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. 2014 Mar 24;16(6):560–568. doi: 10.1111/dom.12281

Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment

P-H Groop 1,2,3, S Del Prato 4, M-R Taskinen 1, D R Owens 5, Y Gong 6, S Crowe 6, S Patel 7, M von Eynatten 6, H-J Woerle 6
PMCID: PMC4288982  PMID: 24612167

Abstract

Aims

Renal disease is a frequent comorbidity of type 2 diabetes mellitus (T2DM) and an important factor complicating the choice of glucose-lowering drugs. The aim of this analysis was to evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (5 mg/day) in mono, dual or triple oral glucose-lowering regimens in subjects with T2DM and mild or moderate renal impairment (RI).

Methods

In this pooled analysis of three 24-week, placebo-controlled, phase 3 trials, subjects with mild (estimated glomerular filtration rate (eGFR) 60–<90 ml/min/1.73 m2, n = 838) or moderate RI (30–<60 ml/min/1.73 m2, n = 93) were compared with subjects with normal renal function (≥90 ml/min/1.73 m2, n = 1212).

Results

Subjects with RI were older, had longer duration of diabetes, and increased prevalence of diabetes-related comorbidities. After 24 weeks, linagliptin achieved consistent placebo-corrected mean glycated haemoglobin (HbA1c) changes across the three renal function categories: normal (−0.63%; p < 0.0001), mild RI (−0.67%; p < 0.0001) and moderate RI (−0.53%; p < 0.01), with no inter-group difference (p = 0.74). Renal function with linagliptin remained stable across all categories. In linagliptin-treated subjects, overall adverse event (AE) rates and serious AE rates were similar to placebo. The incidence of hypoglycaemia with linagliptin and placebo was 11.1 versus 6.9%, 11.9 versus 9.0% and 15.9 versus 12.0% in the normal, mild RI and moderate RI categories, respectively.

Conclusions

This pooled analysis provides evidence that linagliptin is an effective, well-tolerated and convenient treatment in subjects with T2DM and mild or moderate RI.

Keywords: diabetic nephropathy, DPP-4 inhibitor, glycaemic control, incretin therapy, type 2 diabetes

Introduction

Type 2 diabetes mellitus (T2DM) is a leading cause of chronic kidney disease (CKD) 1, with an estimated 40% of subjects with T2DM having some degree of kidney disease 2–5. A similar proportion has been reported in subjects with undiagnosed diabetes 6. CKD contributes to significant morbidity, with the risk of cardiovascular disease (CVD), end-stage renal disease (ESRD), hypoglycaemia and death being greater in subjects with both T2DM and CKD than for either disease alone 1.

Current guidelines recommend optimising glucose control to reduce the risk or slow the progression of CKD 1,7. Intensive glycaemic control can improve kidney outcomes 8–10. However, the presence of reduced renal clearance or renal impairment (RI) can result in the accumulation and prolonged half-lives of certain antidiabetes drugs, which limits or complicates their use because of the increased risk of adverse events (AEs) 11. For example, because exogenous insulin is primarily excreted by the kidneys, reduced renal function can extend the half-life of circulating insulin, thus increasing the risk of hypoglycaemia 1,12. Importantly, clearance of some sulphonylureas (or their active metabolites) decreases as renal function declines, requiring a reduction in drug dose to avoid hypoglycaemia 1. Therefore, certain drugs are contraindicated in subjects with RI whereas the dosages of other drugs require adjustment according to renal function and frequent monitoring to avoid AEs. Thus, there remains a need for glucose-lowering drugs that are suitable and convenient for all subjects irrespective of their renal function 2.

Dipeptidyl peptidase (DPP)-4 inhibitors have beneficial effects on glycaemic control, are generally weight neutral, and are associated with a low incidence of AEs, including hypoglycaemia 13. Although the efficacy and safety of currently available DPP-4 inhibitors are similar 14, important pharmacological differences exist that are relevant in the presence of RI. Saxagliptin, sitagliptin and vildagliptin undergo extensive renal clearance (87, 75 and 85%, respectively) and therefore require dose adjustment in subjects with moderate or severe RI, or ESRD 15–17. Linagliptin has a low rate of renal excretion (˜5% of its overall elimination); the majority (˜80%) is excreted via the enterohepatic system 18. A phase 1 study in subjects with normal-to-severe RI (including ESRD requiring dialysis) showed that RI had minimal impact on linagliptin pharmacokinetics 19. Similarly, an analysis of phase 3 trial data showed that RI had a minor effect on long-term exposure with linagliptin 5 mg once daily 20. Consequently, dose adjustment of linagliptin according to different RI stages and on-treatment monitoring of renal function are not required.

These pharmacological attributes of linagliptin support its use in subjects with T2DM with or without RI. A 1-year study in subjects with severe RI showed that linagliptin 5 mg provided clinically meaningful decreases in glycated haemoglobin (HbA1c) and was well-tolerated with a low risk of hypoglycaemia 21. The aim of this pooled analysis of data from three large phase 3 trials of linagliptin 22–24 was to evaluate the consistency of the efficacy and safety of linagliptin in subjects with T2DM with mild or moderate RI.

Materials and Methods

Study Design

This was a pooled analysis of three 24-week, multicentre, multinational, randomised, double-blind, placebo-controlled, parallel-group clinical trials in subjects with T2DM comparing linagliptin 5 mg once daily versus placebo as monotherapy (NCT00621140) 22, add-on to metformin (NCT00601250) 24, or add-on to metformin and sulphonylurea (NCT00602472) 23. The study designs were homogeneous, which enabled pooling of data, and have been described previously 22–24.

Eligibility criteria for each of the three studies were similar. Inclusion criteria included: age ≥18 and ≤80 years; diagnosis of T2DM; body mass index (BMI) of ≤40 kg/m2; HbA1c of ≥6.5 to ≤9.0% for subjects undergoing washout of previous medication and HbA1c ≥7.0 to ≤10.0% for subjects not undergoing washout of previous medication. The main exclusion criteria were: myocardial infarction, stroke or transient ischaemic attack within 6 months of study enrolment; impaired hepatic function at screening; treatment with rosiglitazone, pioglitazone, glucagon-like peptide-1 analogues, insulin or antiobesity drugs (e.g. sibutramine, rimonabant or orlistat) within 3 months of enrolment. In two of the three studies 23,24, patients with renal failure or RI [serum creatinine ≥135 µmol/l (≥1.5 mg/dl)]) were also excluded.

Efficacy and Safety Assessments

Subjects were grouped according to the degree of renal function (normal, mild RI or moderate RI). Renal function was evaluated using the estimated glomerular filtration rate (eGFR), which was calculated using the modification of diet in renal disease (MDRD) formula 25,26. Staging of renal function was as follows: normal, eGFR ≥90 ml/min/1.73 m2; mild RI, eGFR 60–<90 ml/min/1.73 m2; moderate RI, eGFR 30–<60 ml/min/1.73 m2. Renal function was also categorised based on estimated creatinine clearance (eCcr) rate using the Cockcroft–Gault (C–G) formula 27; C–G staging was as follows (in accordance with Food and Drug Administration guidance 28): normal, ≥80 ml/min; mild RI, 50–<80 ml/min; moderate RI, 30–<50 ml/min. Because the number of subjects with severe RI (<30 ml/min/1.73 m2) included in the three phase 3 trials was low, they were excluded from this analysis; subjects with no renal function measurement (‘missing’) were also excluded.

Efficacy was assessed as change from baseline to week 24 in HbA1c and fasting plasma glucose (FPG) levels. The effect of linagliptin on HbA1c was also analysed according to predefined subgroups: age (<65 or ≥65 years); BMI (<30 or ≥30 kg/m2); gender (male or female); duration of T2DM (≤5 or >5 years); urine albumin-to-creatinine ratio (UACR; <30 or ≥30 mg/g). Safety assessments included AEs, serious AEs (SAEs), treatment-related AEs and AEs of special interest. Investigator-reported hypoglycaemic events were defined as 29: asymptomatic, plasma glucose concentration ≤3.9 mmol/l (≤70 mg/dl) without symptoms; documented symptomatic, plasma glucose concentration ≥3.0 mmol/l (≥54 mg/dl) and ≤3.9 mmol/l (≤70 mg/dl) with symptoms; documented symptomatic, plasma glucose concentration <3.0 mmol/l (<54 mg/dl) with symptoms but not requiring external assistance; severe, requiring external assistance to administer resuscitative actions. Change in renal function (eGFR) over time was also assessed.

Statistical Analysis

The change in HbA1c from baseline to 24 weeks was compared between the linagliptin and placebo groups in each renal function category using an analysis of covariance (ANCOVA). The model included continuous baseline HbA1c, treatment, time since diagnosis of diabetes, gender, baseline BMI, baseline age, washout period, race, study, RI and treatment × RI interaction. The efficacy analyses were performed on the full analysis set (FAS), which comprised all randomised subjects with a baseline HbA1c measurement, ≥1 on-treatment HbA1c measurement and ≥1 dose of study medication. A last observation carried forward (LOCF) approach was used to replace missing data. A similar approach was used to analyse the change in FPG (FPG values were converted from mg/dl to mmol/l after statistical analysis using a factor of 0.0555) with the addition of baseline FPG. All analyses were performed at a significance level of 5%. AEs were summarised using frequency counts for all subjects treated with ≥1 dose of study drug (treated set); consistent with previous reports 22–24, no formal inferential statistical analyses were applied to the safety assessments.

Results

Subject Demographics and Clinical Characteristics at Baseline

Of 2262 subjects randomised in the three trials, data from 2143 subjects were available for the MDRD analysis: 56.6% had normal renal function (linagliptin, n = 870; placebo, n = 342); 39.1% had mild RI (linagliptin, n = 620; placebo, n = 218); 4.3% had moderate RI (linagliptin, n = 68; placebo, n = 25). There were no subjects with severe RI (eGFR <30 ml/min/1.73 m2); 81 subjects had no renal function measurement. Unless stated otherwise, results from the eCcr analyses were essentially similar to those from the eGFR analyses (Tables S1–S3, Supporting Information).

As expected, subjects with RI tended to be older and had a longer known disease duration (>5 years) than subjects with normal renal function (Table1). Baseline HbA1c ranged from 8.0 to 8.2% and FPG ranged from 9.0 to 9.5 mmol/l (162.6–170.6 mg/ml). Overall, the linagliptin and placebo groups were similar in terms of demographics and clinical characteristics.

Table 1.

Subject demographics and clinical characteristics at baseline (FAS)

Normal renal function* Mild RI* Moderate RI*
Linagliptin 5 mg (n = 870) Placebo (n = 342) Linagliptin 5 mg (n = 620) Placebo (n = 218) Linagliptin 5 mg (n = 68) Placebo (n = 25)
Male, n (%) 420 (48.3) 175 (51.2) 317 (51.1) 109 (50.0) 32 (47.1) 9 (36.0)
Age years, mean ± s.d. 54.0 ± 9.6 53.6 ± 10.0 61.3 ± 8.7 59.9 ± 9.1 66.4 ± 8.0 65.6 ± 6.4
Race, n (%)
 White 465 (53.4) 181 (52.9) 386 (62.3) 140 (64.2) 43 (63.2) 12 (48.0)
 Black 9 (1.0) 4 (1.2) 2 (0.3) 0 0 0
 Asian 396 (45.5) 157 (45.9) 232 (37.4) 78 (35.8) 25 (36.8) 13 (52.0)
BMI kg/m2, mean ± s.d. 28.9 ± 4.9 28.9 ± 4.9 29.2 ± 4.8 29.2 ± 4.7 28.6 ± 4.4 28.3 ± 4.9
GFR (MDRD)ml/min/1.73 m2, median (min, max) 107.9 (90.0, 266.4) 105.8 (90.1, 221.0) 78.5 (60.1, 90.0) 80.9 (60.5, 90.0) 56.4 (34.2, 59.5) 53.6 (30.2, 59.5)
UACR mg/g, median (min, max)† 10.6 (0.0, 10584.1) 9.7 (0.0, 4697.6) 12.4 (0.0, 3665.9) 8.8 (0.0, 1388.8) 18.6 (0.9, 1538.2) 19.4 (1.8, 4373.1)
HbA1c %, mean ± s.d. 8.1 ± 0.9 8.1 ± 0.9 8.0 ± 0.8 8.0 ± 0.8 8.2 ± 1.0 8.2 ± 0.9
FPG mmol/l (mg/dl), mean ± s.d.‡ 9.1 ± 2.2 (163.8 ± 39.6) 9.3 ± 2.2 (167.0 ± 39.5) 9.1 ± 2.2 (163.2 ± 40.1) 9.0 ± 2.1 (163.0 ± 38.4) 9.5 ± 2.6 (170.6 ± 47.3) 9.0 ± 2.0 (162.6 ± 36.5)
Duration of diabetes, n (%)
 Up to 1 year 109 (12.5) 44 (12.9) 74 (11.9) 37 (17.0) 4 (5.9) 3 (12.0)
 >1–5 years 265 (30.5) 113 (33.0) 190 (30.6) 58 (26.6) 13 (19.1) 7 (28.0)
 >5 years 496 (57.0) 185 (54.1) 356 (57.4) 123 (56.4) 51 (75.0) 15 (60.0)
Exposure days, mean ± s.d. 169 ± 19.8 168 ± 22.1 169 ± 18.2 166 ± 27.1 166 ± 23.8 155 ± 41.0
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BMI, body mass index; FAS, full analysis set; FPG, fasting plasma glucose; GFR, glomerular filtration rate; HbA1c, glycated haemoglobin; MDRD, modification of diet in renal disease; RI, renal impairment; s.d., standard deviation; UACR, urine albumin-to-creatinine ratio.

Renal function according to MDRD formula: normal, ≥90 ml/min/1.73 m2; mild, 60–<90 ml/min/1.73 m2; moderate, 30–<60 ml/min/1.73 m2.

Normal: linagliptin n = 824, placebo n = 329; mild: linagliptin n = 581, placebo n = 197; moderate: linagliptin n = 65, placebo n = 25.

Normal: linagliptin n = 848, placebo n = 335; mild: linagliptin n = 602, placebo n = 209.

The use of glucose-lowering drugs was broadly similar across all renal function categories. The use of concomitant antihypertensive and lipid-lowering drugs tended to be higher in subjects with RI versus subjects with normal renal function (Table2).

Table 2.

Concomitant therapies at screening

% Normal renal function* Mild RI* Moderate RI*
Linagliptin 5 mg (n = 870) Placebo (n = 342) Linagliptin 5 mg (n = 620) Placebo (n = 218) Linagliptin 5 mg (n = 68) Placebo (n = 25)
Subjects with ≥1 specific drug 66.7 70.5 81.0 80.7 88.2 88.0
ASA 30.5 34.2 37.6 38.1 29.4 48.0
Antihypertensives 51.1 52.6 69.5 70.2 82.4 84.0
 β-blockers 14.9 16.4 23.9 26.1 30.9 20.0
 ACE inhibitors 26.9 26.9 30.0 31.7 33.8 48.0
 Diuretics 8.7 9.6 18.5 14.7 32.4 32.0
 ARBs 10.5 10.8 16.6 13.3 19.1 16.0
 Calcium antagonists 11.0 11.7 20.2 19.7 27.9 24.0
 Combinations 5.9 7.3 12.9 12.4 17.6 24.0
Lipid-lowering drugs 34.5 38.3 43.7 41.7 51.5 40.0
 Niacin 1.6 0.3 1.1 0.5 0 0
 Fibrates 4.8 7.0 7.6 7.3 7.4 16.0
 Statins 30.0 31.9 37.4 35.8 45.6 32.0
 Other 2.3 2.6 2.6 0.5 1.5 4.0
Glucose-lowering drugs
 Treatment-naïve 8.3 11.4 15.6 22.9 10.3 4.0
 Metformin only 28.3 27.5 29.0 30.3 25.0 24.0
 SU only 1.8 3.2 3.1 2.3 1.5 8.0
 Metformin + SU 59.8 56.4 50.6 43.1 60.3 64.0
 Others† 1.8 1.5 1.6 1.4 2.9 0
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ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; ASA, acetyl salicylic acid; MDRD, modification of diet in renal disease; RI, renal impairment; SU, sulphonylurea.

Renal function according to MDRD formula: normal, ≥90 ml/min/1.73 m2; mild, 60–<90 ml/min/1.73 m2; moderate, 30–<60 ml/min/1.73 m2.

Including mono- and combination therapies.

The prevalences of concomitant microvascular diseases (retinopathy, nephropathy and neuropathy) in linagliptin-versus placebo-treated subjects in the normal, mild RI and moderate RI categories were 23.7 versus 19.6%, 27.1 versus 25.2% and 35.3 versus 56.0%, respectively. Corresponding prevalences of CVD were 9.4 versus 11.4%, 17.4 versus 18.3% and 22.1 versus 32.0%, respectively. Prevalences of hypertension were 54.5 versus 57.6%, 72.4 versus 70.6% and 82.4 versus 76.0%, respectively.

Efficacy

Linagliptin was superior to placebo in reducing HbA1c in all renal function categories (Figure 1). After 24 weeks of treatment, the placebo-corrected adjusted mean [95% confidence interval (CI)] changes in HbA1c from baseline in the normal, mild RI and moderate RI categories were −0.63% (−0.73, −0.53; p < 0.0001), −0.67% (−0.80, −0.54; p < 0.0001) and −0.53% (−0.91, −0.14; p < 0.01), respectively. There was no inter-group difference (p-value for interaction = 0.74). Linagliptin treatment resulted in a greater reduction in FPG levels compared with placebo. After 24 weeks, the placebo-corrected adjusted mean (95% CI) changes in FPG from baseline in the normal and mild RI categories were −0.9 mmol/l (−1.1, −0.6) [−16.0 mg/dl (−20.7, −11.4); p < 0.0001] and −1.2 mmol/l (−1.5, −0.9) [−22.0 mg/dl (−27.8, −16.2); p < 0.0001], respectively. The FPG change in the moderate RI category was not statistically significant [−0.3 mmol/l (−1.2, 0.6); −5.5 mg/dl (−22.1, 11.1); p = 0.52], which may be because of the comparatively small number of subjects in this group (n = 92). Overall, for FPG change from baseline, there was a trend toward a treatment effect modification by renal function category (p = 0.096), partially driven by the low number of subjects in the moderate RI category.

Figure 1.

Figure 1

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Adjusted mean change from baseline in HbA1c following treatment with linagliptin 5 mg or placebo after 24 weeks (FAS – LOCF). Model includes continuous baseline HbA1c, baseline body mass index (category), washout period, treatment, study, age group, gender, time since diagnosis of diabetes, race, renal function (MDRD) and treatment × renal function (MDRD). CI, confidence interval; FAS, full analysis set; HbA1c, glycated haemoglobin; LOCF, last observation carried forward; MDRD, modification of diet in renal disease; s.e., standard error.

In subjects with any renal dysfunction (i.e. mild and moderate RI categories combined), significant and comparable reductions from baseline at week 24 in HbA1c were observed within each subgroup analysed (Figure 2).

Figure 2.

Figure 2

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Subgroup analysis of placebo-corrected adjusted mean change in HbA1c from baseline after 24 weeks in subjects with mild and moderate RI (FAS – LOCF). *Subjects with mild or moderate RI (MDRD categorisation) at baseline were pooled in this analysis. †p-value for interaction between treatment and subgroup category. Model includes continuous baseline HbA1c, washout period, treatment, study, variable of interest and treatment × variable of interest. BMI, body mass index; CI, confidence interval; FAS, full analysis set; HbA1c, glycated haemoglobin; LOCF, last observation carried forward; MDRD, modification of diet in renal disease; RI, renal impairment; UACR, urine albumin-to-creatinine ratio.

Safety

Linagliptin treatment was generally well-tolerated across the three renal function categories (Table3). In both treatment groups, a slight trend for higher rates of any AEs, SAEs and drug-related AEs was seen in subjects with RI. The incidence of AEs with linagliptin was comparable to placebo in each renal function category. In the moderate RI category, there were no reported drug-related AEs with placebo compared with an incidence rate of 14.5% (n = 10) with linagliptin. Notably, hypoglycaemia was reported by 7 of 10 linagliptin-treated subjects with drug-related AEs in this category. Overall, there was no clustering of any specific type of unexpected AE (Table3). In an analysis of AEs by system organ class (SOC), the incidences of cardiac disorders for linagliptin and placebo were: normal renal function, 1.9 and 1.4%; mild RI, 3.7 and 0.5%; moderate RI, 1.4 and 4.0%. The incidences of AEs relating to renal and urinary disorders were similar for linagliptin and placebo in subjects with normal renal function (2.5 and 4.0%), mild RI (3.8 and 3.2%) and moderate RI (4.3 and 4.0%). There were no drug-related AEs of renal failure. Renal function (eGFR) remained stable over 24 weeks following linagliptin or placebo treatment (Figure 3). Although only one subject (0.2%) developed hyperkalaemia (from the mild RI category and who received linagliptin), no other clinically significant laboratory findings emerged. According to the eCcr categorisation, there was a trend for higher rates of any AEs, SAEs and drug-related AEs in subjects with RI compared with subjects without RI, but overall rates were similar between linagliptin and placebo (Table S3).

Table 3.

Overall AEs, hypoglycaemic episodes and common AEs (≥5% in any linagliptin group) – treated set

% Normal renal function† Mild RI† Moderate RI†
Linagliptin 5 mg (n = 886) Placebo (n = 346) Linagliptin 5 mg (n = 630) Placebo (n = 221) Linagliptin 5 mg (n = 69) Placebo (n = 25)
Any AE 58.2 58.7 59.0 57.0 66.7 60.0
Serious AEs 2.4 4.0 3.8 2.7 5.8 4.0
Drug-related AEs 10.2 8.4 13.5 11.3 14.5 0
Any investigator-reported hypoglycaemia‡ 11.1 6.9 11.9 9.0 15.9 12.0
Severe hypoglycaemia requiring assistance§ 0.1 0.6 0.3 0 2.9 0
Common AEs
 Cough 2.1 1.4 1.9 0.9 5.8 0
 Dizziness 2.4 1.4 2.4 1.4 7.2 20.0
 Hyperglycaemia 6.4 15.3 5.4 14.0 8.7 4.0
 Nasopharyngitis 4.9 4.6 5.1 4.1 5.8 8.0
 Upper respiratory tract infection 4.6 6.1 3.7 5.0 4.3 12.0
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AEs, adverse events; RI, renal impairment.

MedDRA version 12.1 used for reporting.

Renal function according to modification of diet in renal disease formula: normal, ≥90 ml/min/1.73 m2; mild, 60–<90 ml/min/1.73 m2; moderate, 30–<60 ml/min/1.73 m2.

Hypoglycaemic episodes were classified by the investigator according to the following definitions:

Asymptomatic hypoglycaemia: event not accompanied by typical symptoms of hypoglycaemia but with a measured plasma glucose concentration of ≤3.9 mmol/l (≤70 mg/dl).Documented symptomatic hypoglycaemia with a measured plasma glucose concentration of ≥3.0 mmol/l (≥54 mg/dl) and ≤3.9 mmol/l (≤70 mg/dl), accompanied by typical symptoms of hypoglycaemia.Documented symptomatic hypoglycaemia with a measured plasma glucose concentration of <3.0 mmol/l (<54 mg/dl), accompanied by typical symptoms of hypoglycaemia but no need for external assistance.

Severe hypoglycaemic episode: event requiring assistance of another person to administer carbohydrate, glucagon or other resuscitative actions.

Figure 3.

Figure 3

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Mean change in renal function (eGFR) over time in subjects treated with linagliptin 5 mg or placebo (FAS). Renal function according to MDRD formula; normal, ≥90 ml/min/1.73 m2; mild, 60–<90 ml/min/1.73 m2; moderate, 30–<60 ml/min/1.73 m2. eGFR, estimated glomerular filtration rate; FAS, full analysis set; MDRD, modification of diet in renal disease; s.d., standard deviation.

The incidence of severe hypoglycaemia was low, with no meaningful differences between treatment groups. The incidence of any investigator-reported hypoglycaemia with linagliptin was higher in subjects with RI: 11.1, 11.9 and 15.9% in the normal, mild and moderate renal function categories, respectively; with placebo, these rates were 6.9, 9.0 and 12.0%, respectively (Table3). The incidence of hypoglycaemia was <1% in subjects receiving linagliptin as monotherapy 22 or as an add-on to metformin therapy 24. Subjects receiving linagliptin as add-on to metformin plus sulphonylurea 23 had the highest incidence of hypoglycaemia (linagliptin, 23.7%; placebo, 16.0%).

Discussion

Linagliptin is an oral, once-daily glucose-lowering therapy that does not require dose adjustment in renally impaired subjects with T2DM 18. In subjects with T2DM and severe RI, linagliptin 5 mg was well-tolerated with an acceptable safety profile and, added to existing background therapy, achieved a placebo-corrected reduction in HbA1c of 0.72% after 52 weeks 21. Findings from the current analysis add to this evidence, now reporting the efficacy and safety of linagliptin in subjects with mild or moderate RI (no subjects with severe RI or ESRD were included). On the basis of data from phase 3 clinical trials of linagliptin in either mono, dual or triple glucose-lowering regimens, significant reductions in HbA1c were observed in each RI category which were comparable to the reduction seen in the normal renal function category. Taken together, these data indicate that the degree of RI has no clinically meaningful impact on the efficacy of linagliptin. Elderly subjects often have RI as well as other age-related comorbidities, and therefore selecting the appropriate glucose-lowering therapy in this population can be challenging 30. In the combined analysis of subjects with mild and moderate RI (Figure 2), the effect of linagliptin treatment on reducing HbA1c levels in elderly subjects (≥65 years) and subjects with a longer known duration of diabetes (>5 years) was comparable to younger subjects and subjects with early onset disease. This finding is consistent with the results from a randomised placebo-controlled phase 3 clinical trial of linagliptin in elderly patients (≥70 years) with T2DM 31.

In our analysis, the safety and tolerability profile of linagliptin was comparable to placebo across all renal function categories studied, and is consistent with a previous pooled analysis of eight clinical trials of linagliptin 32. In the moderate RI category, the incidence of drug-related AEs was higher with linagliptin than with placebo, a finding which may have been driven by the high proportion of linagliptin subjects (7 of 10 subjects) who reported hypoglycaemia as a drug-related AE. Slightly higher rates of investigator-reported hypoglycaemia were observed in subjects with moderate RI compared with subjects with normal renal function; however, it is well-known that subjects with RI have an increased risk for hypoglycaemia 12,33. Across all renal function categories, a higher incidence of hypoglycaemia was observed in subjects receiving linagliptin compared with placebo. This finding may have been driven by the large proportion of subjects in the analysis who had sulphonylurea background therapy (50–60% across the linagliptin groups); combining sulphonylurea and incretin therapies may elevate the risk of hypoglycaemia even though the latter compounds have a low risk for hypoglycaemia as monotherapies 34,35. Although subjects with T2DM and CKD are at high risk of CVD 1, including subjects with mild or moderate RI 36, the proportion of subjects with cardiac disorders (SOC) was low and similar across all treatment groups in this analysis. Linagliptin did not appear to cause electrolyte disturbances and no cases of drug-related renal failure were reported. Renal function remained stable throughout the evaluation period in all treatment groups of different RI stages. A similar finding was seen in subjects with severe RI treated with linagliptin for 1 year 21. Interestingly, in a pooled analysis of four phase 3 clinical trials of linagliptin 5 mg, albuminuria, another biomarker of renal disease 37, was significantly reduced by 32% with linagliptin versus 6% with placebo (p < 0.05) 38. It is envisaged that more information concerning the renal effects of linagliptin will be learned from two recently initiated large clinical studies [CARMELINA™ (NCT01897532) and MARLINA-T2D™ (NCT01792518)] which are investigating the effect of linagliptin versus placebo on cardiovascular and/or renal endpoints and changes in prevalent albuminuria, respectively. Patients with evidence of renal complications are allowed to enrol in both studies.

The findings from this analysis have important clinical implications. Many commonly used glucose-lowering therapies are contraindicated in subjects with RI, depending on their degree of RI, such as acarbose (if eCcr <25 ml/min) and some sulphonylureas [e.g. glibenclamide (glyburide) if ≥3 CKD stages (eGFR <60 ml/min)] 1. Owing to reports of metformin-associated lactic acidosis, the use of metformin is also contraindicated in some prescribing guidelines 7, although this contraindication remains controversial and is often disregarded in clinical practice 39,40. Other glucose-lowering therapies may be used at a reduced dose but require periodic renal function monitoring prior to and during treatment to avoid inappropriate dosing; for example, insulin, repaglinide and gliclazide require dose reduction in subjects with severe RI 11. Thiazolidinediones may be given without dose adjustment and with no additional risk of hypoglycaemia, although side-effects such as fluid retention, weight gain and an increased risk of cardiovascular events and fractures may be exacerbated in subjects with RI 41. DPP-4 inhibitors are associated with a low risk of hypoglycaemia and a low incidence of AEs 13. Saxagliptin, sitagliptin and vildagliptin require a reduction in the standard clinical dose in subjects with moderate or severe RI, or ESRD 15–17. Reduced doses of these DPP-4 inhibitors improved glycaemic control in these subjects 42–45, although comparisons of their clinical effectiveness with their respective standard dosing regimens are not available. In addition, because renal function will probably change over time, renal function monitoring is recommended prior to initiating treatment with saxagliptin, sitagliptin or vildagliptin and periodically thereafter 15–17. Linagliptin does not require dose adjustment in subjects with any degree of RI 18–20, a recommendation supported by the findings of this analysis and a previous study in subjects with severe RI 21.

As with all pooled analyses, there are certain inherent limitations. Owing to the retrospective nature of this analysis, the findings should be regarded as exploratory. The comparatively low number of subjects with moderate RI restricts the interpretation of the results observed in this category. In addition, insulin is a commonly used therapy in this subject population and it would have been interesting to investigate the efficacy and safety of linagliptin when added to background insulin therapy; however, subjects receiving insulin were excluded from the three phase 3 trials included. In this regard, a recent analysis of subjects with mild, moderate or severe RI and who were inadequately controlled on insulin therapy showed that linagliptin was well-tolerated and improved glycaemic control without excessive risk of hypoglycaemia 46.

In summary, this pooled analysis showed that the presence of mild or moderate RI has no clinically meaningful impact on the efficacy and safety of linagliptin in subjects with T2DM. Because subjects with RI have additional safety and tolerability concerns, such as increased risk of hypoglycaemia and CVD, treatment choices are limited. Given the convenience of a single daily dose, no requirement for dose adjustment, and no additional drug-induced safety monitoring of kidney function, our analysis indicates that linagliptin is an effective and well-tolerated treatment option in subjects with mild or moderate RI.

Acknowledgments

This study was conducted by Boehringer Ingelheim, the manufacturer of linagliptin. Some of the results from this study were presented at the 71st Scientific Sessions of the American Diabetes Association, San Diego, California, 24–28 June 2011 (Cooper M., et al. Diabetes. 2011;60(Suppl. 1):A293).

The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Paul MacCallum of Envision Scientific Solutions during the preparation of this article.

Conflict of Interest

S. D. P., M.-R. T., D. R. O., Y. G., M. v. E., S. P. and H.-J. W. contributed to the study design. P.-H. G., S. D. P., M.-R. T., D. R. O., Y. G., M. v. E., S. C., S. P. and H.-J. W. participated in the analysis and interpretation of data. All authors were involved in drafting the article and provided intellectual content of critical importance. All authors have seen and approved the final version. P.-H. G. (MD) has served on advisory boards for and has received speakers‘ fees from Boehringer Ingelheim. S. D. P. (MD) has received honoraria for attending meetings, consultancy fees, speaker fees and/or travel grants from Boehringer Ingelheim. M.-R. T. (MD) has received honoraria for attending meetings, consultancy fees, speaker fees and/or travel grants from Boehringer Ingelheim. D. R. O. (MD) has received consultancy fees, speaker fees and/or travel grants from Boehringer Ingelheim. Y. G. (MD), M. v. E. (MD), S. C. (MSc), S. P. (MB CHB) and H.-J. W. (MD) are all employees of Boehringer Ingelheim.

Supporting Information

Figure S1. Adjusted mean change from baseline in glycated haemoglobin (HbA1c) following treatment with linagliptin 5 mg or placebo after 24 weeks [full analysis set – last observation carried forward (FAS – LOCF)]. Model includes continuous baseline HbA1c, baseline body mass index (BMI) (category), washout period, treatment, study, age group, gender, time since diagnosis of diabetes, race, renal function (C–G) and treatment × renal function (C–G).

Figure S2. Subgroup analysis of placebo-corrected adjusted mean change in glycated haemoglobin (HbA1c) from baseline after 24 weeks in subjects with mild and moderate declining renal function [full analysis set – last observation carried forward (FAS – LOCF)]. *Subjects with mild or moderate declining renal function (C–G categorisation) at baseline were pooled in this analysis. †p-value for interaction between treatment and subgroup category. Model includes continuous baseline HbA1c, washout period, treatment, study, variable of interest and treatment × variable of interest.

Figure S3. Mean change in renal function estimated glomerular filtration rate (eGFR) over time in subjects treated with linagliptin 5 mg or placebo [full analysis set (FAS)]. Renal function according to C–G formula; normal, ≥80 ml/min; mild, 50–<80 ml/min; moderate, 30–<50 ml/min.

Table S1. Subject demographics and clinical characteristics at baseline full analysis set (FAS)*.

Table S2. Concomitant therapies at screening.

dom0016-0560-S1.doc (48.5KB, doc)

References

  • 1.National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis. 2012;60:850–886. doi: 10.1053/j.ajkd.2012.07.005. [DOI] [PubMed] [Google Scholar]
  • 2.Koro CE, Lee BH, Bowlin SJ. Antidiabetic medication use and prevalence of chronic kidney disease among patients with type 2 diabetes mellitus in the United States. Clin Ther. 2009;31:2608–2617. doi: 10.1016/j.clinthera.2009.10.020. [DOI] [PubMed] [Google Scholar]
  • 3.Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR UKPDS Study Group. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes. 2006;55:1832–1839. doi: 10.2337/db05-1620. [DOI] [PubMed] [Google Scholar]
  • 4.Meyers JL, Candrilli SD, Kovacs B. Type 2 diabetes mellitus and renal impairment in a large outpatient electronic medical records database: rates of diagnosis and antihyperglycemic medication dose adjustment. Postgrad Med. 2011;123:133–143. doi: 10.3810/pgm.2011.05.2291. [DOI] [PubMed] [Google Scholar]
  • 5.National Institutes of Health. 2011. . National Institute of Diabetes and Digestive and Kidney Diseases: U.S. Renal Data System, USRDS 2011 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda: MD: National Institutes of Health,
  • 6.Plantinga LC, Crews DC, Coresh J, et al. Prevalence of chronic kidney disease in US adults with undiagnosed diabetes or prediabetes. Clin J Am Soc Nephrol. 2010;5:673–682. doi: 10.2215/CJN.07891109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.American Diabetes Association. Standards of medical care in diabetes–2013. Diabetes Care. 2013;36(Suppl. 1):S11–S66. doi: 10.2337/dc13-S011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383–393. doi: 10.1056/NEJMoa021778. [DOI] [PubMed] [Google Scholar]
  • 9.Advance Collaborative Group. Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–2572. doi: 10.1056/NEJMoa0802987. [DOI] [PubMed] [Google Scholar]
  • 10.Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376:419–430. doi: 10.1016/S0140-6736(10)60576-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Bakris GL. Recognition, pathogenesis, and treatment of different stages of nephropathy in patients with type 2 diabetes mellitus. Mayo Clin Proc. 2011;86:444–456. doi: 10.4065/mcp.2010.0713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetes Care. 2012;35:1364–1379. doi: 10.2337/dc12-0413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab. 2011;13:7–18. doi: 10.1111/j.1463-1326.2010.01306.x. [DOI] [PubMed] [Google Scholar]
  • 14.Scheen AJ. A review of gliptins in 2011. Expert Opin Pharmacother. 2012;13:81–99. doi: 10.1517/14656566.2012.642866. [DOI] [PubMed] [Google Scholar]
  • 15.Bristol-Myers Squibb. Onglyza [package insert] Princeton, NJ: Bristol-Myers Squibb; 2013. . Available from URL: http://packageinserts.bms.com/pi/pi_onglyza.pdf. Accessed 10 November 2013. [Google Scholar]
  • 16.Merck & Co Inc. Januvia [package insert] Whitehouse Station, NJ: Merck & Co., Inc; 2013. . Available from URL: http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf. Accessed 10 November 2013. [Google Scholar]
  • 17.Novartis Pharmaceuticals UK Ltd. Galvus [summary of product characteristics] Horsham, West Sussex: Novartis Pharmaceuticals UK, Ltd; 2013. . Available from URL: http://www.medicines.org.uk/EMC/medicine/20734/SPC/Galvus%2050%20mg%20Tablets/. Accessed 10 November 2013. [Google Scholar]
  • 18.Boehringer Ingelheim Pharmaceuticals Inc. Tradjenta [package insert] Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2013. Available from URL: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Tradjenta/Tradjenta.pdf. Accessed 9 November 2013. [Google Scholar]
  • 19.Graefe-Mody U, Friedrich C, Port A, et al. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin(*) Diabetes Obes Metab. 2011;13:939–946. doi: 10.1111/j.1463-1326.2011.01458.x. [DOI] [PubMed] [Google Scholar]
  • 20.Friedrich C, Emser A, Woerle HJ, Graefe-Mody U. Renal impairment has no clinically relevant effect on the long-term exposure of linagliptin in patients with type 2 diabetes. Am J Ther. 2013;20:618–621. doi: 10.1097/MJT.0b013e31826232dc. [DOI] [PubMed] [Google Scholar]
  • 21.McGill JB, Sloan L, Newman J, et al. Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study. Diabetes Care. 2013;36:237–244. doi: 10.2337/dc12-0706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13:258–267. doi: 10.1111/j.1463-1326.2010.01350.x. [DOI] [PubMed] [Google Scholar]
  • 23.Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med. 2011;28:1352–1361. doi: 10.1111/j.1464-5491.2011.03387.x. [DOI] [PubMed] [Google Scholar]
  • 24.Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65–74. doi: 10.1111/j.1463-1326.2010.01326.x. [DOI] [PubMed] [Google Scholar]
  • 25.Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461–470. doi: 10.7326/0003-4819-130-6-199903160-00002. [DOI] [PubMed] [Google Scholar]
  • 26.Rigalleau V, Lasseur C, Perlemoine C, et al. Estimation of glomerular filtration rate in diabetic subjects: Cockcroft formula or modification of diet in renal disease study equation? Diabetes Care. 2005;28:838–843. doi: 10.2337/diacare.28.4.838. [DOI] [PubMed] [Google Scholar]
  • 27.Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41. doi: 10.1159/000180580. [DOI] [PubMed] [Google Scholar]
  • 28.U.S. Department of Health and Human Services. Food and Drug Administration: Guidance for Industry. Pharmacokinetics in Patients with Impaired Renal Function – Study Design, Data Analysis, and Impact on Dosing and Labeling. Rockville, MD: Food and Drug Administration, Center for Drug Evaluation and Research (CDER); 1998. . Available from URL: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072127.pdf. Accessed 10 November 2013. [Google Scholar]
  • 29.Workgroup on Hypoglycemia American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28:1245–1249. doi: 10.2337/diacare.28.5.1245. [DOI] [PubMed] [Google Scholar]
  • 30.Fravel MA, McDanel DL, Ross MB, Moores KG, Starry MJ. Special considerations for treatment of type 2 diabetes mellitus in the elderly. Am J Health Syst Pharm. 2011;68:500–509. doi: 10.2146/ajhp080085. [DOI] [PubMed] [Google Scholar]
  • 31.Barnett AH, Huisman H, Jones R, von Eynatten M, Patel S, Woerle HJ. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet. 382:1413–1423. doi: 10.1016/S0140-6736(13)61500-7. [DOI] [PubMed] [Google Scholar]
  • 32.Schernthaner G, Barnett AH, Emser A, et al. Safety and tolerability of linagliptin: a pooled analysis of data from randomized controlled trials in 3572 patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2013–2014;14:470–478. doi: 10.1111/j.1463-1326.2012.01565.x. [DOI] [PubMed] [Google Scholar]
  • 33.National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis. 2007;49:S12–S154. doi: 10.1053/j.ajkd.2006.12.005. [DOI] [PubMed] [Google Scholar]
  • 34.Nauck MA, Vilsbøll T, Gallwitz B, Garber A, Madsbad S. Incretin-based therapies: viewpoints on the way to consensus. Diabetes Care. 2009;32(Suppl. 2):S223–S231. doi: 10.2337/dc09-S315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Hermansen K, Kipnes M, Luo E, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733–745. doi: 10.1111/j.1463-1326.2007.00744.x. [DOI] [PubMed] [Google Scholar]
  • 36.Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64) Kidney Int. 2003;63:225–232. doi: 10.1046/j.1523-1755.2003.00712.x. [DOI] [PubMed] [Google Scholar]
  • 37.Heerspink HJ, Holtkamp FA, de Zeeuw D, Ravid M. Monitoring kidney function and albuminuria in patients with diabetes. Diabetes Care. 2011;34(Suppl. 2):S325–S329. doi: 10.2337/dc11-s247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Groop PH, Cooper ME, Perkovic V, Emser A, Woerle HJ, von Eynatten M. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care. 2013;36:3460–3468. doi: 10.2337/dc13-0323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care. 2011;34:1431–1437. doi: 10.2337/dc10-2361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Philbrick AM, Ernst ME, McDanel DL, Ross MB, Moores KG. Metformin use in renal dysfunction: is a serum creatinine threshold appropriate? Am J Health Syst Pharm. 2009;66:2017–2023. doi: 10.2146/ajhp080330. [DOI] [PubMed] [Google Scholar]
  • 41.Abe M, Okada K, Soma M. Antidiabetic agents in patients with chronic kidney disease and end-stage renal disease on dialysis: metabolism and clinical practice. Curr Drug Metab. 2011;12:57–69. doi: 10.2174/138920011794520053. [DOI] [PubMed] [Google Scholar]
  • 42.Chan JC, Scott R, Arjona Ferreira JC, et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab. 2008;10:545–555. doi: 10.1111/j.1463-1326.2008.00914.x. [DOI] [PubMed] [Google Scholar]
  • 43.Lukashevich V, Schweizer A, Shao Q, Groop PH, Kothny W. Safety and efficacy of vildagliptin versus placebo in patients with type 2 diabetes and moderate or severe renal impairment: a prospective 24-week randomized placebo-controlled trial. Diabetes Obes Metab. 2011;13:947–954. doi: 10.1111/j.1463-1326.2011.01467.x. [DOI] [PubMed] [Google Scholar]
  • 44.Nowicki M, Rychlik I, Haller H, et al. Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study. Int J Clin Pract. 2011;65:1230–1239. doi: 10.1111/j.1742-1241.2011.02812.x. [DOI] [PubMed] [Google Scholar]
  • 45.Nowicki M, Rychlik I, Haller H, Warren ML, Suchower L, Gause-Nilsson I. Saxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment. Diabetes Obes Metab. 2011;13:523–532. doi: 10.1111/j.1463-1326.2011.01382.x. [DOI] [PubMed] [Google Scholar]
  • 46.McGill J, Yki-Järvinen H, Emser A, von Eynatten M, Woerle HJ. Safety and efficacy of linagliptin in combination with insulin in patients with type 2 diabetes (T2D) and declining renal function. J Am Soc Nephrol. 2012;23:219A. [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Figure S1. Adjusted mean change from baseline in glycated haemoglobin (HbA1c) following treatment with linagliptin 5 mg or placebo after 24 weeks [full analysis set – last observation carried forward (FAS – LOCF)]. Model includes continuous baseline HbA1c, baseline body mass index (BMI) (category), washout period, treatment, study, age group, gender, time since diagnosis of diabetes, race, renal function (C–G) and treatment × renal function (C–G).

Figure S2. Subgroup analysis of placebo-corrected adjusted mean change in glycated haemoglobin (HbA1c) from baseline after 24 weeks in subjects with mild and moderate declining renal function [full analysis set – last observation carried forward (FAS – LOCF)]. *Subjects with mild or moderate declining renal function (C–G categorisation) at baseline were pooled in this analysis. †p-value for interaction between treatment and subgroup category. Model includes continuous baseline HbA1c, washout period, treatment, study, variable of interest and treatment × variable of interest.

Figure S3. Mean change in renal function estimated glomerular filtration rate (eGFR) over time in subjects treated with linagliptin 5 mg or placebo [full analysis set (FAS)]. Renal function according to C–G formula; normal, ≥80 ml/min; mild, 50–<80 ml/min; moderate, 30–<50 ml/min.

Table S1. Subject demographics and clinical characteristics at baseline full analysis set (FAS)*.

Table S2. Concomitant therapies at screening.

dom0016-0560-S1.doc (48.5KB, doc)

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