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Huang R, Chen X. Increased Spot Urine Albumin-to-Creatinine Ratio and Stroke Incidence: A Systematic Review and Meta-Analysis. J Stroke Cerebrovasc Dis 2019; 28:104260. [DOI: 10.1016/j.jstrokecerebrovasdis.2019.06.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 05/27/2019] [Accepted: 06/13/2019] [Indexed: 11/25/2022] Open
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Kopel J, Pena-Hernandez C, Nugent K. Evolving spectrum of diabetic nephropathy. World J Diabetes 2019; 10:269-279. [PMID: 31139314 PMCID: PMC6522757 DOI: 10.4239/wjd.v10.i5.269] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/13/2019] [Accepted: 05/13/2019] [Indexed: 02/05/2023] Open
Abstract
Diabetes remains an important health issue as more patients with chronic and uncontrolled diabetes develop diabetic nephropathy (DN), which classically presents with proteinuria followed by a progressive decrease in renal function. However, an increasing proportion of DN patients have a decline in kidney function and vascular complications without proteinuria, known as non-proteinuric DN (NP-DN). Despite the increased incidence of NP-DN, few clinical or experimental studies have thoroughly investigated the pathophysiological mechanisms and targeted treatment for this form of DN. In this review, we will examine the differences between conventional DN and NP-DN and consider potential pathophysiological mechanisms, diagnostic markers, and treatment for both DN and NP-DN. The investigation of the pathophysiology of NP-DN should provide additional insight into the cardiovascular factors influencing renal function and disease and provide novel treatments for the vascular complications seen in diabetic patients.
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Affiliation(s)
- Jonathan Kopel
- Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79416, United States
| | - Camilo Pena-Hernandez
- Department of Internal Medicine, Division of Nephrology, Lubbock, TX 79430, United States
| | - Kenneth Nugent
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, United States
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Roussel R, Lorraine J, Rodriguez A, Salaun-Martin C. Overview of Data Concerning the Safe Use of Antihyperglycemic Medications in Type 2 Diabetes Mellitus and Chronic Kidney Disease. Adv Ther 2015; 32:1029-64. [PMID: 26581749 DOI: 10.1007/s12325-015-0261-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Indexed: 12/26/2022]
Abstract
INTRODUCTION It can be a challenge to manage glycemic control in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), due to both patient and medication issues. Although most antihyperglycemic medications can be used in mild kidney disease, many medications are either not advised or require dose adjustments in more advanced CKD. This review summarizes product label information, pharmacokinetic and clinical studies, and clinical guidelines relevant to use of antihyperglycemic medications in CKD. METHODS Product labels and guidelines from North America and Europe, as well as pharmacokinetic and clinical studies of diabetes medication use in CKD were identified through Medline and PubMed searches, up to February 2015. Available data are summarized and correlations between treatment recommendations and available research are discussed, as are glycemic targets for patients with CKD. RESULTS Newer medications have significantly more data available than older medications regarding use in CKD, although larger clinical studies are still lacking for some drugs. As CKD advances, dose adjustment is needed for many medications [numerous dipeptidyl peptidase-4 inhibitors, some insulins, sodium glucose co-transporter 2 (SGLT2) inhibitors], although not for others (thiazolidinediones, meglitinides). Some medications are not recommended for use in more advanced CKD (metformin, SGLT2 inhibitors, some glucagon-like protein-1 receptor agonists) for safety or efficacy reasons. There is not always good alignment between label recommendations, pharmacokinetic or clinical studies, and guideline recommendations for use of these drugs in CKD. In particular, controversy remains about the use of metformin in moderate CKD and appropriate use of liraglutide and sulfonylureas in advanced CKD. CONCLUSION Considerable variability exists with respect to recommendations and clinical data for the many antihyperglycemic drugs used in patients with T2DM and CKD. FUNDING Eli Lilly and Company.
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Affiliation(s)
- Ronan Roussel
- Division of Endocrinology Diabetes and Nutrition, DHU FIRE, Groupe Hospitalier Bichat-Claude Bernard, AP-HP, Paris, France.
- INSERM U 1138, Cordeliers Research Center, Paris, France.
- University Paris Diderot-Paris 7, Paris, France.
| | | | | | - Carole Salaun-Martin
- Eli Lilly, Neuilly Cedex, France
- Division of Endocrinology Diabetes and Nutrition, Hopital Max Fourestier, Nanterre, France
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Yan ST, Liu JY, Tian H, Li CL, Li J, Shao YH, Shi HY, Liu Y, Gong YP, Fang FS, Sun BR. Clinical and pathological analysis of renal damage in elderly patients with type 2 diabetes mellitus. Clin Exp Med 2015; 16:437-42. [PMID: 26055459 DOI: 10.1007/s10238-015-0362-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 05/26/2015] [Indexed: 11/28/2022]
Abstract
The aim of this study was to investigate the causes and influential factors of renal damage in elderly patients with type 2 diabetes mellitus (T2DM). Clinical data and pathological findings at autopsy of 161 elderly T2DM patients died between October 1994 and August 2011 were retrospectively reviewed. The mean age of these patients was 80.8 ± 8.3 years (range 60-105 years). The incidences of diabetic nephropathy (DN), non-diabetic renal diseases (NDRD), and DN complicated with NDRD were 31.1, 62.7, and 16.2 %, respectively. In patients with NDRD, the incidence of hypertensive renal damage (HRD) was 54.7 %. In the factors causing renal damage, DN and NDRD accounted for 1/3 and 2/3, respectively. HRD accounted for the largest proportion of NDRD. Blood pressure control may provide additional benefits for elderly T2DM patients by preventing and delaying the occurrence and development of renal disease.
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Affiliation(s)
- Shuang-Tong Yan
- Department of Geriatric Endocrinology, PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Jun-Yan Liu
- Cadre Ward, 306 Hospital of PLA, Beijing, 100853, China
| | - Hui Tian
- Department of Geriatric Endocrinology, PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China.
| | - Chun-Lin Li
- Department of Geriatric Endocrinology, PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Jian Li
- Department of Geriatric Endocrinology, PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Ying-Hong Shao
- Department of Geriatric Endocrinology, PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Huai-Yin Shi
- Department of Pathology, PLA General Hospital, Beijing, 100853, China
| | - Yu Liu
- Department of Geriatric Endocrinology, PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Yan-Ping Gong
- Department of Geriatric Endocrinology, PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Fu-Sheng Fang
- Department of Geriatric Endocrinology, PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Ban-Ruo Sun
- Department of Geriatric Endocrinology, PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China
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Huang DL, Abrass IB, Young BA. Medication safety and chronic kidney disease in older adults prescribed metformin: a cross-sectional analysis. BMC Nephrol 2014; 15:86. [PMID: 24906409 PMCID: PMC4057526 DOI: 10.1186/1471-2369-15-86] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Accepted: 05/01/2014] [Indexed: 11/28/2022] Open
Abstract
Background Medication safety in patients with chronic kidney disease (CKD) is a growing concern. This is particularly relevant in older adults due to underlying CKD. Metformin use is contraindicated in patients with abnormal kidney function; however, many patients are potentially prescribed metformin inappropriately. We evaluated the prevalence of CKD among older adults prescribed metformin for type 2 diabetes mellitus using available equations to estimate kidney function and examined demographic characteristics of patients who were potentially inappropriately prescribed metformin. Methods We conducted a cross-sectional analysis of older adults aged ≥65 years prescribed metformin from March 2008-March 2009 at an urban tertiary-care facility in Seattle, Washington, USA. CKD was defined using National Kidney Foundation-Kidney Disease Outcomes Quality Initiative criteria. Creatinine clearance was calculated using the Cockcroft-Gault equation; estimated glomerular filtration rate was calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) and CKD-Epidemiology (EPI) Collaboration equations. Regression analyses were used to determine the associations between demographic characteristics and prevalent CKD. Results Among 356 subjects (median age 69 years, 52.5% female, 39.4% non-Hispanic black), prevalence of stage 3 or greater CKD calculated by any of the equations was 31.4%. The Cockcroft-Gault equation identified more subjects as having CKD (23.7%) than the abbreviated MDRD (21.1%) or CKD-EPI (21.7%) equations (P < 0.001). Older age (OR = 1.13, 95% CI 1.08-1.19) and female sex (OR = 2.51, 95% CI 1.44-4.38) were associated with increased odds of potentially inappropriate metformin prescription due to CKD; non-Hispanic black race was associated with decreased odds of potentially inappropriate metformin prescription due to CKD (OR = 0.41, 95% CI 0.23-0.71). Conclusions CKD is common in older adults prescribed metformin for type 2 diabetes, raising concern for potentially inappropriate medication use. No single equation to estimate kidney function may accurately identify CKD in this population. Medication safety deserves greater consideration among elderly patients due to the widespread prevalence of CKD.
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Affiliation(s)
- Deborah L Huang
- Division of General Internal Medicine, University of Washington, Box 354765, 4245 Roosevelt Way NE, Seattle, WA 98105, USA.
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Zhou Y, Echouffo-Tcheugui JB, Gu JJ, Ruan XN, Zhao GM, Xu WH, Yang LM, Zhang H, Qiu H, Narayan KMV, Sun Q. Prevalence of chronic kidney disease across levels of glycemia among adults in Pudong New Area, Shanghai, China. BMC Nephrol 2013; 14:253. [PMID: 24238578 PMCID: PMC4225706 DOI: 10.1186/1471-2369-14-253] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2013] [Accepted: 11/12/2013] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Few population-based studies have examined the relationship between glycemic status and chronic kidney disease (CKD) in China. We examined the prevalence of CKD across categories of glycemia [diagnosed diabetes, undiagnosed diabetes (fasting plasma glucose [FPG] ≥ 126 mg/dL), prediabetes (FPG 100-126 mg/dL) and normal glycemia (FPG <100 mg/dL)] among Chinese adults and assessed the relative contribution of dysglycemia (prediabetes and/or diabetes) to the burden of CKD. METHODS 5,584 Chinese adults aged 20-79 years were selected from the Pudong New Area of Shanghai through a multistage random sampling. Demographic and lifestyle characteristics, anthropometry and blood pressure were measured. Biochemical assays included FPG, serum creatinine and lipids, urinary creatinine and albumin. Prevalence of albuminuria [urine albumin-to-creatinine ratio (ACR) ≥ 30 mg/g], decreased kidney function and CKD (either decreased kidney function or albuminuria) across levels of glycemia were estimated. RESULTS The prevalence of albuminuria, decreased kidney function and CKD each increased with higher glycemic levels (P < 0.001). Based on the MDRD Study equation, the unadjusted CKD prevalence was 30.9%, 28.5%, 14.1% and 9.2% in those with diagnosed diabetes, undiagnosed diabetes, prediabetes and normoglycemia, respectively. The corresponding age-, gender- and hypertension-adjusted CKD prevalence were 25.8%, 25.0%, 12.3% and 9.1%, respectively. In a multivariable analysis, the factors associated with CKD were hypertension (Odds ratio [OR] 1.70, 95% confidence interval [CI]: 1.42-2.03), dysglycemia (OR 1.65, 95% CI: 1.39-1.95), female gender (OR 1.48, 95% CI: 1.25-1.75), higher triglycerides (OR 1.14, 95% CI: 1.08-1.20 per mmol/L), higher body mass index (OR 1.08, 95% CI: 1.05-1.10 per kg/m2), and older age (OR 1.02, 95% CI: 1.01 -1.03 per year). The population attributable risks (PARs) associated with diabetes, prediabetes, dysglycemia (diabetes and prediabetes) and hypertension were 18.4%, 19.7%, 30.3% and 44.5% for CKD as defined by the MDRD study equation, and 15.8%, 24.4%, 29.2% and 10.0% with the CKD-EPI equation. Estimates of prevalence and ORs of the relative contribution of various risk factors to CKD obtained with the CKD-EPI equation were similar. CONCLUSIONS As much as 30% of the CKD burden may be associated with dysglycemia among Chinese adults, independent of age, gender and hypertension status. Prevention and control of diabetes and prediabetes should be a high priority in reducing the CKD burden in China.
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Affiliation(s)
- Yi Zhou
- Pudong New Area Center for Disease Control and Prevention, 3039 Zhang Yang Road, Shanghai 200136, China.
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Kuwashiro T, Sugimori H, Ago T, Kuroda J, Kamouchi M, Kitazono T. The impact of predisposing factors on long-term outcome after stroke in diabetic patients: the Fukuoka Stroke Registry. Eur J Neurol 2013; 20:921-7. [DOI: 10.1111/ene.12100] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2012] [Accepted: 12/12/2012] [Indexed: 12/15/2022]
Affiliation(s)
- T. Kuwashiro
- Department of Medicine and Clinical Science; Graduate School of Medical Sciences; Kyushu University; Fukuoka; Japan
| | - H. Sugimori
- Department of Medicine and Clinical Science; Graduate School of Medical Sciences; Kyushu University; Fukuoka; Japan
| | - T. Ago
- Department of Medicine and Clinical Science; Graduate School of Medical Sciences; Kyushu University; Fukuoka; Japan
| | - J. Kuroda
- Department of Medicine and Clinical Science; Graduate School of Medical Sciences; Kyushu University; Fukuoka; Japan
| | - M. Kamouchi
- Department of Medicine and Clinical Science; Graduate School of Medical Sciences; Kyushu University; Fukuoka; Japan
| | - T. Kitazono
- Department of Medicine and Clinical Science; Graduate School of Medical Sciences; Kyushu University; Fukuoka; Japan
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Budhiraja P, Thajudeen B, Popovtzer M. Absence of albuminuria in type 2 diabetics with classical diabetic nephropathy: Clinical pathological study. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/jbise.2013.65a005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Suzuki-Saito T, Yokokawa H, Shimada K, Yasumura S. Self-perception of glycemic control among Japanese type 2 diabetic patients: accuracy
of patient perception and characteristics
of patients with misperception. J Diabetes Investig 2012; 4:206-13. [PMID: 24843654 PMCID: PMC4019277 DOI: 10.1111/jdi.12002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 06/27/2012] [Accepted: 08/14/2012] [Indexed: 11/30/2022] Open
Abstract
Aims Some diabetic patients, despite reporting a good perception of their glycemic control, actually show poor control and this misperception might well hinder successful diabetes management. This study aimed to assess patients' self‐perception of glycemic control and to clarify factors associated with misperception of glycemic control status. Methods Baseline data from a hospital‐based prospective cohort of 519 type 2 diabetic patients were analyzed. Self‐perception of glycemic control and other items, including sociodemographic factors and blood test data, were determined from a self‐administered questionnaire and medical records. Factors associated with misperception were examined by age group (elderly [aged ≥ 65 years] vs non‐elderly [aged < 65 years]) using multiple logistic regression analysis. Results Among poorly controlled patients, misperception was higher in the elderly (glycated hemoglobin [HbA1c] 7.4–8.3, 55.1%; HbA1c >8.4, 44.8%) than in the non‐elderly (HbA1c 7.4–8.3, 20.0%; HbA1c >8.4, 18.9%). The factors significantly associated with misperception were as follows: high lifestyle regimen adherence in both age groups (non‐elderly group odds ratio [OR] 5.23; elderly group OR 5.15, respectively); high family support (OR = 7.32), failure to achieve blood pressure control (OR = 6.94) and having diabetic complications (OR = 0.06) among the non‐elderly; and long duration of diabetes (OR = 4.06) among the elderly. Conclusions For better management of diabetes, physicians should pay attention to the patient characteristics associated with misperception among uncontrolled diabetic patients, particularly among those who are elderly.
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Affiliation(s)
- Tomoko Suzuki-Saito
- Department of Public Health School of Medicine Fukushima Medical University Fukushima Japan
| | - Hirohide Yokokawa
- Department of Public Health School of Medicine Fukushima Medical University Fukushima Japan ; Department of General Medicine School of Medicine Juntendo University Tokyo Japan
| | - Koichi Shimada
- Department of Diabetes and Metabolism Hoshi General Hospital Fukushima Japan
| | - Seiji Yasumura
- Department of Public Health School of Medicine Fukushima Medical University Fukushima Japan
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Ležaić V, Dimković N, Peković GP, Bukvić D, Bajčetić S, Bontić A, Zec N, Pavlović J, Marinković J, Dukanović L. Screening of a population at risk of chronic kidney disease: analysis of factors associated with low eGFR and microalbuminuria. Ren Fail 2011; 33:969-76. [PMID: 21929449 DOI: 10.3109/0886022x.2011.615969] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Numerous screenings of chronic kidney disease (CKD) have been performed all over the world. This screening study was undertaken with the aim of estimating the prevalence of low glomerular filtration rate (eGFR) and microalbuminuria (MAU) and/or proteinuria in a population at risk for CKD and to detect factors associated with these CKD markers. MATERIALS AND METHODS This cross-sectional study included 1617 patients without previously known kidney disease who came for regular check-ups to their general practitioners in 13 Belgrade health centers over a 3-month period. Patients selected were as follows: 1316 with hypertension, 208 with type 2 diabetes, and 93 older than 60 years without hypertension or diabetes. Screening included a questionnaire, blood pressure measurement, single MAU dipstick measurement (Micral-test® strip) and proteinuria and GFR estimation by Modification of Diet in Renal Disease. RESULTS MAU was found in 419 (25.9%) patients, proteinuria in 163 (10.1%), and eGFR < 60 mL/min/1.73 m(2) in 370 (22.9%). Multivariate logistic regression analysis revealed that female gender, age, duration of hypertension, and smoking were associated with eGFR. Male gender, hypertension, treatment with angiotensin-converting enzyme inhibitors, proteinuria, and systolic blood pressure were associated with MAU. CONCLUSIONS High prevalence of MAU/proteinuria and reduced eGFR were found in high-risk persons for CKD. Besides nonmodifiable, significant modifiable factors for MAU were use of angiotensin-converting enzyme inhibitors and strict regulation of hypertension and the factor for reduced eGFR was smoking.
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Affiliation(s)
- Višnja Ležaić
- Department of Nephrology, Clinical Centre of Serbia, Belgrade, Serbia.
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Horie Y, Kanada S, Watada H, Sarashina A, Taniguchi A, Hayashi N, Graefe-Mody EU, Woerle HJ, Dugi KA. Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor linagliptin: a 4-week multicenter, randomized, double-blind, placebo-controlled phase IIa study in Japanese type 2 diabetes patients. Clin Ther 2011; 33:973-89. [PMID: 21723606 DOI: 10.1016/j.clinthera.2011.06.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2011] [Indexed: 10/18/2022]
Abstract
BACKGROUND The dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin is under clinical development for treatment of type 2 diabetes mellitus (T2DM). In previous studies in white populations it showed potential as a once-daily oral antidiabetic drug. OBJECTIVES In compliance with regulatory requirements for new drugs intended for use in the Japanese population, this study investigated the pharmacokinetics, pharmacodynamics, and tolerability of multiple oral doses of linagliptin in Japanese patients with T2DM. METHODS In this randomized, double-blind, placebo-controlled multiple dose study, 72 Japanese patients with T2DM were assigned to receive oral doses of linagliptin 0.5, 2.5, or 10 mg or placebo (1:1:1:1 ratio) once daily for 28 days. For analysis of pharmacokinetic properties, linagliptin concentrations were determined from plasma and urinary samples obtained throughout the treatment phase, with more intensive samplings on days 1 and 28. DPP-4 inhibition, glycosylated hemoglobin A1c (HbA(1c)) levels, and plasma glucose and glucagon-like peptide-1 (GLP-1) levels were compared by mixed effect model. Tolerability was assessed throughout the study by physical examination, including blood pressure and pulse rate measurements, 12-lead ECG, and laboratory analysis. RESULTS Baseline demographic characteristics were well balanced across the 4 treatment groups (mean [SD] age, 59.7 [6.4] years in the placebo group, 60.8 [9.2] years in the 0.5 mg group, 60.2 [6.4] years in the 2.5 mg group, and 59.1 [8.6] years in the 10 mg group; mean [SD] weight, 67.2 [10.0] kg in the placebo group, 64.5 [9.0] kg in the 0.5 mg group, 69.6 [9.4] kg in the 2.5 mg group, and 63.5 [12.2] kg in the 10 mg group; mean [SD] duration of T2DM diagnosis, 5.1 [4.2] years in the placebo group, 5.2 [4.7] years in the 0.5 mg group, 5.9 [4.8] years in the 2.5 mg group, and 2.6 [2.3] years in the 10 mg group). The majority of the patients treated were male (76.4%). Use of previous antidiabetic medication was more common in the 2.5 mg linagliptin group (44%) than in the 0.5 or 10 mg linagliptin (15.8% and 22.2%, respectively) or placebo groups (35.3%). Total systemic exposure in terms of linagliptin AUC and C(max) (which occurred at 1.25-1.5 hours) increased in a less than dose-proportional manner. The terminal half-life was long (223-260 hours) but did not reflect the accumulation half-life (10.0-38.5 hours), resulting in a moderate accumulation ratio of <2.9 that decreased with increasing dose. Urinary excretion increased with linagliptin doses but was <7% at steady state for all dose groups. Inhibition of plasma DPP-4 at 24 hours after the last dose on day 28 was approximately 45.8%, 77.8%, and 89.7% after linagliptin 0.5, 2.5, and 10 mg, respectively. At steady state, linagliptin was associated with dose-dependent increases in plasma GLP-1 levels, and the postprandial GLP-1 response was enhanced. Statistically significant dose-dependent reductions were observed in fasting plasma glucose levels at day 29 for all linagliptin groups (-11.5, -13.6, and -25.0 mg/dL for the 0.5, 2.5, and 10 mg groups, respectively; P < 0.05 for all linagliptin groups). Linagliptin also produced statistically significant dose-dependent reductions from baseline for glucose area under the effect curve over 3 hours after meal tolerance tests (-29.0 to -68.1 mg × h/dL; P < 0.05 for all 3 linagliptin groups). For the 0.5 and 10 mg linagliptin-treated groups, there were statistically significant reductions in HbA(1c) from baseline compared with placebo, despite the relatively low baseline HbA(1c) (7.2%) and small sample size (P < 0.01 for both groups). The greatest reduction in HbA(1c) (-0.44%) was seen in the highest linagliptin dose group (10 mg). On dosing for up to 28 days, linagliptin was well tolerated with no reported serious adverse events or symptoms suggestive of hypoglycemia. Overall, fewer adverse events were reported by patients after linagliptin than after placebo (11 of 55 [20%] vs 6 of 17 [35%]). CONCLUSIONS Linagliptin demonstrated a nonlinear pharmacokinetic profile in these Japanese patients with T2DM consistent with the findings of previous studies in healthy Japanese and white patients. Linagliptin treatment resulted in statistically significant and clinically relevant reductions in HbA(1c) as soon as 4 weeks after starting therapy in these Japanese patients with T2DM, suggesting that clinical studies of longer duration in Japanese T2DM patients are warranted.
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Affiliation(s)
- Yoshiharu Horie
- Medical Data Service Department, Nippon Boehringer Ingelheim Co, Ltd, Shinagawa-ku, Tokyo, Japan.
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Sarashina A, Sesoko S, Nakashima M, Hayashi N, Taniguchi A, Horie Y, Graefe-Mody EU, Woerle HJ, Dugi KA. Linagliptin, a dipeptidyl peptidase-4 inhibitor in development for the treatment of type 2 diabetes mellitus: A phase I, randomized, double-blind, placebo-controlled trial of single and multiple escalating doses in healthy adult male japanese subjects. Clin Ther 2010; 32:1188-204. [DOI: 10.1016/j.clinthera.2010.06.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/20/2010] [Indexed: 10/19/2022]
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