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 Table of Contents  
Year : 2022  |  Volume : 13  |  Issue : 3  |  Page : 189-198

Journey from EMPA-REG to CARMELINA to EMPEROR-Preserved: Empagliflozin/linagliptin in heart failure and diabetes

1 Excel Endocrine Centre, Kolhapur, Maharashtra, India
2 Department of Medicine, D. Y. Patil Medical College, Kolhapur, Maharashtra, India
3 Harmony Health Speciality Clinic, Nashik, Maharashtra, India
4 Supreme Clinic, Akurdi, Pune, Maharashtra, India
5 Rudraksh Superspeciality Care, Siliguri, West Bengal, India
6 Endocrine and Diabetes Research Centre, Miraj, Maharashtra, India

Date of Submission27-Feb-2022
Date of Decision07-Apr-2022
Date of Acceptance19-Apr-2022
Date of Web Publication26-Sep-2022

Correspondence Address:
Dr. Sharvil S Gadve
Excel Endocrine Centre, Kolhapur, Maharashtra 416008
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jod.jod_24_22

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Diabetes mellitus is present in more than two-fifths of the patients suffering from heart failure (HF), with the incidence being more than twice that found in the non-diabetic population. It doubles the risk of hospitalization and increases the risk of fatal outcomes, thus negatively affecting the prognosis in HF patients. The available pharmacological treatment options are limited, particularly in HF with preserved ejection fraction (EF). Empagliflozin is a sodium-glucose transporter-2 inhibitor, which has shown a protective effect against cardiomyocyte dysfunction through various mechanisms. The benefits of empagliflozin has been seen in multiple studies: EMPA-REG (April 2015), EMPRISE (June 18, 2019), EMPIRE-HF (2019), EMPA-AHF-RESPONSE (January 7, 2020), The EMPEROR Reduced (May 28, 2020), The RECEDE-CHF (November 3, 2020), SUGAR-DM (February 9, 2021), and EMPEROR-Preserved (April 26, 2021). Empagliflozin reduced the risk of all-cause mortality, HF hospitalizations, and biomarkers in patients with HF both with reduced and preserved EF in prospective and retrospective studies, regardless of the presence of diabetes. Linagliptin is a DPP-4i that has demonstrated renal safety with potential albuminuria benefits as well. Both these agents in combination have shown favorable effects on elevated blood pressure and intima-media thickness. Unlike some other gliptins, linagliptin was not associated with an increased risk of HF, rather a nominal reduction noted in CARMELINA (January 18, 2018). When added to the standard of care, it reduced the dose of insulin in high-risk diabetic patients with HF. The risk of hypoglycemia is significantly less in patients treated with linagliptin compared with sulfonylurea regimen as seen in CAROLINA (August 21, 2018). Thus, considering the plethora of clinical benefits demonstrated, a combination of empagliflozin and linagliptin in patients of diabetes at high risk of HF may be a suitable option for primary and secondary prevention.

Keywords: Empagliflozin, heart failure, linagliptin, type 2 diabetes

How to cite this article:
Gadve SS, Chavanda S, Gogate YV, Harale V, Dasgupta A, Patwardhan M. Journey from EMPA-REG to CARMELINA to EMPEROR-Preserved: Empagliflozin/linagliptin in heart failure and diabetes. J Diabetol 2022;13:189-98

How to cite this URL:
Gadve SS, Chavanda S, Gogate YV, Harale V, Dasgupta A, Patwardhan M. Journey from EMPA-REG to CARMELINA to EMPEROR-Preserved: Empagliflozin/linagliptin in heart failure and diabetes. J Diabetol [serial online] 2022 [cited 2022 Dec 7];13:189-98. Available from: https://www.journalofdiabetology.org/text.asp?2022/13/3/189/357125

  Introduction Top

Heart failure (HF) has now increasingly been found as a mounting cause of cardiovascular morbidity, especially in the diabetic population.[1],[2],[3] The prevalence of type 2 diabetes (T2D) in HF patients is greater than 40%.[4] Incident HF was more than twice as high in T2D compared with non-T2D (30.9 per 1000 person-years vs. 12.4 per 1000 person-years).[5] This was also corroborated by the Heart and Soul study in a population of patients with stable coronary artery disease with no signs of HF at baseline.[6] Presence of diabetes doubled the risk of hospitalization in those with than without diabetes.[7],[8] Patients hospitalized for HF have a 10% mortality rate within a month of discharge.[9] The Survival And Ventricular Enlargement (SAVE) trial, the Valsartan in Acute Myocardial Infarction Trial (VALIANT), and the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) trial showed increased mortality in patients with diabetes compared with subjects without diabetes, with a cumulative incidence rate of approximately 40% over 3 years.[7],[10],[11],[12]

The available pharmacological alternatives for patients with T2D and HF are not many;[13],[14],[15],[16],[17] further, a meta-analysis by Turnbull et al. could not demonstrate clinical benefit in terms of reduction in the mortality with more intensive glycemic control compared with less intensive glycemic control.[18]

  Empagliflozin and Linagliptin: Pharmacology in T2D and HF Top

Empagliflozin is an effective and selective sodium-glucose cotransporter 2 inhibitor (SGLT2i) for T2D treatment. Linagliptin is a DPP4 inhibitor used for the treatment of T2D. It can be used without dose modification even in patients with renal impairment. Various mechanisms by which empagliflozin [Figure 1](a) and linagliptin [Figure 1](b) may have an impact on T2DM patients with HF have been described.[14],[15],[16],[17],[18]
Figure 1: (a) Mechanisms of empagliflozin in T2D with heart failure. (b) Mechanisms of linagliptin in T2D with heart failure

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Apart from their antihyperglycemic effects, the combination of empagliflozin and linagliptin has shown a significant improvement in systolic blood pressure (BP) (−5.2 ± 1.5 mmHg, P = 0.004), diastolic BP (−1.9 ± 1.0 mmHg, P = 0.036), as well as vascular physiology in diabetic individuals.[17] Experimental data also show that the combination diminishes neointima formation.[18]

  Journey of Empagliflozin/Linagliptin in T2DM and Heart Failure Top

The USFDA and EMA’s ruling of mandating the evaluation of cardiovascular safety of anti-diabetic drugs by conducting cardiovascular outcome trials (CVOTs) proved to be a blessing in disguise.[19] Empagliflozin has demonstrated a significant reduction in HF-related morbidity and mortality in several trials, regardless of the diabetes status and HF severity [heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF)] [Figure 2][Figure 3][Figure 4].
Figure 2: Empagliflozin clinical trials: Distribution of patient population

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Figure 3: Timeline of journey of empagliflozin/linagliptin in T2DM and heart failure

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Figure 4: Effects of empagliflozin in HF: Clinical evidence

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The EMPA-REG OUTCOME study demonstrated that compared with placebo, treatment with empagliflozin significantly reduced the rate of CV events in patients with T2D and established CVD.[20] It reduced the hospitalization for heart failure (hHF) by 35% in comparison with placebo independently of glycemic control.[8],[20] When further analyzed for assessment of its effect in patients (N=7020) at risk of or with HF (10.1%), the study found that the hHF or CV death occurred in a significantly lesser proportion of patients treated with empagliflozin (5.7%) than with placebo (8.5%) [hazard ratio (HR): 0.66 (0.55–0.79); P<0.001]. It improved other HF outcomes, including hHF or death from HF [2.8% vs. 4.5%; HR: 0.61 (0.47–0.79); P < 0.001].[20] When the data were analyzed according to the presence or absence of preexisting HF, the reduction in the risk of these outcomes with empagliflozin was unswerving in both the groups.[21] The 5-year HF risk was low-to-average in 67.2% of the patients, high in 24.2%, and very high in 5.1%.[21] Across these groups, the effect on CV death and hHF with empagliflozin was maintained [HR 0.71 (0.52, 0.96), 0.52 (0.36,0.75), and 0.55 (0.30, 1.00), respectively]. Thus, even in the group with the highest HF risk, empagliflozin had benefits in reducing CV deaths [HR 0.67 (0.47, 0.97)], similar to those in lower-risk groups.[8]

When the patients were grouped according to prior myocardial infarction or stroke, empagliflozin reduced the risk for hHF compared with placebo (hHF events EMPA vs. PL 9.4% vs. 14.5%).[22]

Empagliflozin compared to placebo reduced hHF reliably in patients with atrial fibrillation (AF) [0.58 (0.36–0.92) and without AF 0.67 (0.55–0.82), Pinteraction = 0.56].[23]

Early evidence of possible HF (first edema or the introduction of new loop diuretics) was associated with the significant rise in frequency of events subsequently, which were sensitive to treatment with empagliflozin.[22]

Thus, the EMPA-REG study demonstrated a robust cardiovascular efficacy of empagliflozin (10/25 mg) in rapid reduction of the risk of CV death in a gamut of patients with or without HF at baseline and history of atherosclerotic CVD-MI or stroke.[8],[21],[22],[23],[24]

  Linagliptin—CARMELINA (January 18, 2018) and CAROLINA (August 21, 2018) Top

Results from three CVOTs of various DPP-4i have demonstrated cardiovascular safety concerning hHF outcomes with slight differences between them extending from neutral effect with sitagliptin, numeric disparity that was statistically insignificant with alogliptin, none with sitagliptin but significantly higher risk of hHF with saxagliptin.[25],[26],[27],[28],[29],[30] These inconsistencies observed in the cardiovascular effects among the drugs belonging to the same class raised doubts which were at least in part laid down to rest due to the CARMELINA study with linagliptin.[31] The initial results of this randomized, double-blind, placebo-controlled clinical trial with a median follow-up of 2.2 years in diabetic patients (duration of diabetes >14 years) at very high risk for HF and its complications and renal risk found that linagliptin could be used without increasing the risk for hHF.[32] hHF occurred in 209 of 3494 patients randomized to linagliptin (6.0%; 2.77 per 100 person-years) and in 226 of 3485 patients randomized to placebo (6.5%; 3.04 per 100 person-years), for an absolute incidence rate difference of −0.27 (95% CI: −0.82 to 0.28), with no significant difference between the two treatment groups (HR 0.90; 95% CI: 0.74–1.08; P = 0.26). Thus, unlike saxagliptin, linagliptin was not associated with increased risk for hHF in CARMELINA.[30],[32] It is worth pointing out here that the hHF risk in patient population [duration of diabetes 15 years, estimated glomerular filtration rate (eGFR)=50, albumin-to-creatinine ratio (ACR)=160] enrolled in CARMELINA was considerably higher than that in SAVOR-TIMI (10 years, eGFR=75, ACR=10) and EXAMINE and TECOS (10 years, eGFR=75, ACR=10) CVOTs; the annualized hHF incidence was 3% in CARMELINA vs. 1–2% in the other three trials, respectively. The high-risk patient inclusion corroborates the HF safety of linagliptin.[25] Further subgroup analysis of Asian patients (N= 555/6979 patients), who are generally at higher risk of CV events (lower eGFR, more males, and higher use of glitazone), linagliptin was associated with a slight but significant decrease in the risk of hHF (HR 0.47)[33] in this subgroup analysis. One of the suggested mechanisms is a decrease in the insulin dosage requirement. Insulin is generally preferred in diabetic patients with renal impairment; however, it is known to stimulate the sympathetic nervous system and also cause retention of fluid, both of which increase the risk of HF. The subgroup analysis showed that there was no significant interaction between age and treatment effect (P = 0.9788), with HRs for linagliptin vs. placebo 0.87 (<65 years), 0.89 (65 to <75 years), and 0.92 (≥75 years).[34] The treatment effect was constant across various age groups for the composite kidney outcome (P = 0.9968) with HRs 1.05 (<65 years), 1.06 (65 to >75 years), and 1.06 (≥75 years). Even in participants aged ≥75 years, there was also no increased risk for hHF or the composite kidney outcome with linagliptin compared with placebo in individuals aged 75 to <80 or ≥80 years.[34] The prespecified analysis of CARMELINA showed that linagliptin treatment in the highest risk cohorts, viz., older T2D patients, established CVD with albuminuria, and/or chronic kidney disease, did not increase their risk of atherosclerotic cardiovascular events, HF, or adverse kidney outcomes compared with placebo, but enhances their glycemic control without elevating the risk of hypoglycemia.[34]

Unlike CARMELINA, CAROLINA was an active-comparator study of linagliptin vs. glimepiride in patients with a lesser duration of diabetes (median 5 years) but higher CV risk. In the Asian subgroup (n=933/6033 participants), there were no significant differences among groups for CV death (HR 0.73), non-CV mortality (HR 0.76), and hHF (HR 0.89). However, the hypoglycemia occurred in significantly more patients in the glimepiride group than linagliptin (42.1% vs. 13.1%; P < 0.0001).[35]

  EMPRISE Study (June 18, 2019) Top

Empagliflozin comparative effectiveness and safety

The EMPRISE study compared the safety and efficacy of empagliflozin with DPP4i sitagliptin based on real-world data from 2014 to 2019.[36],[37] After the propensity score matching, among the 16,443 patients identified, 25% had preexisting cardiovascular disease and 5% specifically had HF. The primary outcome was defined as a discharge diagnosis of HF in the primary position (hHF-specific). A broader definition of HF discharge diagnosis in any position (hHF-broad) was also assessed. Compared to sitagliptin, the initiation of empagliflozin decreased the risk of hHF-specific by 50% [HR=0.5 (0.28–0.91)] and the risk of hHF-broad by 49% [HR=0.51 (0.39–0.68)] over a mean follow-up of 5.3 months.[37] Thus, the EMPRISE results propose that empagliflozin may decrease hHF in a larger spectrum of patients in the real world setting compared with the EMPA-REG OUTCOME trial.[36],[37]

  EMPIRE-HF (2019) Top

To determine the effect of empagliflozin in patients with HFrEF (EF ≤ 40%) on markers of cardiac function, hemodynamics, metabolic, and renal parameters, daily activity level, and quality of life, EMPIRE-HF, a placebo-controlled RCT, was conducted.[38] In its HF-renal substudy, compared with placebo, empagliflozin treatment led to a decrease in estimated extracellular volume (AMD −0·12 L, P=0·00056), estimated plasma volume (−7·3%; p<0·0001), and measured GFR (−7·5 mL/min; P=0.0001) compared with placebo.[38] Thus, changes in fluid volume could be an important primary pathway for the clinical advantages of empagliflozin.[38] Further, in another part EMPIRE-HF exercise, a 12-week study, the hemodynamics over the full range of exercise loads, pulmonary capillary wedge pressure (PCWP), was significantly reduced (−2.40 mmHg; P=0.003), regardless of the presence of diabetes, thus resulting in a significant drop in LV filling pressure.[39]

  EMPA-AHF-RESPONSE (January 7, 2020) Top

In both diabetic and non-diabetic patients with acute HF, the EMPA-AHF-RESPONSE, which was a randomized, placebo-controlled, double-blind, parallel-group, multi-center pilot study, showed that empagliflozin (10 mg/day) or placebo for 30 days reduced a combined endpoint of in-hospital worsening HF, rehospitalization for HF, or death at 60 days compared with placebo [10% vs. 33%; P = 0.014].[40] Urinary output till day 4 was significantly higher with empagliflozin vs. placebo [difference 3449 mL; P < 0.01]. These data suggest that empagliflozin can be carefully introduced in a high-risk population of acute HF patients, and results should be reassessed in large studies.[40]

  The Emperor-reduced Trial (May 28, 2020) Top

Among the 3730 patients with HFrEF, the primary outcomes of CV death or hHF were significantly reduced in the empagliflozin group compared with placebo [19.4% vs. 24.7% (HR 0.75, 95% confidence interval (CI) 0.65–0.86, P < 0.001)], whereas hHF specifically was also significantly less in the empagliflozin group compared with the latter (13.2% vs. 18.3%) (HR 0.69, 95% CI 0.59–0.81).[41] These differences correspond to a 24% lower risk attributed to treatment with empagliflozin when compared with placebo (HR 0.76, 95% CI 0.67–0.87, P<0.0001). When the data were sub-analyzed based on the hospitalizations, it was observed that compared with the placebo group, patients in the empagliflozin group had fewer total (first and recurrent) hospitalizations for HF (HR 0.70, 95% CI 0.58–0.85, P=0.0003), fewer total (first and recurrent) hospitalizations for a CV reason (HR 0.78, 95% CI 0.67–0.91, P<0.0001), and fewer total (first and recurrent) hospitalizations for any reason (HR 0.85, 95% CI 0.75–0.95, P=0.007] [Figure 5](a). When compared with placebo, fewer patients in the empagliflozin group were hospitalized for HF [Figure 5](b).
Figure 5: (a) Effect of empagliflozin on first and recurrent hospitalizations. (b) Frequency of hHF

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Empagliflozin delayed the time to the first hHF that required intensive care by 35% (HR 0.65, 95% CI 0.50–0.85, P=0.002) and reduced the total number of HF admissions by 33% (HR 0.67, 95% CI 0.50–0.90, P=0.008). Empagliflozin-treated patients required less pharmacological and mechanical support compared with the placebo group [Figure 6].
Figure 6: Need for various pharmacological agents and mechanical support in decompensated HF

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The patients in the empagliflozin group needed lesser and delayed ED or urgent care appointments for deteriorating HF by nearly 34% (HR 0.66, 95% CI 0.53–0.83, P=0.0004) and reduced the number of overall such visits by 37% (HR 0.63, 95% CI 0.49–0.831, P=0.0004) [Figure 7].[42]
Figure 7: Effect of empagliflozin on HF worsening and ED visits (EMPEROR-REDUCED) and on the primary outcome of death/hHF and hHF (EMPEROR-PRESERVED)

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Escalation of diuretics (297 vs. 414) and associated study visits (380 vs. 564) were fewer in the empagliflozin group compared with placebo; rather, the number of visits (334 vs.291) associated with a reduction in diuretic doses in patients (281 vs. 246) was higher in the empagliflozin group.[42]

When the data were analyzed based on whether the patients received sacubitril/valsartan at baseline, empagliflozin was found to reduce the risk of CV death or hHF in patients receiving or not receiving sacubitril/valsartan [HR 0.64 (95% CI 0.45–0.89), P = 0.009 and HR 0.77 (95% CI 0.66–0.90), P = 0.0008, respectively, interaction P = 0.31].[43]

Thus, the EMPEROR-Reduced trial is an important study. These data, therefore, support the use of empagliflozin in addition to the SOC in patients with HFrEF, regardless of T2D.

  The RECEDE-CHF Trial (November 3, 2020) Top

Another randomized, double-blind, placebo-controlled, crossover trial in patients with T2D and HFrEF already taking loop diuretic started on empagliflozin (25 mg OD) for 6 weeks showed that there was a significant rise in 24-h urinary volume at both day 3 (535 mL; P=0.005) and week 6 (545 mL; P=0.005).[44]

Combining empagliflozin with a loop diuretic could especially be advantageous for HF patients to reduce fluid overload without increased risk of hyponatremia, the risk of which is higher when loop diuretics are combined with the thiazides.[44]

  SUGAR-DM Trial (February 9, 2021) Top

The SUGAR-DM-HF trial included 105 patients with either diabetes (78.1%) or prediabetes (21.9%) with mean left ventricular EF <40% and New York Heart Association (NYHA) class II (77.1%) and III (22.9%). These patients were already being treated with renin–angiotensin system blockers and β-blockers, and 33% of these were also being treated with sacubitril/valsartan.[45] Empagliflozin decreased the LV end-systolic and -diastolic volume index by 6.0 mL/m2 (P=0.015) and by 8.2 mL/m2 (P=0.0042), respectively, in 36 weeks as determined by cardiovascular magnetic resonance.

  The Emperor-preserved Trial (April 26, 2021) Top

The EMPEROR-Preserved trial compared empagliflozin 10 mg with placebo in patients with chronic HF with NYHA classes II–IV and preserved EF (EF > 40 %) and elevated N-terminal (NT)-pro hormone BNP (NT-proBNP) (> 300 pg/mL for patients without AF, or NT-proBNP > 900 pg/mL for patients with AF) with or without diabetes with a follow-up period of more than 3 years. [46,47] As the treatment of patients with HFpEF is one of the most daunting HF conditions, EMPAGLIFLOZIN benefits would change its management landscape.[48],[49]

Among the 5988 patients with HFpEF, the primary outcome of CV death or hHF was significantly reduced in the empagliflozin group compared with placebo [13.8% vs. 17.1%, HR 0.79, 95% CI0.69–0.90, P < 0.001), whereas hHF specifically was also significantly less in the empagliflozin group compared with the latter 8.6% vs. 11.8% (HR 0.71, 95% CI 0.60–0.83).[50] These differences correspond to a 21% lower risk attributed to treatment with empagliflozin when compared with placebo, primarily owing to the 29% lower risk of HHF with empagliflozin[50] [Figure 5]. Thus, the number of patients who needed to be treated with empagliflozin to prevent one primary outcome event was 31 (95% CI 20–69). Thus, empagliflozin reduced the risk of cardiovascular death or hHF in patients with HFpEF, regardless of the patients’ diabetes status.[50]

  Impact on Recommendations of Heart Failure in Global Guidelines Top

The ESC guidelines 2016 earlier suggested that empagliflozin should be considered in patients with T2D to prevent or delay the onset of HF. These recommendations which were further updated in 2019 stated that Sglt2 inhibitors should be considered in T2D patients with CVD or those at very high/high CV risk, to lessen CV events and to reduce the risk of death and hHF.[19],[51

Additionally],[ the ESC/Heart Failure Association (HFA) position paper 2019 stated that as this class of drugs has undoubtedly demonstrated benefit in reduction of hHF across patient subgroups regardless of history of HF],[ this class should be recommended for primary prevention of hHF in diabetic patients with elevated CV risk.[52]

Based on the outcomes of the SUGAR-DM study, the subsequent update in the ESC/HFA position paper stated that SGLT2i such as empagliflozin should be used in all patients with HFrEF at the earliest either along with or in addition to the HF effective therapy including not only conventional drug therapy (beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin-receptor blocker, and mineralocorticoid receptor antagonists) but also newer combination sacubitril/valsartan.[53]

The USFDA, NICE UK, and the German IQWiG have recommended the use of the generated data from RWE for developing clinical recommendations.[54],[55] Therefore, studies such as EMPRISE which evaluated the SGLT2i have demonstrated that clinicians have empagliflozin as a robust cardiovascular drug for the prevention of HHF as also resonated in the American College of Cardiology consensus pathway.[56],[57]

The ADA and EASD consensus reports recommend that people with T2D with high CV risk established CVD, HF, or chronic kidney disease (CKD), including older individuals, inadequately controlled on metformin alone, should receive second-line treatment with an antidiabetic drug-like SGLT2i with established CV, HF, or CKD benefit.[58],[59] This has been further emphasized in the recently updated ESC guideline on HF, which recommends that the appropriate combination treatment in such patients should be individualized and should be initiated as early as possible.[60] Considering the high prevalence of multiple comorbidities such as CKD and T2DM in HF patients, ESC recommendations for use of new drugs such as SGLT-2i as first-line only further highlight and corroborate the importance of a multipronged approach for managing such high-risk patients. In patients intolerant to these drugs or those who need a third-line agent, the report recommends other drugs with similar benefits. Thus, evidence for linagliptin with proven CV safety including those concerning HF across various age groups, even in those with very high CV risk, is encouraging, particularly when compared with data for alogliptin and saxagliptin.[29],[30]

Thus, it is noteworthy that guidelines are recommending a fundamental change in the approach toward management of HF with a patient-centric, tailored approach that focusses on saving lives.

  Conclusion Top

There is a wall of clinical evidence available with empagliflozin in the prevention and treatment of HFrEF and HFpEF across age groups and severity spectrum in patients with T2D. The CV safety and potential benefits of linagliptin, with proven HF safety in very high-risk patients such as those with CKD, ASCVD, and elderly, are reassuring. In T2D patients at high risk of HF, a combination of empagliflozin and linagliptin may be beneficial with its metabolic and cardiorenal effects.

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Conflicts of interest

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]


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