Treating heart failure in patients with diabetes: The view of the cardiologist

Nina Kumowski, Nikolaus Marx, Katharina Schu¨tt *

Abstract

Heart failure with preserved ejection fraction (HFpEF) SGLT-2 inhibitors Diabetes is a very important comorbidity in patients with heart failure. When both diseases coexist cardiovascular morbidity and mortality is greatly increased. Therefore, it is of clinical importance to treat both diseases as early as possible with an optimal therapy.
Hitherto, heart failure therapy did not differ if a patient had concomitant diabetes. However, with SGLT-2 inhibitors having demonstrated to reduce hospitalization of heart failure independent of diabetes state and expected to be included into the ESC heart failure treatment guidelines in 2021 coexisting diabetes potentially will make a difference when to start therapy.
In this article we provide an overview of current recommendations and also provide clinical considerations for the therapy of heart failure with concomitant diabetes.

Keywords:
Type 2 diabetes
Cardiovascular outcomes
Heart failure
Heart failure with reduced ejection fraction (HFrEF)

1. Introduction

Heart failure affects 1–2% of the general population with a prevalence > 10% in patients over 70 years of age. In patients with diabetes mellitus (DM) heart failure occurs not only more often but also at younger age [1,2]. Heart failure is the most common reason for hospitalization over the age of 65 [3]. A comparison of the survival rates of patients with heart failure with those of patients with common tumor diseases shows that patients with heart failure have a similarly poor survival as patients with colorectal cancer in men or ovarian cancer in women [4].
Type 2 Diabetes is an increasing problem with 463 million people affected worldwide in 2019 and an expected increase of 51% to 700 million people in 2045 [5,6]. Already patients with prediabetes have an increased risk for heart failure [7]. In prospective and retrospective cohort studies patients with diabetes mellitus showed nearly doubled risk to develop heart failure [8,9]. Matsue et al. summarized various registry studies and demonstrated a 25–40% prevalence of diabetes in patients with HF [10]. In studies with patients with diabetes up to 30% had also a concomitant HF [9]. The prognosis of heart failure patients with diabetes is significantly reduced. Several trials documented an increased risk of death and hospitalization for heart failure in the group with concomitant diabetes mellitus [11–15]. Therefore, specific treatment and interdisciplinary collaboration is crucially important for treatment of patients with heart failure and diabetes mellitus to improve outcomes in this high-risk population.
While improving glucose control demonstrated no benefit in regard of heart failure outcomes [16], SGLT-2 inhibitors reduce heart failure hospitalization or cardiovascular death in both patients with and without diabetes. This article provides an overview on therapeutic options in heart failure treatment with a special focus on distinct features in patients with diabetes.

2. Therapy of heart failure in patients with diabetes

The current heart failure guidelines from European and American cardiology societies from 2016 and the new ESC guideline on diabetes, pre-diabetes, and cardiovascular diseases and do not recommend specific treatment with or without diabetes mellitus [17–19].
Therefore, we first give an overview of current treatment of heart failure according to the guidelines and supplement some clinical consideration for patients with DM beyond the guidelines. Furthermore, we refer to recent developments regarding SGLT-2 Inhibitors in the heart failure treatment.
According to the current guideline on heart failure from 2016, a distinction is made between three heart failure entities: heart failure with preserved ejection fraction (HFpEF; systolic ejection fraction 50%); Heart failure with midrange ejection function (HFmrEF; ejection fraction 40–49%) and heart failure with reduced ejection fraction (HFrEF; ejection fraction <40%) [17]. Since the majority of all data collected so far is based on the old classification, which only distinguishes HFpEF and HFrEF, the present article focuses on patients with preserved or reduced ejection fraction.

2.1. Therapy of heart failure with preserved ejection fraction (HFpEF) in patients with diabetes mellitus

At the present time there are no studies demonstrating an improvement in the prognosis in patients with HFpEF. Also, in the recently published PARAGON-HF (Angiotensin – Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction) study, in which the effect of sacubitril/valsartan versus valsartan in patients with an ejection fraction 45% was examined, there was no significant difference in primary endpoint consisting of hospitalization for heart failure or cardiovascular death [20]. Therefore, the guidelines emphasize the treatment of comorbidities including weight loss and life style modification as well as therapy of symptoms e.g., with diuretics in patients with congestion [17].
The group of SGLT2 inhibitors showed promising results in the recently published cardiovascular endpoint studies [21]. The EMPEROR-preserved [EMPEROR-Preserved; NCT03057951] and the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; NCT03619213) will determine the impact of empagliflozin and dapagliflozin on cardiovascular and heart failure outcomes in people with HFpEF with or without diabetes.

2.2. Therapy of heart failure with reduced ejection fraction (HFrEF) in patients with diabetes mellitus

2.2.1. Treatment according to guidelines

In contrast to the therapy of HFpEF, there is an evidencebased treatment algorithm for symptomatic HFrEF patients with NYHA class II-IV and with a left ejection fraction <40% (see Fig. 1) [17]:
Currently, the 2016 treatment algorithm of the European society of cardiology is still valid [17]: A combined basic therapy consisting of neurohumoral blockade of the reninangiotensin system using ACE inhibitors (ACEI) (or angiotensin receptor blockers = ARB) and beta blockers should be established. A slow titration (dose increase every 2–4 weeks) up to the maximum (tolerable) dose of both drugs is crucial.
In the case of persistent symptoms (NYHA II-IV) and reduced LV function (<35%), the existing basic therapy should be extended to include a mineralocorticoid receptor antagonist (MRA) such as spironolactone or eplerenone. Here, too, a slow increase in dosewhile monitoring the retention and electrolyte parameters (especially potassium) is recommended.
In the case of hyperkalemia under this therapy, the use of a potassium binder such as patiromer can be considered.
In patients who continue to be symptomatic during this therapy, switching from ACEI/ARB therapy to angiotensin neprilysin inhibitor (ARNI), a macromolecule made from sacubitril and valsartan, should be considered. A slow increase in dose also applies to this substance, with doubling of the dose within a 2–4-week rhythm towards the maximum tolerated dose.
If the patient is in sinus rhythm with a heart rate >70/min and the maximum tolerated beta blocker dose has been reached, the use of the If channel blocker ivabradine can be considered. The target heart rate for heart failure is <70 beats per minute.
If the ECG of the sinus rhythm shows a QRS duration of >130 ms with left bundle branch block morphology, the implantation of a CRT implant (cardiac resynchronization therapy) can also be considered.
In addition, diuretics should be prescribed at all times at the first signs of congestion as well as in patient with symptoms (NYHA III and IV). With clinical stability, the dose can be slowly reduced over time; however, complete discontinuation should be avoided in order not to increase the risk of hydropic decompensation.
If there is no improvement in symptoms under these therapeutic measures, therapy with digitalis preparations for further control of the heart rate can be considered for both sinus rhythm and atrial fibrillation. However, the use of these substances is controversial since data suggest a higher mortality which is not confirmed in a meta-analysis.
According to guidelines, ICD implantation is provided for patients with ischemic or dilated cardiomyopathy who have previously received optimal drug therapy for at least 3 months, who have a life expectancy with a good functional status of more than 12 months and whose LVEF is <35%.

2.2.2. Clinical considerations in patients with diabetes beyond the guidelines

In post-hoc analysis of the CHARM and SOLVD trial showed reduced incidence of DM in patients treated with candesartan and enalapril [22,23]. In the PARADIGM-HF trial the treatment with sacubitril-valsartan compared to enalapril was associated with an 29% reduction in new insulin use. Stimulation of lipolysis, increased lipid oxidation and enhanced oxidative capacity as well as the fact that neprilysin also degrades GLP1 and might contribute to glucose lowering were suggested as possible underlying mechanisms [24]. RAAS (ACE/ARB) and angiotensin neprilysin inhibitors (ARNI) showed similar reduction in morbidity and mortality in patients with HF with or without DM [15,25,26]. This is of substantial importance because of the higher baseline mortality risk of DM patients. ACEI/ARB and ARNI have favorable effects on DM and glycemic control and should therefore be used according to guideline recommendations.

2.2.3. New treatment options: SGLT2-Inhibitors

Within the last years SGLT-2 inhibitors demonstrated a profound reduction of heart failure hospitalization or cardiovascular death in a variety of studies including patients with and without diabetes. Given these data SGLT-2 inhibitors are already seen as one of the” fantastic four” (together with ß-blockers, ARNI and MRA) in heart failure treatment [27]. Currently there is a lively discussion about the upcoming new 2021 ESC guidelines on heart failure and position of SGLT2 inhibition within the new therapy algorithm.
SGLT2 inhibitors were primarily developed for the treatment of diabetes mellitus and act by inhibiting the sodium glucose transporter 2 in the proximal tubule of the kidney. This leads to the excretion of 80–100 g glucose per day (corresponding to approx. 400 kcal) and increased natriuresis.
Since the initial cardiovascular safety studies in patients with diabetes mellitus showed a highly significant decrease in hospitalization rates due to heart failure by around 35%, these substances were subsequently tested in patients with heart failure regardless of the presence of diabetes mellitus.
In 2019, DAPA-HF (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction) was published as the first study that included patients with symptomatic heart failure with (45% of all patients) and without diabetes mellitus (55% of all patients) and an ejection fraction 40% randomized to dapagliflozin 10 mg or placebo. Over a mean follow-up of 18 months, dapagliflozin led to a significant reduction in the combined primary endpoint of cardiovascular death or worsening heart failure by 26% with a number-needed-to-treat of 21 to prevent 1 event. This composite endpoint was not only driven by a 30% relative risk reduction in worsening heart failure, but also by a significant reduction in cardiovascular death (18% relative risk reduction). The overall mortality could also be significantly reduced (17% relative risk reduction) by dapagliflozin. A predefined subgroup analysis showed that the benefit of therapy with the SGLT-2 inhibitor dapagliflozin was independent of the presence of diabetes [28].
The recently published EMPEROR-Reduced study (Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure) provided similar data. In 3730 patients with heart failure and an ejection fraction 40% in the mean follow-up of 16 months, there was a significant reduction in the primary endpoint (cardiovascular death or hospitalization due to heart failure) through the administration of empagliflozin compared to placebo (25% relative Risk reduction) [29].
On the basis of these data, therapy with SGLT-2 inhibitors represents a breakthrough in heart failure therapy regardless of the presence of diabetes mellitus. Since November 2020, dapagliflozin, the first SGLT2 inhibitor for the treatment of heart failure with reduced LV-EF (EF <40%) up to a GFR of 30 ml/min, has been officially approved.
It is to also be expected that the SGLT2 inhibitors will find a permanent place in the guidelines of the European Society of Cardiologists for the treatment of heart failure, which will be published soon.

3. Therapy of diabetes in patients with heart failure

Regardless of the classification of SGLT2 inhibitors in the therapy scheme for heart failure, SGLT2 inhibitors are important in the treatment of diabetes and especially in patients who have both diseases combined.
This is reflected in the 2019 update of the consensus paper of the European and American diabetes societies (EASD and ADA) as well as the guideline on diabetes/prediabetes and cardiovascular diseases of the European Cardiologist Society (ESC) with a preferred use of SGLT2 inhibitors in patients with diabetes and heart failure [19,30].
In addition, with regard to the remaining substance classes, some features have to be considered in patients with heart failure (see Table 1):

3.1. SGLT2 inhibitors

The EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) was the first study to show beneficial effects on a combined cardiovascular endpoint of cardiovascular death, non-fatal stroke, and myocardial infarction under therapy with empagliflozin. Furthermore, there was also a highly significant reduction in all-cause mortality. The analysis of secondary endpoints also showed a highly significant decrease in hospitalization rates for heart failure by 35%; this result was independent of the pre-existing heart failure [21].
Similar data are available for canagliflozin using the Integrated CANVAS Program (CANagliflozin cardioVascular Assessment Study & A Study of the Effects of Canagliflozin (JNJ-28431754) on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus); Here, too, there was a relevant reduction in heart failure hospitalization rates of 33% and a 14% reduction in the primary combined endpoint of cardiovascular death, non-fatal stroke and myocardial infarction. However, there was no significant reduction in overall or cardiovascular mortality with canagliflozin [31].
Comparable, the DECLARE-TIMI 58 study (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events) showed a 17% reduction in cardiovascular mortality or hospitalization for heart failure in patients with diabetes and a cardiovascular risk profile [32].
In the recently published VERTIS (Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes) study, the SGLT2 inhibitor ertugliflozin in 8246 patients with diabetes and cardiovascular disease showed cardiovascular safety with regard to the primary endpoint consisting of cardiovascular death, myocardial infarction and stroke. Only hospitalization due to heart failure could be reduced, similar to the studies described above. It has not yet been fully clarified why ertugliflozin has no protective effects with regard to 3P-MACE. This may be due to substance-specific properties or an overall shorter study duration for a large part of the study collective [33].
In the SOLOIST-WHF trial (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) the SGLT2 inhibitor sotagliflozin was recently investigated in a collective of patients with diabetes mellitus who were recently hospitalized for heart failure. The study was terminated early due to a lack of funding. After a mean follow-up of 9 months, a significant reduction in the primary endpoint consisting of a combination of cardiovascular death or hospitalization due to heart failure or worsening heart failure event was found in 1222 patients [34].
SGLT2 inhibitors are the first glucose lowering agents that reduce the rate of heart failure-related hospitalization in patients with and without HF. SGLT-2 inhibitors should therefore be used as early as possible in the treatment of both diseases. They are also recommended as first line therapy by the current ESC guideline [19] and should be considered independently of baseline HbA1c or individualized HbA1c target according to ADA/EASD [30].

3.2. Biguanides (Metformin)

The European cardiological guidelines no longer recommend metformin as a first-line therapy in case of high cardiovascular risk or prevalent CVD. In this case SGLT-2 inhibitors or GLP-1 analoga are first line therapy. In heart failure SGLT-2 inhibitors are recommended with an evidence class IA recommendation [17]. If a patient with type 2 diabetes has neither cardiovascular disease nor a very high/high cardiovascular risk, metformin monotherapy should be considered (Class IIaC recommendation) [19].
In the 2018 update from ADA and EASD metformin continues to be the basic therapy for diabetes mellitus in patients with previous cardiac disease.
The evidence for metformin is based on the UKPDS study published in 1998, in which metformin showed a significant reduction in the risk of acute myocardial infarction in a subgroup of 342 overweight patients compared to conventional blood sugar lowering therapy [35].
In the past, it was unclear whether metformin could lead to increased lactic acidosis in the context of heart failure and chronic kidney failure. A meta-analysis with 34 000 patients showed a reduced mortality (pooled adjusted risk estimate, 0.80 [95% CI, 0.74–0.87]) and a small reduction in all-cause hospitalization (pooled adjusted risk estimate, 0.93 [95% CI, 0.89–0.98]) in patients with HF compared to control patients [36]. An observational study showed a significant reduction in mortality and a non-significant trend in favor of a reduced hospitalization rate [37].
Thus, current data suggest, that metformin is safe, effective and well tolerated substance for the use in heart failure patients.

3.3. DPP-4 (dipeptidyl peptidase 4) inhibitor

DPP-4 inhibitors prolong the half-life of the incretin hormones glucagon-like-peptide 1 and gastric inhibitory polypeptide, which in turn increase glucose-dependent insulin secretion and reduce glucagon secretion. Various large cardiovascular outcome trials with DDP-4 inhibitors demonstrated cardiovascular safety for 3P-MACE; superiority with benefical effect. Other agents might be used before considering Sulfonylureas regard to cardiovascular endpoints has not yet been demonstrated [19].
In the SAVOR-TIMI53 study (Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus) saxagliptin led to an increased hospitalization rate due to heart failure [38].
However, this is not a class effect. For sitagliptin, the TECOS study (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) and for linagliptin in the CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus) study showed no risk of hospitalization for heart failure at all [39,40]. For alogliptin, EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in patients with type 2 diabetes mellitus and acute coronary syndrome) found a non-significant risk increase for the hospitalization for heart failure [41]. Thus, DPP-4 inhibitors are safe for clinical use in patients with heart failure, with the exception of saxagliptin, which should not be used or discontinued in patients with heart failure.

3.4. Thiazolidinediones

In the randomized controlled PROactive and RECORD trial Piogliatzone and Rosiglitazone respectively demonstrated increased rates of HF hospitalization [42,43]. Glitazones increase insulin sensitivity, but they cause sodium and associated water retention. This results in an increased risk of hydropic cardiac decompensation in heart failure patients [44]. Therefore, the use of glitazones in patients with heart failure is contraindicated [17].

3.5. GLP-1 receptor agonists

Most GLP-1 receptor agonists activate the GLP-1 receptor and thus lower blood-glucose levels along with other beneficial effects e.g., on blood pressure and weight. Several large cardiovascular outcome trials have shown a reduction in CV events by GLP-1 RA. In the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial Liraglutide decreased MACE (cardiovascular death, myocardial infarction or stroke) by 13% and all cause as well as cardiovascular death in patients with or with high risk of CVD [45]. The SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) demonstrated that semaglutide decreased rate of MACE by 26% compared to placebo [46]. The same was true for albiglutide in the HARMONY (Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus) study [47] and for dulaglutide in REWIND (Dulaglutide and cardiovascular outcomes in type 2 diabetes) study [48]. Thus, many GLP-1 agonists reduce the risk of major cardiovascular events in patients with DM and the cardiovascular beneficial effects of these substances can most likely be explained by a reduction in atherosclerosis-associated endpoints. With regard to hospitalization for heart failure, GLP-1 agonists showed no benefit. However, these substances were safe in the large endpoint studies mentioned above and can be used in HF patients

3.6. Insulin

Subcutaneous insulin therapy usually is indicated in type 2 diabetes when other therapies are not sufficient to achieve glycemic control. Insulin therapy is associated with an increased risk of hypoglycemia and weight gain. The ORIGIN study in 2012 showed that there was a slight, nonsignificant, trend towards a reduction in hospitalizations due to heart failure under therapy with the long-acting insulin glargine (hazard ratio 0.95; 4.9% vs. 5.5%, p = 0.16) [49]. Based on these results of a total of 12,537 patients included, the cardiovascular safety of insulin therapy in the context of heart failure can be assumed. The use should be closely monitored, and other agents might be preferred if possible.

3.7. Sulfonylureas

The oral administered sulphonylureas cause an increased pancreatic release of insulin, as well as an inhibition of the hepatic gluconeogenesis. Since insulin secretion by sulfonylureas is glucose-independent, hypoglycemia and weight gain occur more frequently. This effect is less pronounced with the sulfonylureas of the new generations. The recently published CAROLINA (Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes) study, in which the DPP-4 inhibitor linagliptin (previously show to be neutral with respect to heart failure endpoints in the CARMELINA trial) was compared with the sulphonylurea glimepiride, showed glimepiride does not lead to an increased risk of hospitalization for heart failure. Thus, modern sulfonylureas like glimepiride appear safe in patients with heart failure but have no beneficial effect.

4. Conclusion

In conclusion, concomitant DM and HF increase cardiovascular risk and significantly determines the patient’s prognosis. The treatment is complex and still a therapeutic challenge. In order to improve the patient’s outcome, an early differentiated drug therapy with exhaustion of all possible therapy options is therefore of crucial importance. SGLT2 inhibitors are the first blood glucose lowering agents that reduce the rate of HF-related hospitalization and CV death in patients with and without DM and should therefore be used as first line therapy for patients with DM and HF. Based on the data of DAPA-HF and EMPEROR-Reduced, it is to be expected that SGLT2 inhibitors will find a permanent place in the guidelines for the treatment of heart failure in both, patients with and without diabetes.

R E F E R E N C E S

[1] Savarese G, Lund LH. Global Public Health Burden of Heart Failure. Card Fail Rev 2017;3:7–11.
[2] 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;27:1879–84.
[3] Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 2007;93:1137–46.
[4] Mamas MA, Sperrin M, Watson MC, Coutts A, Wilde K, Burton C, et al. Do patients have worse outcomes in heart failure than in cancer? A primary care-based cohort study with 10year follow-up in Scotland. Eur J Heart Fail 2017;19:1095–104.
[5] Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388:1545–602.
[6] International Diabetes Federation. IDF Diabetes Atlas, 9th ed. Brussels, Belgium: International Diabetes Federation; 2019.
[7] Thrainsdottir IS, Aspelund T, Thorgeirsson G, Gudnason V, Hardarson T, Malmberg K, et al. The association between glucose abnormalities and heart failure in the populationbased Reykjavik study. Diabetes Care 2005;28:612–6.
[8] Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, et al. Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008;29:270–6.
[9] Boonman-de Winter LJ, Rutten FH, Cramer MJ, Landman MJ, Liem AH, Rutten GE, et al. High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes. Diabetologia 2012;55:2154–62.
[10] 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. [11] Gustafsson I, Brendorp B, Seibaek M, Burchardt H, Hildebrandt P, Kober L, et al. Influence of diabetes and diabetes-gender interaction on the risk of death in patients hospitalized with congestive heart failure. J Am Coll Cardiol 2004;43:771–7.
[12] Pfeffer MA, Braunwald E, Moye 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. The SAVE Investigators. N Engl J Med 1992;327:669–77.
[13] 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.
[14] 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.
[15] 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.
[16] 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.
[17] Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891–975.
[18] Yancy CW, Jessup M, Bozkurt B, Butler J, Casey Jr DE, Colvin MM, et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines and the Heart KWA 0711 Failure Society of America. J Am Coll Cardiol 2016;68:1476–88.
[19] Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, prediabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323.
[20] Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, et al. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med 2019;381:1609–20.
[21] 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.
[22] Yusuf S, Ostergren JB, Gerstein HC, Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on the development of a new diagnosis of diabetes mellitus in patients with heart failure. Circulation 2005;112:48–53.
[23] Vermes E, Ducharme A, Bourassa MG, Lessard M, White M, Tardif JC, et al. Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation 2003;107:1291–6.
[24] Seferovic JP, Claggett B, Seidelmann SB, Seely EW, Packer M, Zile MR, et al. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol 2017;5:333–40.
[25] Shekelle PG, Rich MW, Morton SC, Atkinson CS, Tu W, Maglione M, et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials. J Am Coll Cardiol 2003;41:1529–38.
[26] Kristensen SL, Preiss D, Jhund PS, Squire I, Cardoso JS, Merkely B, et al. Risk Related to Pre-Diabetes Mellitus and Diabetes Mellitus in Heart Failure With Reduced Ejection Fraction: Insights From Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial. Circ Heart Fail 2016;9.
[27] Bauersachs J. Heart failure drug treatment: the fantastic four. Eur Heart J 2021;42:681–3.
[28] McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 2019;381:1995–2008.
[29] Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–24.
[30] Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, et al. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018;2020(63):221–8.
[31] Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377:644–57.
[32] Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57.
[33] Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383:1425–35.
[34] Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2020.
[35] ] Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65.
[36] Eurich DT, Weir DL, Majumdar SR, Tsuyuki RT, Johnson JA, Tjosvold L, et al. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail 2013;6:395–402.
[37] Aguilar D, Chan W, Bozkurt B, Ramasubbu K, Deswal A. Metformin use and mortality in ambulatory patients with diabetes and heart failure. Circ Heart Fail 2011;4:53–8.
[38] 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.
[39] 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.
[40] 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.
[41] 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. [42] Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, MassiBenedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–89.
[43] Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 2009;373:2125–35.
[44] Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 2005;111:583–90.
[45] Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22.
[46] Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–44. [47] Hernandez AF, Green JB, Janmohamed S, D’Agostino Sr RB, Granger CB, Jones NP, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392:1519–29.
[48] Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394:121–30.
[49] Investigators OT, Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367:319–28.
[50] Holman RR, Bethel MA, Hernandez AF. Once-weekly exenatide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:2502.
[51] Ou SM, Shih CJ, Chao PW, Chu H, Kuo SC, Lee YJ, et al. Effects on clinical outcomes of adding dipeptidyl peptidase-4 inhibitors versus sulfonylureas to metformin therapy in patients with type 2 diabetes mellitus. Ann Intern Med 2015;163:663–72.