratio was also associated with a higher risk of the primary composite outcome (HR per unit increase: 1.57; 95% CI 1.09-2.26; P; 0.01).
These results further suggest potential importance of IGF biology in the risk for cardio-renal outcomes in type 2 diabetes. SGLT2 inhibition has no impact on the biology of IGF despite its significant influence on outcomes.
CREDENCE; ClinicalTrials.gov Identifier: NCT02065791.
摘要：
背景：胰岛素样生长因子（IGF）在调节细胞增殖中起着至关重要的作用，凋亡，和关键的代谢途径。IGF-1与IGF结合蛋白-3(IGFBP-3)的比例是决定IGF-1生物活性的重要因素。我们试图调查IGF-1和IGFBP-3与2型糖尿病患者心肾结局的关系。
方法：从2627名2型糖尿病和慢性肾脏疾病患者中获得样本，这些患者被随机分配接受canagliflozin或安慰剂，并对偶发的心肾事件进行随访。主要结局定义为终末期肾脏疾病的复合，血清肌酐水平加倍,或肾/心血管死亡。在基线测量IGF-1和IGFBP-3，1年和3年。升高的IGF-1水平根据年龄特异性截止值定义。Cox比例风险回归用于研究IGF-1水平之间的关联，IGFBP-3和IGF-1/IGFBP-3的比值与临床结果。
结果：IGF-1升高与基线时肾小球滤过率降低相关。canagliflozin治疗3年后未显著改变IGF-1和IGFBP-3浓度(p值>0.05)。在多变量模型中，升高的IGF-1（高于与低于特定年龄的临界值）与主要复合结局相关（发生率：17.8％与12.7％，风险比[HR]：1.52；95％置信区间1.09-2.13；P：0.01），肾脏综合结局（HR：1.65;95％CI1.14-2.41;P：0.01），和全因死亡率(HR:1.52;95%CI1.00-2.32;P;0.05)。IGFBP-3的对数升高与任何临床结果无关。IGF-1/IGFBP-3对数比值的增加也与主要复合结局的较高风险相关(每单位增加的HR:1.57;95%CI1.09-2.26;P;0.01)。
结论：这些结果进一步表明IGF生物学在2型糖尿病心肾结局风险中的潜在重要性。SGLT2抑制对IGF的生物学没有影响，尽管它对结果有显著影响。
背景：CREDENCE;ClinicalTrials.gov标识符：NCT02065791。
方法：从2627名2型糖尿病和慢性肾脏疾病患者中获得样本，这些患者被随机分配接受canagliflozin或安慰剂，并对偶发的心肾事件进行随访。主要结局定义为终末期肾脏疾病的复合，血清肌酐水平加倍,或肾/心血管死亡。在基线测量IGF-1和IGFBP-3，1年和3年。升高的IGF-1水平根据年龄特异性截止值定义。Cox比例风险回归用于研究IGF-1水平之间的关联，IGFBP-3和IGF-1/IGFBP-3的比值与临床结果。
结果：IGF-1升高与基线时肾小球滤过率降低相关。canagliflozin治疗3年后未显著改变IGF-1和IGFBP-3浓度(p值>0.05)。在多变量模型中，升高的IGF-1（高于与低于特定年龄的临界值）与主要复合结局相关（发生率：17.8％与12.7％，风险比[HR]：1.52；95％置信区间1.09-2.13；P：0.01），肾脏综合结局（HR：1.65;95％CI1.14-2.41;P：0.01），和全因死亡率(HR:1.52;95%CI1.00-2.32;P;0.05)。IGFBP-3的对数升高与任何临床结果无关。IGF-1/IGFBP-3对数比值的增加也与主要复合结局的较高风险相关(每单位增加的HR:1.57;95%CI1.09-2.26;P;0.01)。
结论：这些结果进一步表明IGF生物学在2型糖尿病心肾结局风险中的潜在重要性。SGLT2抑制对IGF的生物学没有影响，尽管它对结果有显著影响。
背景：CREDENCE;ClinicalTrials.gov标识符：NCT02065791。
