|Year : 2022 | Volume
| Issue : 3 | Page : 189-198
Journey from EMPA-REG to CARMELINA to EMPEROR-Preserved: Empagliflozin/linagliptin in heart failure and diabetes
Sharvil S Gadve1, Sneha Chavanda2, Yashpal V Gogate3, Vinayak Harale4, Arundhati Dasgupta5, Milind Patwardhan6
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 Submission||27-Feb-2022|
|Date of Decision||07-Apr-2022|
|Date of Acceptance||19-Apr-2022|
|Date of Web Publication||26-Sep-2022|
Dr. Sharvil S Gadve
Excel Endocrine Centre, Kolhapur, Maharashtra 416008
Source of Support: None, Conflict of Interest: None
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|| |
Heart failure (HF) has now increasingly been found as a mounting cause of cardiovascular morbidity, especially in the diabetic population.,, The prevalence of type 2 diabetes (T2D) in HF patients is greater than 40%. 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). 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. Presence of diabetes doubled the risk of hospitalization in those with than without diabetes., Patients hospitalized for HF have a 10% mortality rate within a month of discharge. 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.,,,
The available pharmacological alternatives for patients with T2D and HF are not many;,,,, 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.
| Empagliflozin and Linagliptin: Pharmacology in T2D and HF|| |
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.,,,,
|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. Experimental data also show that the combination diminishes neointima formation.
| Journey of Empagliflozin/Linagliptin in T2DM and Heart Failure|| |
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. 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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| EMPA-REG OUTCOME (2015)|| |
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. It reduced the hospitalization for heart failure (hHF) by 35% in comparison with placebo independently of glycemic control., 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]. 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. 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%. 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.
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%).
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].
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.
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.,,,,
| Linagliptin—CARMELINA (January 18, 2018) and CAROLINA (August 21, 2018)|| |
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.,,,,, 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. 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. 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., 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. 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) 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). 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. 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.
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).
| EMPRISE Study (June 18, 2019)|| |
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., 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. 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.,
| EMPIRE-HF (2019)|| |
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. 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. Thus, changes in fluid volume could be an important primary pathway for the clinical advantages of empagliflozin. 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.
| EMPA-AHF-RESPONSE (January 7, 2020)|| |
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]. 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.
| The Emperor-reduced Trial (May 28, 2020)|| |
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). 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].
|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.
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].
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)|| |
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).
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.
| SUGAR-DM Trial (February 9, 2021)|| |
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. 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)|| |
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.,
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). 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 [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.
| Impact on Recommendations of Heart Failure in Global Guidelines|| |
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.,[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.
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.
The USFDA, NICE UK, and the German IQWiG have recommended the use of the generated data from RWE for developing clinical recommendations., 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.,
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., 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. 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.,
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|| |
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
There are no conflicts of interest.
| References|| |
Lehrke M, Marx N Diabetes mellitus and heart failure. Am J Cardiol 2017;120:S37-S47.
McMurray JJ, Stewart S Epidemiology, aetiology, and prognosis of heart failure. Heart 2000;83:596-602.
Matsue Y, Suzuki M, Nakamura R, Abe M, Ono M, Yoshida S, et al
. Prevalence and prognostic implications of pre-diabetic state in patients with heart failure. Circ J 2011;75:2833-9.
Nichols GA, Gullion CM, Koro CE, Ephross SA, Brown JB The incidence of congestive heart failure in type 2 diabetes: An update. Diabetes Care 2004;27:1879e-1884.
Dunlay SM, Givertz MM, Aguilar D, Allen LA, Chan M, Desai AS, et al
; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and the Heart Failure Society of America. Type 2 diabetes mellitus and heart failure: A scientific statement from the American Heart Association and the Heart Failure Society of America: This statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure guideline update. Circulation 2019;140:e294-e324. Erratum in: Circulation. 2019;140(12):e692.
van Melle JP, Bot M, de Jonge P, de Boer RA, van Veldhuisen DJ, Whooley MA Diabetes, glycemic control, and new-onset heart failure in patients with stable coronary artery disease: Data from the Heart and Soul Study. Diabetes Care 2010;33:2084-9.
MacDonald MR, Petrie MC, Varyani F, Ostergren J, Michelson EL, Young JB, et al
. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: An analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J 2008;29:1377-85.
Fitchett D, Butler J, van de Borne P, Zinman B, Lachin JM, Wanner C, et al
. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME® trial. Eur Heart J 2018;39:363-70.
Lam CSP, Chandramouli C, Ahooja V, Verma S SGLT-2 inhibitors in heart failure: Current management, unmet needs, and therapeutic prospects. J Am Heart Assoc 2019;8:e013389.
Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown Jr EJ, Cuddy TE, et al
. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: Results of the survival and ventricular enlargement trial. N Engl J Med 1992;327:669-77.
Solomon SD, St John Sutton M, Lamas GA, Plappert T, Rouleau JL, Skali H, et al
. Ventricular remodeling does not accompany the development of heart failure in diabetic patients after myocardial infarction. Circulation 2002;106:1251-5.
Aguilar D, Solomon SD, Kober L, Rouleau JL, Skali H, McMurray JJ , et al
. Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Circulation 2004;110:1572-8.
Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, Duckworth WC, et al
. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009;52:2288–98.
Sano M Anti-diabetic agents and heart failure. Response to the CARMELINA study. Circ Rep 2019;1:4-7.
Kanasaki K, Shi S, Kanasaki M,He J, Nagai T, Nakamura Y , et al
. Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen. Diabetes 2014;63:2120-31.
Tanaka Y, Kume S, Chin-Kanasaki M, Araki H, Araki SI, Ugi S, et al
. Renoprotective effect of DPP-4 inhibitors against free fatty acid-bound albumin-induced renal proximal tubular cell injury. Biochem Biophys Res Commun 2016;470:539-45.
Jung S, Bosch A, Kannenkeril D, Karg MV, Striepe K, Bramlage P, et al
. Combination of empagliflozin and linagliptin improves blood pressure and vascular function in type 2 diabetes. Eur Heart J Cardiovasc Pharmacother 2020;6:364-71.
Takahashi H, Nomiyama T, Terawaki Y, Horikawa T, Kawanami T, Hamaguchi Y, et al
. Combined treatment with DPP-4 inhibitor linagliptin and SGLT2 inhibitor empagliflozin attenuates neointima formation after vascular injury in diabetic mice. Biochem Biophys Rep 2019;18:100640.
Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al
. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: A systematic review and metaanalysis of cardiovascular outcome trials. Lancet 2019;393:31–9.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al
. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28.
Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, EMPA-REG OUTCOME® Trial Investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG OUTCOME® trial. Eur Heart J 2016;37:1526-34.
Fitchett D, Inzucchi SE, Cannon CP, McGuire DK, Scirica BM, Johansen OE, et al
. Empagliflozin reduced mortality and hospitalization for heart failure across the spectrum of cardiovascular risk in the EMPA-REG OUTCOME trial. Circulation 2019;139:1384-95 .
Böhm M, Slawik J, Brueckmann M, Mattheus M, George JT, Ofstad AP, et al
. Efficacy of empagliflozin on heart failure and renal outcomes in patients with atrial fibrillation: Data from the EMPA-REG OUTCOME trial. Eur J Heart Fail 2020;22:126-35.
Packer M, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, et al
EMPEROR-Reduced Trial Committees and Investigators. Evaluation of the effect of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: Rationale for and design of the EMPEROR-Reduced trial. Eur J Heart Fail 2019;21:1270-8 .
McGuire DK, Van de Werf F, Armstrong PW, Standl E, Koglin J, Green JB, et al
. Association between sitagliptin use and heart failure hospitalization and related outcomes in type 2 diabetes mellitus: Secondary analysis of a randomized clinical trial. JAMA Cardiol 2016;1:126–35.
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al
. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–26.
White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al
. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–35.
Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al
. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232–42.
Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, et al
. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 2015;385:2067–76.
Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, et al
. Heart failure, saxagliptin, and diabetes mellitus: Observations from the SAVOR-TIMI 53 randomized trial. Circulation 2014;130:1579–88.
Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, 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, Perkovic V, Rosenstock J, Cooper ME, 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;139:351-61.
Inagaki N, Yang W, Watada H, Ji L, Schnaidt S, Pfarr E, et al
. Linagliptin and cardiorenal outcomes in Asians with type 2 diabetes mellitus and established cardiovascular and/or kidney disease: Subgroup analysis of the randomized CARMELINA® trial. Diabetol Int 2019;11:129-41.
Cooper ME, Rosenstock J, Kadowaki T, Seino Y, Wanner C, Schnaidt S, et al
. Cardiovascular and kidney outcomes of linagliptin treatment in older people with type 2 diabetes and established cardiovascular disease and/or kidney disease: A prespecified subgroup analysis of the randomized, placebo-controlled CARMELINA® trial. Diabetes Obes Metab 2020;22:1062-73.
Kadowaki T, Wang G, Rosenstock J, Yabe D, Peng Y, Kanasaki K, et al
. Effect of linagliptin, a dipeptidyl peptidase-4 inhibitor, compared with the sulfonylurea glimepiride on cardiovascular outcomes in Asians with type 2 diabetes: Subgroup analysis of the randomized CAROLINA® trial. Diabetol Int 2020;12:87-100.
Verma S, Lam CSP, Kosiborod M Empagliflozin and heart failure. What can we learn from EMPRISE? Circulation 2019;139:2831–4.
Patorno E, Pawar A, Franklin JM, Najafzadeh M, Déruaz-Luyet A, Brodovicz KG, et al
. Empagliflozin and the risk of heart failure hospitalization in routine clinical care. Circulation 2019;139:2822-30 .
Jensen J, Omar M, Kistorp C, Poulsen MK, Tuxen C, Gustafsson I, et al
. Empagliflozin in heart failure patients with reduced ejection fraction: A randomized clinical trial (Empire HF). Trials 2019;20:374.
Jensen J, Omar M, Kistorp C, Tuxen C, Gustafsson I, Køber L, et al
. Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): A prespecified substudy of a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2021;9:106-16.
Damman K, Beusekamp JC, Boorsma EM, Swart HP, Smilde TD, Elvan A, et al
. Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). Eur J Heart Fail 2020;22:713-22.
Kumbhani DJ, Bhatt DL Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and a Reduced Ejection Fraction - EMPEROR-Reduced. Available from https://www.acc.org/sitecore/content/Sites/ACC/Home/Latest-in-Cardiology/Clinical-Trials/2020/08/28/16/12/EMPEROR-Reduced#references-for-article
. [Last accessed on 2021 Aug 05].
Packer M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, et al
. Effect of Empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: The EMPEROR-reduced trial. Circulation 2021;143:326-36 .
Packer M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, et al
. Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: The EMPEROR-Reduced trial. Eur Heart J 2021;42:671-80 .
Mordi NA, Mordi IR, Singh JS, McCrimmon RJ, Struthers AD, Lang CC Renal and cardiovascular effects of SGLT2 inhibition in combination with loop diuretics in patients with type 2 diabetes and chronic heart failure: The RECEDE-CHF trial. Circulation 2020;142:1713-24.
Lee MM, Brooksbank KJ, Wetherall K, Mangion K, Roditi G, Campbell RT, et al
. Effect of empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF). Circulation 2020;143:516–25.
Shah KS, Xu H, Matsouaka RA, et al
. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol 2017;70:2476–86.
Anker SD, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, et al
EMPEROR-Preserved Trial Committees and Investigators. Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: Rationale for and design of the EMPEROR-Preserved Trial. Eur J Heart Fail 2019;21:1279-87.
EMPEROR-Preserved First Trial to Show Positive Results in HFpEF. Available from https://www.ajmc.com/view/emperor-preserved-first-trial-to-show-positive-results-in-hfpef
. [Last accessed on 2021 Aug 9].
EMPEROR-Preserved: Positive Top-Line Results for Empagliflozin in HFpEF. Available from https://www.medscape.com/viewarticle/ 954284
. [Last accessed on 2021 Aug 9].
Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al
EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021.
Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al
. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323.
Seferovic PM, Coats AJS, Ponikowski P, Filippatos G, Huelsmann M, Jhund PS, et al
. European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose-lowering drugs in patients with heart failure. Eur J Heart Fail 2020;22:196–213.
Seferovic´ PM, Fragasso G, Petrie M, Mullens W, Ferrari R, Thum T, et al
. Sodium glucose co-transporter-2 inhibitors in heart failure: Beyond glycaemic control. The Position Paper of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2020;2:1495–503.
Framework for FDA’s real-world evidence program. Available from https://www.fda.gov/media/120060/download
. [Last accessed on 2021 Aug 14].
Schernthaner G, Karasik A, Abraitienė A, Ametov AS, Gaàl Z, Gumprecht J, et al
. Evidence from routine clinical practice: EMPRISE provides a new perspective on CVOTs. Cardiovasc Diabetol 2019;18:115.
Das SR, Everett BM, Birtcher KK, Brown JM, Cefalu WT, Januzzi Jr JL, et al
. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: A report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2018;72: 3200–23.
Cherney DZ, Udell JA Use of sodium glucose cotransporter 2 inhibitors in the hands of cardiologists: With great power comes great responsibility. Circulation 2016;134: 1915–7.
Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al
. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:2669-701. 34.
Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, et al
. 2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2020;63:221-8.
2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure: Developed by the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) With the Special Contribution of the Heart Failure Association (HFA) of the ESC.Eur Heart J2021.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]