Linagliptin in patients with type 2 diabetes and cardiovascular and/or renal disease: results from a cardiovascular and renal outcomes trial

ABSTRACT

Review of:

Rosenstock J, Perkovic V, Johansen, OE, et al. 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. JAMA. 2019;321:69–79.

McGuire DK, Alexander JH, Johansen OE, et al. Linagliptin effects on heart failure and related outcomes in individuals with type 2 diabetes mellitus at high cardiovascular and renal risk in CARMELINA. Circulation. 2019;139:351–361.

These two papers describe the findings from the CARMELINA trial (Cardiovascular and Renal Microvascular Outcome Study with Linagliptin): the first paper reported results for the primary cardiovascular composite outcome (cardiovascular [CV] death, nonfatal myocardial infarction [MI], or nonfatal stroke; 3-point major adverse cardiovascular event [3P-MACE]) and the key secondary renal composite outcome (renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline); the second paper reported secondary analyses of heart failure (HF) and related outcomes. The CARMELINA trial was a randomized, placebo-controlled, multicenter non-inferiority trial of adults with type 2 diabetes mellitus (T2DM) and elevated CV and renal risk. After a median 2.2-year follow-up of 6979 participants, patients allocated to linagliptin demonstrated no increase in the risk of 3P-MACE versus placebo: hazard ratio (HR) 1.02 [95% confidence interval (CI) 0.89–1.17]; P < 0.001 for non-inferiority. There was also no increase in the risk of hospitalization for HF for linagliptin versus placebo (HR 0.90 [0.74–1.08]). There was no increased risk of progression to end-stage kidney disease or death due to kidney disease (HR 0.87 [0.69–1.10]). Additionally, progression of albuminuria occurred less frequently in patients who received linagliptin versus placebo (HR 0.86 [0.78–0.95]). Overall, no new safety findings were identified for linagliptin, and no increased risk of hypoglycemia was observed for linagliptin versus placebo. Together, these findings from the CARMELINA trial reaffirm treatment guidelines for choosing additional therapies for patients with T2DM at elevated CV and/or renal risk, and provide new information on the role of linagliptin in the management of T2DM.

KEYWORDS:

• Type 2 diabetes mellitus
• linagliptin
• cardiovascular events
• heart failure
• renal events

History of condition

Cardiovascular disease (CVD) and chronic kidney disease (CKD) are leading causes of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM) [1,2]. In 2017, 16% (N ≈ 111,000) of cardiovascular (CV)-related deaths were estimated to be attributable to T2DM [3]. Individuals with T2DM are also at increased risk of hospitalization due to heart failure (HF) [4,5]. In the United States, about one-third of adults with diagnosed diabetes also had CKD (stages 1–4) [6]. The presence of CKD in patients with T2DM is associated with an increased risk of both all-cause and CV mortality. The CV safety of glucose-lowering therapies has become an important consideration and, more than 10 years ago, the US Food and Drug Administration (FDA) mandated that CV risk be evaluated during the development of treatments for T2DM. Since then, CV outcomes trials (CVOTs) have been designed to evaluate the effect of glucose-lowering therapies on major adverse cardiovascular events (MACE). Additional trials in patients with HF or CKD have also commenced. In response to data from recent CVOTs, selection of pharmacologic agents for patients with T2DM has evolved, and now includes consideration of atherosclerotic CVD (ASCVD), HF, and CKD [7].

Historically, the first several CVOTs of dipeptidyl peptidase-4 (DPP-4) inhibitors demonstrated a neutral effect on MACE and discrepant results on HF outcomes (Table 1). The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial [8], the Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care (EXAMINE) [9] trial, and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) [10] demonstrated that, compared with placebo, the addition of saxagliptin, alogliptin and sitagliptin, respectively, neither increased nor decreased the event rate for the primary composite endpoint (defined as CV death, nonfatal stroke, or nonfatal myocardial infarction [MI] in SAVOR-TIMI 53 and EXAMINE; and as CV death, stroke, MI, or hospitalization for unstable angina in TECOS) in patients with T2DM and high baseline risk for CV events. In SAVOR-TIMI 53 [8], the addition of saxagliptin to existing therapy had a neutral effect on individual components of the primary composite endpoint versus placebo; however, this treatment was associated with a significantly increased risk of HF-related hospital admissions.Consequently, the effect of DPP-4 inhibitors on HF risk in patients with T2DM has been further evaluated in patients with T2DM, and trials of alogliptin, sitagliptin, and vildagliptin did not demonstrate similar results [11]. CVOTs have also been conducted with the selective DPP-4 inhibitor, linagliptin, to further examine its efficacy and safety in high-risk populations. One such trial was CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study with Linagliptin, NCT01897532), a randomized, double-blind, placebo-controlled CVOT of linagliptin in individuals with T2DM and at elevated risk of CV and renal events [12–14]. Unlike previously conducted CVOTs, where a limited number of participants had renal impairment (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m²) at baseline, 74% of participants in CARMELINA had prevalent CKD [14]. A further linagliptin CVOT, CAROLINA (The Cardiovascular Outcome Trial of Linagliptin versus Glimepiride in Type 2 Diabetes) included patients with T2DM and elevated CV risk, but used an active comparator rather than a placebo. CAROLINA was the first and largest randomized, double-blind CVOT to provide a head-to-head comparison of a DPP-4 inhibitor with another class of glucose-lowering agent (glimepiride, a sulfonylurea) [15,16].

Table 1. Summary of CVOTs of DPP4 inhibitors in patients with T2DM.

CVOT	Comparators	Participants randomized (N)	Characteristics of study population	Median duration of follow up (years)	Primary outcomes	CV outcomes	HF outcomes	Kidney outcomes
SAVOR-TIMI 53 [8]	Saxagliptin versus placebo	16,492	History of or at risk for CV events	2.1	CV death, MI, or stroke	No increased risk of ischemic events	Increased risk of HHF with saxagliptin (HR 1.27; 95% CI, 1.07 to 1.51)	Not designed to study kidney outcomes
EXAMINE [9,34]	Alogliptin versus placebo	5,380	Recent acute coronary syndrome	1.5	CV death, MI, or stroke	No increased risk of MACE	No significant difference (HR 1.07; 95% CI, 0.79 to 1.46)	Not designed to study kidney outcomes
TECOS [10]	Sitagliptin versus placebo	14,671	Existing CVD	3.0	CV death, MI, UA, or stroke	No increased risk of MACE	No increase in risk of HHF	Not designed to study kidney outcomes
CAROLINA [16]	Linagliptin versus glimepiride	6,042	Early T2DM and risk factors for or established atherosclerotic disease	6.3	CV death, MI, or stroke	No increase in risk of composite CV outcome	No significant difference (HR 0.90; 95% CI, 0.74 to 1.08)	Not designed to study kidney outcomes
CARMELINA [12,13]	Linagliptin versus placebo	6,979	High risk of CV and kidney events	2.2	CV death, MI, or stroke	No increase in risk of composite CV outcome	No increase in risk of HHF	No increased risk of composite kidney endpoint*; significant reduction in albuminuria progression

*Composite kidney endpoint of time to first occurrence of sustained end-stage kidney disease, renal death (adjudicated death due to kidney disease), or a sustained decrease of ≥40% in estimated glomerular filtration rate from baseline.

CI, confidence interval; CV, cardiovascular, CVD, cardiovascular disease, T2DM, type 2 diabetes mellitus, HF, heart failure, HHF, hospitalization for heart failure; HR, hazard ratio; MACE, major adverse cardiovascular events;

MI, myocardial infarction; UA, unstable angina.

Objectives

Recently, two papers have been published describing the findings from the CARMELINA trial [12,13]. The first paper reported results for the primary MACE composite outcome (CV death, nonfatal MI, or nonfatal stroke; 3-point [3P]-MACE) and the key secondary renal composite outcome. The second paper reported secondary analyses of HF and related outcomes [12]. This article summarizes the findings of these two CARMELINA reports, highlighting the clinical importance of these evaluations in the context of current research and clinical practice guidelines. This is important new evidence that can help to inform evidence-based decision-making in clinical practice and further define the role of linagliptin in T2DM treatment regimens.

Research design and outcomes

CARMELINA has been described previously [14]. Briefly, the trial was a randomized, placebo-controlled, multicenter non-inferiority trial performed in 27 countries among adults with T2DM, glycated hemoglobin (HbA1 c) 6.5%–10.0%, body mass index ≤45 kg/m², and elevated CV and renal risk [13,14]. The study was designed to evaluate the effect of linagliptin versus placebo on CV and renal outcomes in a population of patients with T2DM at high macrovascular CV risk and renal microvascular risk (history of vascular disease and urine albumin-to-creatinine ratio [UACR] ≥30 mg/g) and/or elevated renal risk (eGFR <45 ml/min/1.73 m² regardless of UACR, or eGFR ≥45–75 ml/min/1.73 m² and UACR >200 mg/g). Participants were randomized to receive linagliptin or matching placebo in addition to standard of care, which included treatment for CV risk factors, in accordance with local or regional standards. Standard care could include additional glucose-lowering therapy; participants were either drug-naïve or receiving any glucose-lowering therapy except glucagon-like peptide-1 (GLP-1) receptor agonists, DPP-4 inhibitors, and/or sodium-glucose co-transporter 2 (SGLT2) inhibitors. Major exclusion criteria included individuals with acute coronary syndrome (≤2 months before screening), patients with stroke or transient ischemic attack (≤3 months before screening), and individuals scheduled to have percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG), or previous PCI and/or CABG (≤2 months before screening) [14]. Individuals with end-stage kidney disease (eGFR <15 ml/min/1.73 m²) and/or receiving maintenance dialysis were also excluded.

The primary endpoint was the time to first occurrence of the CV composite outcome of 3P-MACE (CV death, nonfatal MI, or nonfatal stroke). The key secondary endpoint was time to first occurrence of a renal composite outcome of renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline [14].

Findings

A total of 6991 participants were randomized in CARMELINA, 6979 of whom received at least one dose of study medication (mean age, 65.9 years; mean eGFR, 54.6 ml/min/1.73 m²; UACR >30 mg/g, 80.1%; mean duration of T2DM, 14.7 years); 98.7% of patients completed the study. At baseline, more than half of patients received background insulin therapy (57.9%), a similar proportion received metformin (54.8%), and around a third received sulfonylurea (34.9%) [14]. Approximately 40% of patients were receiving two glucose-lowering therapies at baseline, and around 5% were receiving three background glucose-lowering therapies [13]. At baseline, 57% of patients had established CVD, 74% had prevalent kidney disease (defined as eGFR <60 ml/min/1.73 m² and/or UACR >300 mg/g creatinine), 33% had both CV and kidney disease, and 15.2% had stage 4 CKD (eGFR <30 ml/min/1.73 m²) [14]. Furthermore, 26.8% had a history of HF at baseline [12].

During a median follow-up of 2.2 years, patients allocated to linagliptin demonstrated no increase in the risk of 3P-MACE versus placebo: hazard ratio (HR) 1.02 [95% confidence interval (CI) 0.89–1.17]; P < 0.001 for non-inferiority, with no difference between linagliptin and placebo for any of the MACE endpoints (CV death, nonfatal MI, or nonfatal stroke). Additionally, linagliptin did not increase the risk of all-cause mortality (HR 0.98 [0.84–1.13]) or the risk of non-CV death (HR 1.02 [0.78–1.33]) in this high-risk patient population [13]. There was also no increase in the risk of hospitalization for HF for linagliptin versus placebo (HR 0.90 [0.74–1.08]), regardless of history of HF or kidney disease at baseline [12]. The relatively high event rate for hospitalization for HF (209 events [6.0%] linagliptin, 226 events [6.5%] placebo) [13] is consistent with the high-risk population enrolled in the trial. The CV safety of linagliptin was demonstrated across patient subgroups.

With regard to renal outcomes, CARMELINA demonstrated the long-term renal safety of linagliptin across all subgroups [13]. There was no increased risk of death due to kidney disease, progression to end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline among patients receiving linagliptin compared with placebo (HR 1.04 [0.89–1.22]). These results were consistent across subgroups by age, region, systolic blood pressure, eGFR, and UACR categories. There was also no increased risk of progression to end-stage kidney disease or death due to kidney disease (HR 0.87 [0.69–1.10]). Additionally, progression of albuminuria (i.e. change from normoalbuminuria to micro-/macroalbuminuria, or change from microalbuminuria to macroalbuminuria) occurred less frequently in the linagliptin than in the placebo group (HR 0.86 [0.78–0.95]) [13].

As a CV safety study, CARMELINA – like other CVOTs – was designed to have similar glycemic control between treatment groups. For this reason, investigators blinded to treatment allocation were encouraged to use additional glucose-lowering therapies for patients with insufficient glycemic control. Nevertheless, an analysis of glycemic outcomes after 12 weeks of treatment showed an adjusted mean difference in HbA1c favoring linagliptin over placebo of −0.51% (95% CI, −0.55% to −0.46%), with an overall difference over the full study duration of −0.36% (95% CI, −0.42% to −0.29% based on least-square means), with no increase in the occurrence of hypoglycemia. This modest change in HbA1 c was observed in patients with a relatively high baseline HbA1c of 8%, which is as expected since patients with kidney impairment commonly have long-term hyperglycemia. This is likely to be related, at least in part, to the limited choice of glucose-lowering treatments for these patients. The modest HbA1c reductions observed with linagliptin are, therefore, important for patients with established kidney disease for whom many glucose-lowering therapies are contraindicated or associated with an increased risk of adverse events, such as hypoglycemia. In global phase 3 trials, linagliptin was associated with HbA1 c reductions of 0.51%–0.69% when given as monotherapy or in addition to pioglitazone, metformin, or metformin and sulfonylurea [17–20].

Overall, no new safety findings were identified for linagliptin in the CARMELINA trial [13]. Importantly, rates of hypoglycemia were low, and no increased risk of hypoglycemia was observed for linagliptin compared with placebo. Although there was a numerically higher rate of hypoglycemia with linagliptin versus placebo in patients receiving sulfonylurea at baseline, no increased risk was observed in patients with eGFR <45 ml/min/1.73 m² and in those receiving insulin. Among the adverse events (AEs) pre-specified as being of special interest, numerical increases with linagliptin versus placebo were observed for adjudication-confirmed acute pancreatitis events (9 [0.3%] vs 5 [0.1%]), but not for chronic pancreatitis events (2 [0.1%] vs 3 [0.1%]). There was also a numerical increase in pancreatic cancer with linagliptin (n = 11 [0.3%] versus placebo (n = 4 [0.1%]); although, overall cancer cases were similar across treatment arms. These AE findings were consistent with data from previous trials [13]. While a safety signal for pancreatitis has been suggested for DPP-4 inhibitors in recent CVOTs, the small numbers of patients with an adjudication-confirmed event make it difficult to draw firm conclusions [21]. Recent analyses have indicated either no increased risk [22] or a small increase in absolute risk for pancreatitis associated with DPP-4 inhibitor therapy [22,23]. Evidence from ongoing trials and continued pharmacovigilance will provide further insights into the long-term pancreatic safety of this drug class. The safety findings of CARMELINA are consistent with findings observed for the DPP-4 inhibitor class as a whole; these agents have been shown to be well tolerated with a favorable safety profile, including a low risk of hypoglycemia [7,24,25].

Application in practice

CARMELINA evaluated the effects of linagliptin on the progression of kidney disease in patients with T2DM, and provides new information on the role of this DPP-4 inhibitor in T2DM management, particularly among high-risk patients with long-standing T2DM and concomitant CVD or CKD [13]. Since these comorbidities are frequently present in patients with T2DM, it is important that glucose-lowering therapies can be used safely in these individuals with CVD and/or CKD, and the CARMELINA trial provides further evidence of the safety of linagliptin in a vulnerable patient population. Thus, the findings of CARMELINA will be of interest to physicians treating patients with T2DM who can use the new data to inform evidence-based treatment choices for a broad range of patients in their daily practice, and gain further understanding of the place of linagliptin in the management of patients who require additional glucose-lowering therapy. The pattern of AEs in the high-risk population studied was similar to previously reported event rates for linagliptin, with a reassuringly low rate of hypoglycemia. As with many patients in clinical practice, the patients enrolled in CARMELINA had standard of care; at baseline, the majority (97.4%) [14] of study participants received concurrent glucose-lowering therapy and 54.8% received concurrent metformin [14]. However, as the patients in CARMELINA were selected for elevated CV and renal risk, many of those with CKD were not candidates for metformin therapy. Also, the overall population had advanced T2DM with mean duration of T2DM of 14.7 years, with 57.9% receiving insulin therapy [12] and approximately 40% of patients receiving ≥2 glucose-lowering medications [13].

Although metformin and comprehensive lifestyle management (including dietary intervention and physical activity) are first-line therapies for individuals with T2DM [7], metformin is contraindicated for individuals with T2DM and severe renal impairment (eGFR <30 ml/min/1.73 m²) due to the risk of lactic acidosis, and is not recommended at eGFR levels of 30–45 ml/min/1.73 m² [26]. This reflects recent guidance from the FDA that recommended an update to the labeling of metformin-containing products in 2016, and now advises that renal function be assessed on the basis of eGFR instead of serum creatinine [27]. If metformin is not appropriate or if additional therapy is needed, treatment recommendations for use of glucose-lowering therapies are based on the presence of indicators of high CV risk or established ASCVD or the presence of HF or CKD [7]. Since current data for SGLT2 inhibitors show that a reduction in CV events (empagliflozin and canagliflozin) [28,29] and evidence of renoprotection (empagliflozin, canagliflozin, dapagliflozin) are associated with treatment [28–31], SGLT2 inhibitors and, potentially, GLP-1 receptor agonists with proven CVD benefit are suitable options for patients with ASCVD requiring second-line therapy after metformin [7]. Also, for patients with concurrent CKD or HF, current evidence supports SGLT2 inhibitor use to lower the risk of progression of diabetic kidney disease and/or CV events in these patients [4,32]. It is important to note, however, that the patient’s eGFR level must be adequate to achieve the glucose-lowering effects of SGLT2 inhibitors, and that dosage adjustment or treatment discontinuation may be required for SGLT2 inhibitors depending on the individual agent and indicated level of eGFR for initiation and continued use [7,32]. Specifically, for patients with T2DM and renal disease, use of an SGLT2 inhibitor should be considered for patients with an eGFR ≥30 ml/min/1.73 m², and particularly in those with >300 mg/g albuminuria, to reduce the risk of CKD progression, CV events, or both [32,33]. If SGLT2 inhibitors cannot be tolerated or are contraindicated, or if eGFR is inadequate, a GLP-1 receptor agonist with proven CVD benefit can be used [7]. If additional glucose-lowering therapy is then required for the subgroups of patients with ASCVD, HF, or CKD, DPP-4 inhibitors (except saxagliptin due to the possible increased risk of HF) can be added for patients not receiving GLP-1 receptor agonists [7]. Within the DPP-4 inhibitor class, linagliptin differs from the other agents (alogliptin, saxagliptin, and sitagliptin in the United States) as it does not require dose adjustment in patients with T2DM and renal impairment since it is not predominantly cleared through the kidneys [7]. Furthermore, CARMELINA showed no risk of progression of renal disease with linagliptin therapy, and a reduced risk of progression of albuminuria in these high-risk patients. Concerns have been raised about the risk of HF associated with DPP-4 inhibitor therapy (largely following the publication of SAVOR-TIMI 53 with saxagliptin [8]); however, the results of CARMELINA have demonstrated the safety of linagliptin in terms of HF risk. It is also reassuring to note that the CARMELINA trial showed no increase in risk of hospitalization for HF among participants with and without a history of HF [12]. Together, these findings can assist physicians with their therapeutic decision-making for patients with T2DM.

Further light has been shed on the CV safety of linagliptin by the recent publication of the CAROLINA trial, which was conducted in a population with early T2DM and elevated CV risk that may be reflective of those typically observed in routine clinical practice [15,16]. At baseline, the median duration of T2DM was 6.3 years [16] and, consistent with this relatively short disease duration, 9.2% of participants were drug-naïve, 66.0% were receiving monotherapy (of whom 88.4% were taking metformin), and 24.0% were receiving dual glucose-lowering therapy [15]. Patients requiring insulin were excluded from the trial.

CAROLINA demonstrated the noninferiority of linagliptin to glimepiride for the primary outcome (3P-MACE) (HR 0.98 [0.84–1.14]; P < 0.0001 for noninferiority) and these findings were consistent across a range of patient subgroups [16]. Linagliptin did not increase the risk for any of the MACE components of CV death, nonfatal MI, or nonfatal stroke compared with glimepiride. There was also no difference between linagliptin and glimepiride in the key secondary outcome of 4P-MACE, which included unstable angina (HR 0.99 [0.86–1.14]; P = 0.87). Furthermore, for HF-related outcomes, no significant differences were demonstrated between the groups: hospitalization for HF (HR 1.21 [0.92–1.59]) and hospitalization for HF or CV-related death (HR 1.00 [0.84–1.20]). In contrast with the relatively high event rate in CARMELINA, there were fewer hospitalizations for HF in CAROLINA (112 events [3.7%] in the linagliptin group, 92 events [3.1%] for glimepiride). CAROLINA also assessed a secondary composite outcome of HbA1c < 7% without rescue medication, without hypoglycemia, and without ≥2% weight gain. The results suggested a higher occurrence of this composite endpoint with linagliptin versus glimepiride (OR 1.68 [1.44–1.96]). There was also the suggestion of modest weight loss among patients receiving linagliptin versus glimepiride, with an average between-group difference of −1.5 kg (95% CI −1.8, −1.3). In CAROLINA, rates of hypoglycemia were lower among patients receiving linagliptin versus glimepiride: 2.3 versus 11.1 per 100 person-years for any hypoglycemia, 1.4 versus 8.4 per 100 person-years for moderate/severe hypoglycemia, and <0.1 versus 0.2 per 100 person-years for hypoglycemia-related hospitalization. In summary, DPP-4 inhibitors provide a useful therapeutic option, as they are well tolerated, weight neutral, and not associated with an increased risk of hypoglycemia, especially when compared with sulfonylureas.

For physicians treating patients with T2DM, the choice of additional glucose-lowering therapy in patients without high CV risk or established ASCVD, HF, or CKD is generally based on minimizing hypoglycemia, minimizing weight gain or promoting weight loss, and cost [7]. The CAROLINA trial supports the use of linagliptin after metformin [16]. Additionally, the findings of CAROLINA suggest that linagliptin was associated with a lower rate of hypoglycemia as well as modest weight loss compared with glimepiride [16]. The lower risk of hypoglycemia for linagliptin compared with glimepiride was consistent across all subgroups analyzed. In contrast, the risk of hypoglycemia with glimepiride was increased early and sustained across the entire dose range, suggesting that even short-term or low-dose sulfonylurea therapy might not mitigate the increased risk of hypoglycemia typically associated with these agents, particularly in the high-risk patients studied in CAROLINA. Overall, the significantly higher risk of hypoglycemia and modest weight gain with glimepiride compared with linagliptin suggest an important, clinically relevant safety advantage of linagliptin over glimepiride, and reaffirms a DPP-4 inhibitor as a treatment option for add-on therapy. The CARMELINA findings further support the use of linagliptin as a treatment option in addition to insulin if kidney safety and hypoglycemia are key considerations. Taken together, the results from CARMELINA and CAROLINA confirm the CV and renal safety of linagliptin, with low risk of hypoglycemia and minimized weight gain or modest weight loss, which reaffirms linagliptin as a DPP-4 inhibitor treatment of choice in guideline-directed management of T2DM.

Conclusions

In summary, treatment safety is an important consideration for patients with T2DM and comorbidities, and the findings of CARMELINA indicate that linagliptin is an appropriate choice to use in addition to other agents across a range of patient populations. The results of CAROLINA support the findings of CARMELINA in a complementary population of patients with T2DM of shorter duration and without CKD, together demonstrating the long-term CV and renal safety of linagliptin in T2DM across a broad range of patients at elevated CV risk. When additional glucose-lowering is required, these two trials reaffirm treatment guidelines for choosing additional therapies for high-risk patients with T2DM at high CV and/or renal risk, and further enhance our understanding of how linagliptin and DPP-4 inhibitors fit into evolving treatment approaches for patients with T2DM.

Declaration of interest

No potential conflict of interest was reported by the author.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The author meets criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), and was fully responsible for all content and editorial decisions, was involved at all stages of manuscript development, and approved the final version that reflects the author’s interpretations and conclusions. The author received no direct compensation related to the development of the manuscript. Writing support was provided by Jennifer Garrett MBBS of Elevate Scientific Solutions, which was contracted and compensated by BIPI for this service.

Additional information

Funding

This article was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.