Diabetic nephropathy is one of the most important complications of diabetes, being strongly associated with increased overall mortality, cardiovascular mortality, cardiovascular events, and end-stage renal disease [
Dipeptidyl-peptidase IV inhibitors (DPP-4i) are among the most popular and effective oral antidiabetic agents. They have many advantages, including high glucose-lowering potency, low risk of hypoglycemia, no association with weight gain, and being tolerable in chronic renal failure patients. However, their efficacy for preventing diabetic complications, especially diabetic nephropathy, is not well-established. Physiologically, dipeptidyl-peptidase IV (DPP-4) acts on nephrons to exert various functions [
The majority of clinical studies investigating the renoprotective effects of DPP-4i have only focused on evaluating their albuminuria-lowering ability [
The current study aimed to determine the renoprotective effects of DPP-4i, using albuminuria and GFR as indicators, in type 2 diabetes mellitus (T2DM) patients.
A retrospective observational cohort study was conducted using the clinical database of Ajou University Hospital, which is a South Korean tertiary hospital with 1,108 beds. The study protocol was approved by the Institutional Review Board of Ajou University Hospital.
The inclusion criteria for study participants were as follows: (1) aged ≥ 19 years with T2DM identified by the International Classification of Disease, Tenth Revision code E11; (2) prescribed DPP-4i from March 1, 2010, to February 28, 2014; and (3) data on urine albumin and creatinine levels at baseline, 1 year prior to starting DPP-4i, and 1 year after DPP-4i treatment initiation.
Exclusion criteria were as follows: glycosylated hemoglobin (HbA1c) ≤ 6.5% (48 mmol/mol) or >10% (86 mmol/mol); baseline estimated GFR (eGFR) ≤ 15 mL/min/1.73 m2; currently undergoing dialysis; body mass index (BMI) > 40 kg/m2; treatment with insulin; treatment with steroids for >7 days; and patients with dual blockade of the renin-angiotensin system (RAS).
A total of 414 patients were included in this cohort. The patients were divided into three groups according to their baseline urine albumin creatinine ratio (UACR): (1) a macroalbuminuria group (UACR ≥ 300 mg/g,
The first prescription date of DPP-4i was defined as the index date, and the first prescribed DPP-4i was classified as the treatment drug in patients who were prescribed more than one DPP-4i. Cessation of DPP-4i therapy was designated as the date of changing to another antidiabetic drug, a drug prescription gap of more than 30 days, or the study end date (May 31, 2015). Drug adherence was measured using the proportion of days covered (PDC, the days of taking the medicine divided by a whole follow-up duration). PDC ≥ 0.80 was considered to indicate drug adherence and patients with PDC < 0.80 were removed from the analyses.
Demographic characteristics, including age and gender, were extracted from index data. Blood pressure, height, weight, diabetes mellitus (DM) duration, and baseline laboratory tests—including HbA1c, lipid profile, serum creatinine, urine creatinine, and urine albumin—were collected (i.e., the most recent values measured within 90-day range prior to the index date). Values for these parameters before and after treatment were also extracted using the same method. UACR was calculated using urine albumin and creatinine levels from an untimed spot urine collection. eGFR was measured using the Modification of Diet in Renal Disease Study Equation [
All analyses were performed using R software (ver. 3.2.3; R Development Core Team, Vienna, Austria). Data are expressed as means ± standard deviation. A self-controlled design, in which comparisons are made within individuals, was used to estimate the renoprotective effect of DPP-4i. Using this method, all time-invariant confounders (e.g., sex, smoking, ethnicity, albuminuria status, other underlying diseases, and coadministrated drugs) were eliminated, and time-constant covariates (e.g., age, eGFR deterioration due to DM, and DM duration) were properly adjusted for. The paired Student’s
A total of 414 patients with T2DM satisfied the eligibility criteria of this study. The mean age of the included patients was
Patient baseline characteristics (
Characteristics | Results |
---|---|
Age (years) | 59.2 ± 11.5 |
Sex ( | 224/190 |
Body mass index (kg/m2) | 25.2 ± 3.6 |
DM duration (years) | 11.0 ± 7.4 |
Systolic blood pressure (mmHg) | 125.4 ± 17.2 |
Diastolic blood pressure (mmHg) | 73.3 ± 10.6 |
HbA1c (%) | 8.6 ± 1.5 |
LDL-cholesterol (mg/dL) | 89.8 ± 39.5 |
HDL-cholesterol (mg/dL) | 46.4 ± 12.0 |
Triglycerides (mg/dL) | 168.0 ± 35.5 |
eGFR (mL/min/1.73 m2) | 68.3 ± 17.6 |
Antidiabetic drugs (%) | |
Metformin | 74.9 |
Sulfonylurea | 69.8 |
Thiazolidinedione | 3.6 |
Alpha-glucosidase inhibitor | 0.2 |
RAS inhibitor (%) | 56.8 |
Statin (%) | 59.2 |
Data are presented as means ± standard deviation or frequencies.
eGFR: estimated glomerular filtration rate; HbA1c: glycosylated hemoglobin; HDL: high density lipoprotein; LDL: low density lipoprotein; RAS: renin-angiotensin system.
The mean UACR in all patients increased approximately 39 mg/g from 1 year before DPP-4i treatment to the point of DPP-4i treatment initiation, while it was decreased approximately 45 mg/g 1 year after initiation of DPP-4i treatment (
Changes in urine albumin/creatinine ratio 1 year before and 1 year after DPP-4i treatment initiation. Changes in urine albumin/creatinine ratio in all patients (a) and in patients with macroalbuminuria (b), microalbuminuria (c), and normoalbuminuria (d). (Data are presented as means with standard errors.) DPP-4i: dipeptidyl-peptidase IV inhibitor; UACR: urine albumin/creatinine ratio.
The mean HbA1c improved from 8.6% (70 mmol/mol) to 7.8% (62 mmol/mol) (
Changes in UACR, HbA1c, eGFR, and lipid profiles 1 year before and 1 year after DPP-4i treatment initiation.
Changes during | Changes during | | |
---|---|---|---|
UACR (mg/g) | 40.8 ± 307.8 | −44.5 ± 351.9 | <0.05 |
HbA1c (%) | 0.4 ± 1.1 | −0.8 ± 1.5 | <0.01 |
Systolic blood pressure (mmHg) | −1.2 ± 20.5 | 1.9 ± 20.7 | 0.13 |
Diastolic blood pressure (mmHg) | −0.3 ± 12.8 | 1.4 ± 12.7 | 0.37 |
LDL-cholesterol (mg/dL) | −1.2 ± 26.32 | −3.5 ± 30.2 | <0.05 |
HDL-cholesterol (mg/dL) | −0.3 ± 8.7 | −0.9 ± 8.4 | 0.30 |
eGFR (mL/min/1.73 m2) | −0.7 ± 8.7 | 1.2 ± 11.3 | 0.69 |
Data are presented as means ± standard deviation.
‡The paired Student’s
DPP-4i: dipeptidyl-peptidase IV inhibitor; eGFR: estimated glomerular filtration rate; HbA1c: glycosylated hemoglobin; HDL: high density lipoprotein; LDL: low density lipoprotein; UACR: urine albumin/creatinine ratio.
To estimate the effect of covariates on albuminuria reduction, multiple linear regression analysis was performed. Although a reduction of HbA1c was shown using the paired Student’s
Multiple linear regression analysis for predictors of change of UACR.
| ||
---|---|---|
Age | −0.002 | 0.78 |
Sex (male) | 0.263 | 0.06 |
Duration of diabetes | 0.010 | 0.18 |
BMI | 0.003 | 0.77 |
Systolic blood pressure | 0.006 | 0.12 |
ΔHbA1c | 0.035 | 0.36 |
ΔLDL-cholesterol | 0.001 | 0.63 |
eGFR | 0.001 | 0.98 |
BMI: body mass index; eGFR: estimated glomerular filtration rate; HbA1c: glycosylated hemoglobin; LDL: low-density lipoprotein.
To verify the long-term effects of DPP-4i on eGFR, the change in eGFR from a point of treatment to 4 years before DPP-4i treatment and 4 years after treatment was compared in patients who were prescribed DPP-4i for more than 4 years. A total of 78 patients were included in the analysis (characteristics of those patients were present in Supplementary Table 1 in Supplementary Material available online at
Changes in eGFR 4 years before and 4 years after DPP-4i treatment initiation. Changes in eGFR in all patients (a) and in patients with macroalbuminuria (b), microalbuminuria (c), and normoalbuminuria (d). Baseline values are the means with standard errors. DPP-4i: dipeptidyl-peptidase IV inhibitor; UACR: urine albumin/creatinine ratio; −4 Y: 4 years before DPP-4i treatment initiation; −2 Y: 2 years before DPP-4i treatment initiation; 2 Y: 2 years after DPP-4i treatment initiation; 4 Y: 4 years after DPP-4i treatment initiation.
A subgroup analysis was performed to determine which subgroup was associated with UACR changes and what factors were associated with the albuminuria-lowering effect of DPP-4i. Albuminuria significantly decreased in patients < 65 years old of both genders (
Subgroup analysis for sex, age, obesity, chronic kidney disease stage, and drug coadministration.
| UACR | Baseline UACR | UACR | UACR change during | UACR change during | | |
---|---|---|---|---|---|---|---|
| |||||||
Male | 224 | 127.2 ± 401.4 | 168.5 ± 541.8 | 135.6 ± 398.1 | 41.3 ± 227.3 | −32.9 ± 282.6 | <0.05 |
Female | 190 | 212.4 ± 802.2 | 252.5 ± 979.7 | 194.3 ± 714.3 | 40.1 ± 380.4 | −58.2 ± 419.5 | <0.05 |
| |||||||
≥65 years | 133 | 153.2 ± 384.0 | 166.0 ± 551.2 | 151.7 ± 484.5 | 12.8 ± 231.3 | −14.3 ± 273.4 | 0.66 |
<65 years | 281 | 171.0 ± 715.1 | 226.5 ± 860.1 | 167.7 ± 600.9 | 55.5 ± 340.9 | −58.8 ± 382.8 | <0.05 |
| |||||||
Obese | 151 | 162.0 ± 654.5 | 232.5 ± 869.5 | 172.3 ± 585.1 | 70.5 ± 437.2 | −60.2 ± 433.2 | 0.24 |
Nonobese | 159 | 206.0 ± 770.5 | 256.8 ± 887.4 | 220.6 ± 691.7 | 50.8 ± 267.1 | −36.2 ± 348.6 | 0.10 |
| |||||||
eGFR ≥ 90 | 41 | 131.2 ± 231.1 | 126.6 ± 491.6 | 62.2 ± 158.0 | −4.6 ± 67.3 | −64.4 ± 419.3 | 0.92 |
90 > eGFR ≥ 60 | 229 | 91.1 ± 496.3 | 104.6 ± 524.7 | 81.6 ± 368.7 | 13.5 ± 149.0 | −23.0 ± 229.9 | 0.29 |
60 > eGFR ≥ 30 | 115 | 306.2 ± 652.8 | 338.2 ± 864.5 | 286.7 ± 716.5 | 32 ± 261.5 | −51.5 ± 383.8 | 0.11 |
30 > eGFR ≥ 15 | 13 | 861.8 ± 1631.2 | 917.6 ± 2446.1 | 886.9 ± 1599.0 | 55.8 ± 1181.9 | −30.7 ± 1074.0 | 0.27 |
| |||||||
Yes | 310 | 156.0 ± 573.2 | 187.5 ± 678.2 | 137.0 ± 508.3 | 21.9 ± 193.7 | −50.5 ± 319.8 | <0.05 |
No | 104 | 174.6 ± 737.5 | 265.3 ± 1009.5 | 238.7 ± 707.0 | 90.7 ± 495.1 | −26.6 ± 435.0 | 0.25 |
| |||||||
Yes | 289 | 170.4 ± 401.0 | 179.0 ± 560.8 | 153.7 ± 465.1 | 8.6 ± 171.4 | −25.3 ± 310.1 | 0.46 |
No | 125 | 130.9± 1039.6 | 271.9 ± 1122.5 | 182.9 ± 750.1 | 141 ± 537.1 | −89 ± 431.5 | <0.05 |
| |||||||
Yes | 245 | 201.8 ± 752.9 | 259.6 ± 933.4 | 203.5 ± 687.3 | 57.8 ± 382.9 | −56.1 ± 398.3 | <0.05 |
No | 169 | 114.5 ± 352.9 | 131.0 ± 445.5 | 103.3 ± 307.2 | 16.5 ± 142.1 | −27.7 ± 271.1 | 0.54 |
| |||||||
Yes | 235 | 238.9 ± 765.7 | 299.3 ± 941.2 | 219.1 ± 645.9 | 60.4 ± 383.0 | −80.2 ± 438.8 | <0.05 |
No | 179 | 73.3 ± 289.1 | 86.0 ± 447.5 | 88.4 ± 429.2 | 12.7 ± 140.7 | 2.4 ± 173.9 | 0.95 |
| |||||||
Vildagliptin | 136 | 185.6 ± 779.5 | 245.1 ± 855.5 | 191.2 ± 618.5 | 59.5 ± 266.2 | −53.8 ± 257.1 | 0.08 |
Sitagliptin | 96 | 208.0 ± 181.3 | 209.0 ± 590.3 | 143.9 ± 349.2 | 1.0 ± 88.3 | −65.1 ± 479.4 | 0.66 |
Linagliptin | 77 | 144.8 ± 776.5 | 243.2 ± 1073.1 | 200.4 ± 724.2 | 98.4 ±54.3 | −42.8 ± 45.3 | 0.30 |
Saxagliptin | 56 | 233.7 ± 530.9 | 221.1 ± 688.9 | 188.8 ± 709.8 | −12.6 ± 206.5 | −32.3 ± 287.4 | 0.20 |
Gemigliptin | 48 | 3.3 ± 27.1 | 7.2 ± 44.8 | 12.3 ± 63.6 | 3.9 ± 28.8 | 5.1 ± 32.0 | 0.60 |
Data are presented as means ± standard deviation.
Some patients were not included in the subgroup analyses due to missing data.
CKD: chronic kidney disease; DPP-4i: dipeptidyl-peptidase IV inhibitor; eGFR: estimated glomerular filtration rate; RAS: renin-angiotensin-system; UACR: urine albumin
This retrospective cohort study suggests that DPP-4i could reduce UACR, especially in T2DM patients with macroalbuminuria. Interestingly, DPP-4i reduced albuminuria in patients who were coadministered metformin or statins. Furthermore, DPP-4i could preserve eGFR in patients with T2DM, regardless of their baseline UACR.
Some mechanisms have been suggested to underlie the renoprotective effects of DPP-4i in previous studies. DPP-4 shows the highest expression in the kidneys among all organs and is mainly expressed in the kidney proximal tubule in healthy humans [
In our study, eGFR was increased in patients with macroalbuminuria or normoalbuminuria after taking DPP-4i (
Urine albumin excretion was decreased after DPP-4i treatment in the macroalbuminuria group (
In the subgroup analysis pertaining to coadministration of other drugs, urine albumin excretion was decreased in patients who were given metformin, statins, and RAS inhibitors. The renoprotective efficacy of metformin in T2DM patients remains controversial. Some studies insist that metformin lowers urine albumin excretion and has renoprotective effects [
An important strength of our study was that the cohort contained long-term treatment data. Previous studies investigating the renoprotective effects of DPP-4i used only short-term data, and they showed only albuminuria-lowering effects [
There were some limitations to our study. First, this study used a self-controlled design, as there was no control group. In this design, patient data prior to DPP-4i treatment were compared with data after DPP-4i treatment to estimate the effect of DPP-4i. Although there are some weaknesses in this design, time-invariant confounders and time-constant covariates were properly adjusted for using each patient’s own data. Secondly, UACR was calculated from an untimed spot urine collection. A timed urine collection would better confirm albuminuria, as there are some diurnal variations and other conditions that affect creatinine excretion. However, timed urine collection is difficult under clinical circumstances because it is inconvenient. Unlike our retrospective study, a prospective cohort study, like MARLINA-T2D study, will be able to circumvent such disadvantages [
In conclusion, the present study demonstrated that DPP-4i treatment could ameliorate diabetic nephropathy, by reducing urine albumin excretion and mitigating the reduction of eGFR in T2DM patients.
The authors declare no competing interests.
Young-Gun Kim and Jung Hyun Byun contributed equally to this work as co-first authors. Young-Gun Kim designed the study, analyzed data, and wrote the manuscript. JungHyun Byun and Dukyong Yoon collected the data and analyzed data. Ja Young Jeon, Seung Jin Han, Dae Jung Kim, and Kwan-Woo Lee contributed to the discussion and reviewed and edited the manuscript. Rae Woong Park and Hae Jin Kim designed the study and wrote the manuscript.
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (Grant no. NRF-2014R1A1A3050777); the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grants nos. HI16C0992 and HI14C3201).