Characterization and implications of the initial estimated glomerular filtration rate 'dip' upon sodium-glucose cotransporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial.

Treatment with sodium-glucose co-transporter-2 inhibitors induces an initial 3-5 ml/min/1.73 m2 decline in estimated glomerular filtration rate (eGFR). Although considered to be of hemodynamic origin and largely reversible, this 'eGFR dip' may cause concern in clinical practice, which highlights the need to better understand its incidence and clinical implications. In this post hoc analysis of the EMPA-REG OUTCOME trial, 6,668 participants randomized to empagliflozin 10 mg, 25 mg or placebo with eGFR available at baseline and week four were categorized by initial eGFR change into three groups; over 10% decline ('eGFR dipper'), over 0 and up to 10% decline ('eGFR intermediate'), no eGFR decline ('eGFR non-dipper'). Baseline characteristics of 'eGFR intermediate' and 'eGFR non-dipper' were generally comparable. An initial 'eGFR dip' was observed in 28.3% of empagliflozin versus 13.4% of placebo-treated participants; odds ratio 2.7 [95% Confidence Interval 2.3-3.0]. In multivariate logistic regression, diuretic use and higher KDIGO risk category at baseline were independently predictive of an 'eGFR dip' in empagliflozin versus placebo. Safety and beneficial treatment effects with empagliflozin on cardiovascular and kidney outcomes were consistent across subgroups based on these predictive factors. The initial 'eGFR dip' did not have a major impact on the treatment effect of empagliflozin on subsequent cardiovascular death, hospitalization for heart failure, and incident or worsening kidney disease. Thus, patients with type 2 diabetes with more advanced kidney disease and/or on diuretic therapy were more likely to experience an 'eGFR dip' of over 10% with empagliflozin, but reduction in cardiovascular and kidney outcomes was not relevantly modified by such 'eGFR dip.'

Urinary dipeptidyl peptidase-4 protein is increased by linagliptin and is a potential predictive marker of urine albumin-to-creatinine ratio reduction in patients with type 2 diabetes.

Results of a post hoc analysis of urinary dipeptidyl peptidase-4 (DPP-4) protein as a predictor of urine albumin-to-creatinine ratio (UACR) response to linagliptin treatment based on MARLINA-T2D trial data are described. MARLINA was a 24-week, phase 3b, multinational, placebo-controlled clinical trial, in which patients with type 2 diabetes (T2D), HbA1c 6.5%-10.0% and UACR 30-3000 mg/g (n = 360) were treated with linagliptin or placebo. After 24 weeks of treatment, linagliptin significantly inhibited urinary DPP-4 activity and increased urinary DPP-4 protein. Furthermore, medium urinary DPP-4 protein levels (between 5.5 and 7.5 natural logarithmic [ln] µg/g creatinine) at baseline allowed for prediction of improved UACR in linagliptin-treated individuals. In patients with lower or higher levels of urinary DPP-4 protein at baseline, no association between linagliptin treatment and improved UACR was present. This might suggest a varying degree of importance of DPP-4 as a pathophysiological factor in T2D-associated kidney disease. In summary, urinary DPP-4 might be a useful predictive biomarker for UACR improvement by linagliptin.

Linagliptin Effects on Heart Failure and Related Outcomes in Individuals With Type 2 Diabetes Mellitus at High Cardiovascular and Renal Risk in CARMELINA.

BACKGROUND: Individuals with type 2 diabetes mellitus are at increased risk for heart failure (HF), particularly those with coexisting atherosclerotic cardiovascular disease and/or kidney disease. Some but not all dipeptidyl peptidase-4 inhibitors have been associated with increased HF risk. We performed secondary analyses of HF and related outcomes with the dipeptidyl peptidase-4 inhibitor linagliptin versus placebo in CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), a cardiovascular outcomes trial that enrolled participants with type 2 diabetes mellitus and atherosclerotic cardiovascular disease and/or kidney disease. METHODS: Participants in 27 countries with type 2 diabetes mellitus and concomitant atherosclerotic cardiovascular disease and/or kidney disease were randomized 1:1 to receive once daily oral linagliptin 5 mg or placebo, on top of standard of care. All hospitalization for HF (hHF), cardiovascular outcomes, and deaths were prospectively captured and centrally adjudicated. In prespecified and post hoc analyses of HF and related events, Cox proportional hazards models adjusting for region and baseline history of HF were used. Recurrent hHF events were analyzed using a negative binomial model. In a subset of participants with left ventricular ejection fraction captured within the year before randomization, HF-related outcomes were assessed in subgroups stratified by left ventricular ejection fraction > or ≤50%. RESULTS: CARMELINA enrolled 6979 participants (mean age, 65.9 years; estimated glomerular filtration rate, mL/min per 1.73m2; hemoglobin A1c, 8.0%; 62.9% men; diabetes mellitus duration, 14.8 years), including 1873 (26.8%) with a history of HF at baseline. Median follow-up was 2.2 years. Linagliptin versus placebo did not affect the incidence of hHF (209/3494 [6.0%] versus 226/3485 [6.5%], respectively; hazard ratio [HR], 0.90; 95% CI, 0.74-1.08), the composite of cardiovascular death/hHF (HR, 0.94; 95% CI, 0.82-1.08), or risk for recurrent hHF events (326 versus 359 events, respectively; rate ratio, 0.94; 95% CI, 0.75-1.20). There was no heterogeneity of linagliptin effects on hHF by history of HF at baseline, baseline estimated glomerular filtration rate or urine albumin-creatinine ratio, or prerandomization left ventricular ejection fraction. CONCLUSIONS: In a large, international cardiovascular outcome trial in participants with type 2 diabetes mellitus and concomitant atherosclerotic cardiovascular disease and/or kidney disease, linagliptin did not affect the risk of hHF or other selected HF-related outcomes, including among participants with and without a history of HF, across the spectrum of kidney disease, and independent of previous left ventricular ejection fraction. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01897532.

Choice of endpoint in kidney outcome trials: considerations from the EMPA-REG OUTCOME® trial.

BACKGROUND: Doubling of serum creatinine [equivalent to 57% reduction in estimated glomerular filtration rate (eGFR)] is an established surrogate for end-stage kidney disease (ESKD); however, this endpoint necessitates lengthy follow-up and large sample sizes in clinical trials. We explored whether alternative eGFR decline thresholds provide more feasible surrogate kidney endpoints. METHODS: The study involved post hoc analysis of the EMPA-REG OUTCOME® trial. Adults with type 2 diabetes, high cardiovascular risk and eGFR ≥30 mL/min/1.73 m2 were assigned empagliflozin 10 mg or 25 mg (n = 4687) or placebo (n = 2333), on top of standard of care. We assessed composite endpoints incorporating different eGFR decline thresholds (≥30, ≥40, ≥50 or ≥57%) combined with initiation of renal replacement therapy (RRT) or renal death. This trial is registered with ClinicalTrials.gov (NCT01131676). RESULTS: Empagliflozin versus placebo significantly lowered the risk of decline in eGFR for each threshold listed above, combined with initiation of RRT or renal death, ranging from a hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.72-0.91] for endpoints based on 30% eGFR decline to an HR of 0.37 (0.23-0.61) for endpoints based on 57% eGFR decline. Lower thresholds (e.g. 30%) were associated with higher event rates but weaker treatment effects. The time to the 95% CI of the HR falling to <1.0 decreased with increasing eGFR threshold. CONCLUSIONS: The composite of 40% decline in eGFR, ESKD or renal death appears to provide reliable results similar to the traditional 57% decline in eGFR.

Consistent effects of empagliflozin on cardiovascular and kidney outcomes irrespective of diabetic kidney disease categories: Insights from the EMPA-REG OUTCOME trial.

AIM: To explore the cardiovascular (CV) and kidney effects of empagliflozin in patients with different clinical phenotypes of diabetic kidney disease (DKD) (i.e. with the presence or absence of overt albuminuria) participating in the EMPA-REG OUTCOME trial. MATERIALS AND METHODS: EMPA-REG OUTCOME randomized participants (1:1:1) to empagliflozin 10 mg, 25 mg or placebo, added to standard of care. Post hoc, patients with different clinical phenotypes of DKD at baseline were categorized in three subgroups: (a) overt DKD (overt albuminuria [urinary albumin-to-creatinine ratio of >300 mg/g] with any estimated glomerular filtration rate [eGFR]; n = 769); (b) non-overt DKD (kidney impairment [eGFR < 60 mL/min/1.73 m2 ] without overt albuminuria [urinary albumin-to-creatinine ratio of ≤300 mg/g]; n = 1290); and (c) 'all others' (eGFR ≥ 60 mL/min/1.73 m2 without overt albuminuria; n = 4893). Analyses included CV (death, hospitalization for heart failure, all-cause hospitalization) and selected kidney outcomes, change in eGFR and kidney safety. Cox proportional hazards models assessed the consistency of treatment effect across subgroups. RESULTS: Empagliflozin significantly reduced the risk of CV and kidney outcomes across all subgroups (P-values for interaction >.05), consistent with the overall trial population findings. Empagliflozin also significantly reduced the yearly loss of eGFR, assessed by chronic slopes, in all subgroups. The adverse event profile of empagliflozin was similar across all subgroups. CONCLUSIONS: Empagliflozin may improve CV and kidney outcomes and slow the progression of kidney disease in type 2 diabetes patients with DKD, irrespective of its clinical form, both with or without the presence of overt albuminuria.

Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease.

BACKGROUND: Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus and established cardiovascular disease in the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Urinary glucose excretion with empagliflozin decreases with declining renal function, resulting in less potency for glucose lowering in patients with kidney disease. We investigated the effects of empagliflozin on clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. METHODS: Patients with type 2 diabetes mellitus, established cardiovascular disease, and estimated glomerular filtration rate (eGFR) ≥30 mL·min-1·1.73 m-2 at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. We analyzed cardiovascular death, hospitalization for heart failure, all-cause hospitalization, and all-cause mortality in patients with prevalent kidney disease (defined as eGFR <60 mL·min-1·1.73 m-2 and/or urine albumin-creatinine ratio >300 mg/g) at baseline. Additional analyses were performed in subgroups by baseline eGFR (<45, 45-<60, 60-<90, ≥90 mL·min-1·1.73 m-2) and baseline urine albumin-creatinine ratio (>300, 30-≤300, <30 mg/g). RESULTS: Of 7020 patients treated, 2250 patients had prevalent kidney disease at baseline, of whom 67% had a diagnosis of type 2 diabetes mellitus for >10 years, 58% were receiving insulin, and 84% were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In patients with prevalent kidney disease at baseline, empagliflozin reduced the risk of cardiovascular death by 29% compared with placebo (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52-0.98), the risk of all-cause mortality by 24% (HR, 0.76; 95% CI, 0.59-0.99), the risk of hospitalization for heart failure by 39% (HR, 0.61; 95% CI, 0.42-0.87), and the risk of all-cause hospitalization by 19% (HR, 0.81; 95% CI, 0.72-0.92). Effects of empagliflozin on these outcomes were consistent across categories of eGFR and urine albumin-creatinine ratio at baseline and across the 2 doses studied. The adverse event profile of empagliflozin in patients with eGFR <60 mL·min-1·1.73 m-2 was consistent with the overall trial population. CONCLUSIONS: Empagliflozin improved clinical outcomes and reduced mortality in vulnerable patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01131676.

Analysis from the EMPA-REG OUTCOME® trial indicates empagliflozin may assist in preventing the progression of chronic kidney disease in patients with type 2 diabetes irrespective of medications that alter intrarenal hemodynamics.

In patients with type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease, empagliflozin (EMPA) decreased progression of chronic kidney disease (CKD), likely via a reduction in intraglomerular pressure. Due to prevalent comorbidities, such as hypertension and albuminuria, patients often receive other agents that alter intrarenal hemodynamics, including angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs), calcium channel blockers (CCBs) and diuretics. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used by some individuals. In this exploratory, non-prespecified analysis, we investigated whether the kidney benefits of EMPA are altered in individuals already using the medications in these categories. In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME®) trial, 7020 patients were essentially equally randomized to EMPA 10 mg, 25 mg or placebo added to their standard care. Differences in risk of incident or worsening nephropathy for pooled EMPA vs placebo across subgroups by baseline background medications (to which patients were not randomized) were assessed using a Cox proportional hazards model. Risk reductions in incident or worsening nephropathy with EMPA were consistent across medication subgroups, with no heterogeneity of treatment effect. As a representative example, the risk for acute renal failure was overall slightly increased in patients using ACEi/ARBs in all groups (placebo, EMPA 10 mg or EMPA 25 mg) but incidence rates were numerically lower in those assigned to EMPA. Similar patterns were observed for other medications included in this analysis. Thus, EMPA may assist to prevent CKD progression in patients with T2DM with CV disease, irrespective of common background medications that alter intrarenal hemodynamics, and without increasing acute renal adverse events.

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes.

BACKGROUND: Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial. METHODS: We randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m(2) of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria. RESULTS: Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61; 95% confidence interval, 0.53 to 0.70; P<0.001). Doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the empagliflozin group and in 60 of 2323 (2.6%) in the placebo group, a significant relative risk reduction of 44%. Renal-replacement therapy was initiated in 13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group, representing a 55% lower relative risk in the empagliflozin group. There was no significant between-group difference in the rate of incident albuminuria. The adverse-event profile of empagliflozin in patients with impaired kidney function at baseline was similar to that reported in the overall trial population. CONCLUSIONS: In patients with type 2 diabetes at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care. (Funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).

Efficacy and safety of linagliptin to improve glucose control in older people with type 2 diabetes on stable insulin therapy: A randomized trial.

AIM: To assess the addition of linagliptin as an alternative to insulin uptitration in older people with type 2 diabetes on stable insulin therapy. MATERIALS AND METHODS: This phase 4, randomized, multicentre, double-blinded, placebo-controlled, 24-week study recruited individuals on stable insulin, with baseline HbA1c 7.0%-10.0%, aged ≥60 years and body mass index ≤45 kg/m2 . HbA1c and fasting plasma glucose were measured at study visits, and participants assessed glycaemic control with a self-monitoring blood glucose device. Adverse events (AEs) were reported during the study. RESULTS: Three hundred and two participants were randomized 1:1 to linagliptin 5 mg qd and placebo, with one third of patients from Japan. Study population age and HbA1c (baseline mean ± SD) were 72.4 ± 5.4 years and 8.2 ± 0.8%, respectively; ~80% of participants were aged ≥70 years; 80% had macrovascular complications, one third had a baseline estimated glomerular filtration rate <60 mL/min/1.73 m2 ; and half had been diagnosed with diabetes for >15 years. Linagliptin significantly improved glucose control at 24 weeks (HbA1c-adjusted mean change vs. placebo: -0.63%; P <0.0001) and the probability of achieving predefined HbA1c targets without hypoglycaemia (HbA1c <8.0%: OR 2.02; P <0.05 and HbA1c <7.0%: OR 2.44; P <0.01). Linagliptin versus placebo was well tolerated, with similar incidences of AEs, including clinically important hypoglycaemia (blood glucose <54 mg/dL) or severe hypoglycaemia. CONCLUSIONS: Addition of linagliptin improves glucose control without an excess of hypoglycaemia in older patients with type 2 diabetes on stable insulin therapy.

Empagliflozin and Kidney Function Decline in Patients with Type 2 Diabetes: A Slope Analysis from the EMPA-REG OUTCOME Trial.

BACKGROUND: Empagliflozin slowed the progression of CKD in patients with type 2 diabetes and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes. METHODS: Participants (n=7020) were randomized (1:1:1) to empagliflozin 10 mg/d, empagliflozin 25 mg/d, or placebo added to standard of care. We calculated eGFR slopes using random-intercept/random-coefficient models for prespecified study periods: treatment initiation (baseline to week 4), chronic maintenance treatment (week 4 to last value on treatment), and post-treatment (last value on treatment to follow-up). RESULTS: Compared with placebo, empagliflozin was associated with uniform shifts in individual eGFR slopes across all periods. On treatment initiation, adjusted mean slope (eGFR change per week, ml/min per 1.73 m2) decreased with empagliflozin (-0.77; 95% confidence interval, -0.83 to -0.71; placebo: 0.01; 95% confidence interval, -0.08 to 0.10; P<0.001). However, annual mean slope (ml/min per 1.73 m2 per year) did not decline with empagliflozin during chronic treatment (empagliflozin: 0.23; 95% confidence interval, 0.05 to 0.40; placebo: -1.46; 95% confidence interval, -1.74 to -1.17; P<0.001). After drug cessation, the adjusted mean eGFR slope (ml/min per 1.73 m2 per week) increased and mean eGFR returned toward baseline level only in the empagliflozin group (0.56; 95% confidence interval, 0.49 to 0.62; placebo -0.02; 95% confidence interval, -0.12 to 0.08; P<0.001). Results were consistent across patient subgroups at higher CKD risk. CONCLUSIONS: The hemodynamic effects of empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function.

Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial.

IMPORTANCE: Type 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator. OBJECTIVE: This trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5% to 8.5%, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August 2018. INTERVENTIONS: Patients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need. MAIN OUTCOMES AND MEASURES: The primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3. RESULTS: Of 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P < .001 for noninferiority), meeting the noninferiority criterion but not superiority (P = .76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]). CONCLUSIONS AND RELEVANCE: Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01243424.

Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial.

Importance: Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease. Objective: To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events. Design, Setting, and Participants: Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A1c of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/g), and high renal risk (reduced eGFR and micro- or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018. Interventions: Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines. Main Outcomes and Measures: Primary outcome was time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline. Results: Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73 m2; 80.1% with UACR >30 mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI, -0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P < .001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4%) and 306 of 3485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, -0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P = .62). Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis. Conclusions and Relevance: Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT01897532.

Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk.

BACKGROUND: Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA® trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. METHODS: CARMELINA® is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, ≥ 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA® was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided α-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure. RESULTS: Between July 2013 and August 2016, 6980 patients were randomized and took ≥ 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean ± SD age was 65.8 ± 9.1 years, HbA1c 7.9 ± 1.0%, BMI 31.3 ± 5.3 kg/m2, and eGFR 55 ± 25 mL/min/1.73 m2. A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m2 or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common. CONCLUSIONS: CARMELINA® will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk. Trial registration ClinicalTrials.gov identifier-NCT01897532; registered July 9, 2013.

A randomised, active- and placebo-controlled, three-period crossover trial to investigate short-term effects of the dipeptidyl peptidase-4 inhibitor linagliptin on macro- and microvascular endothelial function in type 2 diabetes.

BACKGROUND: Studies of dipeptidyl peptidase (DPP)-4 inhibitors report heterogeneous effects on endothelial function in patients with type 2 diabetes (T2D). This study assessed the effects of the DPP-4 inhibitor linagliptin versus the sulphonylurea glimepiride and placebo on measures of macro- and microvascular endothelial function in patients with T2D who represented a primary cardiovascular disease prevention population. METHODS: This crossover study randomised T2D patients (n = 42) with glycated haemoglobin (HbA1c) ≤7.5%, no diagnosed macro- or microvascular disease and on stable metformin background to linagliptin 5 mg qd, glimepiride 1-4 mg qd or placebo for 28 days. Fasting and postprandial macrovascular endothelial function, measured using brachial flow-mediated vasodilation, and microvascular function, measured using laser-Doppler on the dorsal thenar site of the right hand, were analysed after 28 days. RESULTS: Baseline mean (standard deviation) age, body mass index and HbA1c were 60.3 (6.0) years, 30.3 (3.0) kg/m2 and 7.41 (0.61)%, respectively. After 28 days, changes in fasting flow-mediated vasodilation were similar between the three study arms (treatment ratio, gMean [90% confidence interval]: linagliptin vs glimepiride, 0.884 [0.633-1.235]; linagliptin vs placebo, 0.884 [0.632-1.235]; glimepiride vs placebo, 1.000 [0.715-1.397]; P = not significant for all comparisons). Similarly, no differences were seen in postprandial flow-mediated vasodilation. However, under fasting conditions, linagliptin significantly improved microvascular function as shown by a 34% increase in hyperaemia area (P = 0.045 vs glimepiride), a 34% increase in resting blow flow (P = 0.011 vs glimepiride, P = 0.003 vs placebo), and a 25% increase in peak blood flow (P = 0.009 vs glimepiride, P = 0.003 vs placebo). There were no significant differences between treatments in postprandial changes. Linagliptin had no effect on heart rate or blood pressure. Rates of overall adverse events with linagliptin, glimepiride and placebo were 27.5, 61.0 and 35.0%, respectively. Fewer hypoglycaemic events were seen with linagliptin (5.0%) and placebo (2.5%) than with glimepiride (39.0%). CONCLUSIONS: Linagliptin had no effect on macrovascular function in T2D, but significantly improved microvascular function in the fasting state. Trial registration ClinicalTrials.gov identifier-NCT01703286; registered October 1, 2012.

Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA-T2D trial.

AIMS: The MARLINA-T2D study (ClinicalTrials.gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria. METHODS: A total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48-86 mmol/mol), estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 30-3000 mg/g despite single agent renin-angiotensin-system blockade were randomized to double-blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively. RESULTS: Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8% ± 0.9% (62.2 ± 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was -0.60% (-6.6 mmol/mol) (95% confidence interval [CI], -0.78 to -0.43 [-8.5 to -4.7 mmol/mol]; P < .0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was -6.0% (95% CI, -15.0 to 3.0; P = .1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups. CONCLUSIONS: In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics.

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Sodium glucose cotransporter 2 (SGLT2) inhibition lowers HbA1c, systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension. As lowering HbA1c, SBP, weight and intraglomerular pressure is associated with anti-albuminuric effects in diabetes, we hypothesised that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent. METHODS: We examined the effect of the SGLT2 inhibitor empagliflozin on UACR by pooling data from patients with type 2 diabetes and prevalent microalbuminuria (UACR = 30-300 mg/g; n = 636) or macroalbuminuria (UACR > 300 mg/g; n = 215) who participated in one of five phase III randomised clinical trials. Primary assessment was defined as percentage change in geometric mean UACR from baseline to week 24. RESULTS: After controlling for clinical confounders including baseline log-transformed UACR, HbA1c, SBP and estimated GFR (according to the Modification of Diet in Renal Disease [MDRD] formula), treatment with empagliflozin significantly reduced UACR in patients with microalbuminuria (-32% vs placebo; p < 0.001) or macroalbuminuria (-41% vs placebo; p < 0.001). Intriguingly, in regression models, most of the UACR-lowering effect with empagliflozin was not explained by SGLT2 inhibition-related improvements in HbA1c, SBP or weight. CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes and either micro- or macroalbuminuria, empagliflozin reduced UACR by a clinically meaningful amount. This effect was largely independent of the known metabolic or systemic haemodynamic effects of this drug class. Our results further support a direct renal effect of SGLT2 inhibitors. Prospective studies are needed to explore the potential of this intervention to alter the course of kidney disease in high-risk patients with diabetes. TRIAL REGISTRATION: Clinicaltrials.gov NCT01177813 (study 1); NCT01159600 (study 2); NCT01159600 (study 3); NCT01210001 (study 4); and NCT01164501 (study 5).

Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus.

BACKGROUND: The primary objective of this mechanistic open-label, stratified clinical trial was to determine the effect of 8 weeks' sodium glucose cotransporter 2 inhibition with empagliflozin 25 mg QD on renal hyperfiltration in subjects with type 1 diabetes mellitus (T1D). METHODS AND RESULTS: Inulin (glomerular filtration rate; GFR) and paraaminohippurate (effective renal plasma flow) clearances were measured in individuals stratified based on having hyperfiltration (T1D-H, GFR ≥ 135 mL/min/1.73m(2), n=27) or normal GFR (T1D-N, GFR 90-134 mL/min/1.73m(2), n=13) at baseline. Renal function and circulating levels of renin-angiotensin-aldosterone system mediators and NO were measured under clamped euglycemic (4-6 mmol/L) and hyperglycemic (9-11 mmol/L) conditions at baseline and end of treatment. During clamped euglycemia, hyperfiltration was attenuated by -33 mL/min/1.73m(2) with empagliflozin in T1D-H, (GFR 172±23-139±25 mL/min/1.73 m(2), P<0.01). This effect was accompanied by declines in plasma NO and effective renal plasma flow and an increase in renal vascular resistance (all P<0.01). Similar significant effects on GFR and renal function parameters were observed during clamped hyperglycemia. In T1D-N, GFR, other renal function parameters, and plasma NO were not altered by empagliflozin. Empagliflozin reduced hemoglobin A1c significantly in both groups, despite lower insulin doses in each group (P≤0.04). CONCLUSIONS: In conclusion, short-term treatment with the sodium glucose cotransporter 2 inhibitor empagliflozin attenuated renal hyperfiltration in subjects with T1D, likely by affecting tubular-glomerular feedback mechanisms. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01392560.

Kidney Disease End Points in a Pooled Analysis of Individual Patient-Level Data From a Large Clinical Trials Program of the Dipeptidyl Peptidase 4 Inhibitor Linagliptin in Type 2 Diabetes.

BACKGROUND: Although assessment of cardiovascular safety is mandated by regulatory agencies for the development of new drugs to treat type 2 diabetes, evaluation of their renal safety has been relatively neglected. STUDY DESIGN: Individual patient-level data pooled analysis of 13 phase 2 or 3 randomized, double-blind, placebo-controlled, clinical trials of the dipeptidyl peptidase 4 inhibitor linagliptin. SETTING & PARTICIPANTS: Participants who participated in any of 13 randomized clinical trials and fulfilled predefined inclusion/exclusion criteria, such as being drug-naive (hemoglobin A1c, 7.0%-11.0% [53-97 mmol/mol]) or being on background glucose-lowering therapy (hemoglobin A1c, 6.5%-10.5% [48-91 mmol/mol]). INTERVENTION: Of 5,466 consenting individuals with inadequately controlled type 2 diabetes, 3,505 received linagliptin, 5mg/d, and 1,961 received placebo. OUTCOMES: The primary kidney disease outcome was defined as first occurrence during the study of 6 predefined safety end points: new onset of moderate elevation of albuminuria (urinary albumin-creatinine ratio [ACR] >30 mg/g with baseline values ≤ 30 mg/g), new onset of severe elevation of albuminuria (ACR > 300 mg/g with baseline values ≤ 300 mg/g), reduction in kidney function (serum creatinine increase to ≥250 µmol/L from a baseline value <250 µmol/L), halving of estimated glomerular filtration rate (loss of baseline eGFR >50%), acute renal failure (ascertained from diagnostic codes), or death from any cause. MEASUREMENTS: Albuminuria was assessed using ACR. GFR was estimated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. RESULTS: Cumulative exposure (person-years) was 1,751 for linagliptin and 1,055 for placebo. The primary composite outcome occurred in 448 (12.8%) and 306 (15.6%) participants in the linagliptin and placebo groups, respectively. Linagliptin treatment significantly reduced the hazard of kidney disease events by 16% compared with placebo (HR, 0.84; 95% CI, 0.72-0.97; P=0.02). LIMITATIONS: Retrospective and hypothesis-generating study involving short- to midterm clinical trials. CONCLUSIONS: Linagliptin was not associated with increased kidney disease risk in patients with type 2 diabetes. The potential of this drug to improve kidney disease outcomes warrants further investigation.