The rising prevalence of diabetes mellitus (DM) in heart failure (HF) patients is becoming a global burden. It is a more frequently coexisting risk factor for incident HF, given its increasing role in morbidity and mortality.1 Reports of its coexistence in HF range from 10% to 47%.2–4 The optimal therapeutic approach to DM (especially type 2) has gained much importance in the recent past. Early introduction of sodium-glucose transport protein 2 (SGLT2) inhibitors in the treatment strategy seems beneficial to reduce frequent HF-related hospitalizations. The coexistence of both DM and HF warrants a multidisciplinary approach in such patients. The importance of lifestyle modifications along with glucose-lowering agents plays a major role in achieving better outcomes in HF patients with DM.5 The risk of HF in patients with DM is more evident in women and young adults.6 The risk of developing HF in DM is multifactorial and is mainly related to poor glycemic control, older age, obesity, hypertension, and coronary artery disease (CAD).7

There is scant data on the morbidity and mortality of HF patients with DM stratified by left ventricular ejection fraction (LVEF) in the Arabian Gulf. Hence, we sought to evaluate the morbidity and mortality of diabetic HF patients in the Arabian Gulf stratified by LVEF.

Methods

We used the data from a prospective, multicenter, multinational registry of acute heart failure (AHF) patients admitted to 47 hospitals in seven Middle Eastern countries (Bahrain, Oman, Qatar, UAE, Kuwait, Saudi Arabia, and Yemen). The methods of Gulf Acute Heart Failure Registry (CARE) have been published previously.8 In summary, demographic and clinical characteristics, as well as outcomes, were captured. Follow-up for all-cause mortality and re-hospitalization history were collected via telephone at three-months and either via telephone or through outpatient clinic visits at one-year. The registry is listed on clinicaltrials.gov (number NCT01467973).

Data entry was carried out online using a custom-designed electronic case-record form (CRF) at the Gulf CARE website (www.gulfcare.org). Institutional ethical committee approvals were obtained. Trained abstractors collected the data from medical records at each participating site, and this information was recorded using an electronic CRF.

AHF was defined, according to the European Society of Cardiology,9,10 as the rapid onset of symptoms and signs secondary to abnormal cardiac function.

HF with reduced ejection fraction (HFrEF) was diagnosed when patients with symptoms and signs of HF had a measured EF < 40%. HF with mid-range EF (HFmrEF) was diagnosed when patients with symptoms and signs of HF had a measured EF between 40–49%. HF with preserved EF (HFpEF) was diagnosed when patients with symptoms and signs of HF had a measured EF between ≥ 50%.11–13 Patients with HF that did not require admission were excluded from the registry. Furthermore, those that did not have a record of EF were also excluded from the analysis.

CAD was diagnosed if any of the following conditions were present: at least one major epicardial coronary artery determined by coronary angiography to have > 70% obstruction, history of myocardial infarction associated with wall motion abnormality seen on echocardiography or gated blood pool imaging, and/or stress testing (with or without imaging) results that are diagnostic of CAD. Hypertension was defined when any of the following conditions were present: untreated systolic blood pressure > 160 mmHg or diastolic blood pressure > 105 mmHg for at least three months and/or hypertension requiring at least two drugs for control for ≥ 5 years.14 DM was diagnosed based on fasting plasma glucose levels (FPG) ≥ 126 mg/dL (7.0 mmol/L), two-hour plasma glucose levels (2-h PG) ≥ 200 mg/dL (11.1 mmol/L) during oral glucose tolerance test, and glycated hemoglobin A1c (HbA1c) ≥ 6.5% (48 mmol/mol).15

Descriptive statistics were used to present the data. Categorical variables were summarized as frequencies and percentages and analyzed using Pearson’s chi-squared test. Continuous variables were summarized using means and standard deviations and analysis performed using ordinary least squares regression.

Multivariable logistic regression models, utilizing the simultaneous method, were performed to evaluate the impact of HF (HFrEF, HFmrEF, and HFpEF) on all-cause mortality and re-hospitalization (primary outcomes) at three-months and one-year post-hospital discharge. The multivariate logistic models were adjusted for significant demographic and clinical characteristics as well as medications outlined in Tables 1 and 2. The goodness-of-fit of the multivariable logistic model was examined using the Hosmer and Lemeshow goodness-of-fit statistic, and the discriminatory power of the logistic model was assessed by the area under the receiver operating characteristics curve also known as C-index. An a priori two-tailed level of significance was set at p < 0.050. Statistical analyses were conducted using STATA version 13.1 (STATA Corporation, College Station, TX, USA).

Results

A total of 2258 patients with diabetes with a diagnosis of AHF were recruited to the study; 60.3% (n = 1362) of the patients were male. The mean age was 63.0±11.0 years, ranging from 18 to 99 years. A total of 1658 (73.4%) had CAD, 1843 (81.6%) patients had hypertension, and 1228 (54.4%) patients had known dyslipidemia. Atrial fibrillation was observed in 274 (12.1%) patients and chronic kidney disease was observed in 525 (23.3%) patients.

The median EF was 35% (25–45%). HFrEF was observed in 1268 (56.2%) patients, whereas 515 (22.8%) patients had HFmrEF and 475 (21.0%) patients had HFpEF. At hospital discharge, the etiology of HF was recorded as being acute coronary syndrome in 739 (32.7%) patients, primary cardiomyopathy in 285 (12.6%) patients, hypertensive heart disease in 388 (17.2%) patients, primary valve pathology in 106 (4.7%) patients, and pulmonary hypertension in 41 (1.8%) patients. The median duration of hospitalization was six (4–10) days. The overall in-hospital mortality was 5.3% (n = 120).

Compared with the HFmrEF and HFpEF groups, patients with HFrEF were younger (61.0 vs. 64.0 vs. 66.0 years; p < 0.001), more likely to be male (70.7% vs. 55.5% vs. 37.9%; p < 0.001) and smokers (21.5% vs. 18.4% vs. 9.5%; p < 0.001) and have higher levels of estimated glomerular filtration rate (eGFR) (63.0 vs. 60.0 vs. 57.0 mL/min/m2; p = 0.001) but less likely to have chronic kidney disease requiring dialysis (21.5% vs. 22.5% vs. 28.6%; p = 0.007), hypertension (78.0% vs. 83.3% vs. 89.5%; p < 0.001), and sleep apnea requiring therapy (1.8% vs. 3.3% vs. 6.7%; p < 0.001), respectively. Patients in the HFpEF group had an elevated pulmonary artery pressure than patients with HFrEF and HFmrEF (57.0 vs. 53.0 vs. 52.0 mmHg; p = 0.015). A higher prevalence of atrial fibrillation (15.8% vs. 12.3% vs. 8.4%; p = 0.002) but lower levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) (1885 vs. 2962 vs. 3372 pg/mL; p = 0.008) was seen with HFpEF patients when compared to those with HFmrEF and HFrEF [Table 1].

At hospital discharge, compared with the HFmrEF and HFpEF groups, patients with HFrEF were more likely to receive diuretics (97.2%. vs. 94.1% vs. 90.9%; p < 0.001), beta-blockers (77.2% vs. 71.7% vs. 56.8%; p < 0.001), angiotensin-converting-enzyme inhibitors (64.2% vs. 56.1% vs. 41.1%; p < 0.001), and aldosterone antagonists (50.4% vs. 21.2% vs. 14.8%; p < 0.001), whereas they were less likely to be administered calcium antagonists (11.2% vs. 25.1% vs. 45.5%; p < 0.001) and angiotensin-receptor blockers (17.5% vs. 19.2% vs. 24.5%; p = 0.006) [Table 2]. During hospitalization, patients with HFmrEF and HFpEF were less likely to receive IV furosemide infusion than the HFrEF group (16.5% vs. 13.3% vs. 21.6%; p < 0.001).

The overall cumulative all-cause mortalities at three-month and 12-month follow-up were 11.8% (n = 266) and 20.7% (n = 467), respectively. Those with HFpEF were associated with lower three-month cumulative all-cause mortality compared to those with HFrEF (7.6% vs. 5.9%; adjusted odds ratio (aOR) = 0.54, 95% confidence interval (CI): 0.31–0.95; p = 0.031) but not significantly different when compared to those with HFmrEF (aOR = 0.86, 95% CI: 0.53–1.40; p = 0.554). There were no significant differences among the groups with regards to the 12-month all-cause cumulative mortality (11% vs. 11% vs. 10%; overall p = 0.984). There were also no significant differences in re-hospitalization rates between the three HF groups not only at three-months (23% vs. 20% vs. 22%; overall p = 0.520), but also at one-year follow-up (28% vs. 30% vs. 32%; overall p = 0.335) [Table 3].

Discussion

The observations from this multinational registry showed that three-month cumulative all-cause mortality was high in diabetic HFrEF patients compared to those with HFpEF. However, there were no significant differences in mortality at one-year follow-up between the HF groups. There were also no significant differences in re-hospitalization rates between the HF groups not only at three-months but also at one-year follow-up in the Middle East.

In the Framingham Heart Study, the risk of incident HF was two-fold higher in diabetic males and four-folds higher in diabetic females.16 The study has also shown a 34% mortality at one-year for diabetic HF patients.17 In the Heart and Soul Study in a cohort of CAD patients with DM were associated with a higher risk of incident HF.18 The risk of incident HF rises from 8% to 36% with each 1% rise in HbA1c.19 The Atherosclerosis Risk in Communities (ARIC) study has shown rising HF-related hospitalization rates with increases in HbA1c.20 Various other studies have also documented poor outcomes in patients with HF and with elevated HbA1c.21 In another study that consists of 18 084 non-diabetic patients with a higher risk of cardiovascular diseases has also shown that a mild increase in blood glucose of 1 mmol/L increases the risk of hospitalization by 1.23-fold.22

In the Candesartan in Heart failure-Assessment of moRtality and Morbidity (CHARM) trial, the rate of hospitalizations was higher in patients with HFpEF than in those with HFrEF. Furthermore, the observed all-cause mortality risk in patients with DM was the same in both HFrEF and HFpEF.23 In acute HF patients, the presence of DM increases mortality in both ambulatory and hospitalized patients.23,24 In another community-based study, it was shown that T2DM increases mortality and morbidity in both HFrEF and HFpEF.25 In another study, a moderate difference in in-hospital mortality between HFrEF and HFpEF diabetic patients has been observed.26 The incidence of DM was high (67%) in AHF patients with cardio-renal anemia syndrome in the Arabian Gulf.27 A new risk calculator for HFrEF (www.hfriskcalc.in) has been suggested.28,29

Many HF risk models take DM as an important variable and consider it as an independent risk factor for predicting mortality.30 In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial, the presence of diabetes had shown a two-fold rise in mortality and morbidity.31 In the Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) trial, cardiovascular mortality and HF-related morbidity was 34% in diabetic HF patients.32 The Studies of Left Ventricular Dysfunction (SOLVD) trial also demonstrated higher rates of hospitalizations and mortality in asymptomatic ischemic cardiomyopathy patients with diabetes.33 The same study also showed that African-Americans with HFrEF were at higher risk of developing AHF compared to Caucasians.34 A meta-analysis of eight trials demonstrated that the risk of HF remains same in both strict the glycemic control group and standard treatment group.35

Many randomized controlled trials have shown that in diabetic HF patients, strict glycemic control has no benefits in terms of outcome.36 In the Arabian Gulf, the AHF patients were a decade younger compared to those from the rest of the world.37 The Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial has shown mortality and morbidity benefits in diabetic HF patients on dapagliflozin treatment.38 In a study of black diabetic cardiomyopathic patients, a reduced stroke and end-diastolic volume were associated with an increased left ventricular mass.39 In the Empagliflozin Cardiovascular Outcome Event (EMPA-REG) trial, HF-related hospitalizations were associated with those treated with SGLT2 inhibitors.40 In the Saxagliptin Assessment of Vascular Outcomes Recorded (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial, the use of saxagliptin was associated with an increased risk of HF hospitalizations.41 Middle East data on diabetic and non-diabetic AHF patients showed no significant differences in all-cause mortality and rehospitalizations at three and 12 months.42 In HF and diabetes, genetics plays an important role and further studies are needed.43,44

Various limitations of this registry are noteworthy. In some countries, only a few hospitals took part in the registry; hence, the results might not be entirely generalizable. Since this study was derived from a HF registry in the Arabian Gulf, it is unfortunate that diabetic medications were not captured. Mortality rates at three-months and one-year follow-up were only recorded without the specification of the exact date of death of each patient. Hence, survival analysis, which might have been more appropriate, could not have been performed. Future studies need to overcome these limitations.

Conclusion

Three-month cumulative all-cause mortality was high in diabetic HFrEF patients compared to those with HFpEF. However, there were no significant differences in mortality at one-year follow-up between the HF groups in the Middle East. There were also no significant differences in re-hospitalization rates between the HF groups not only at three-months but also at one-year follow-up.

Disclosure

The authors declared no conflict of interest. No funding was received for this study.

Acknowledgements

Thanks to Prof. Dr. Eugene Braunwald for introducing the word cardio-diabetology and explaining its importance.

Gulf CARE is an investigator-initiated study conducted under the auspices of the Gulf Heart Association and funded by Servier, Paris, France; and for centers in Saudi Arabia by the Saudi Heart Association.

references

1. 1. 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. 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 Aug;140(7):e294-e324.
2. 2. Sandesara PB, O’Neal WT, Kelli HM, Samman-Tahhan A, Hammadah M, Quyyumi AA, et al. The prognostic significance of diabetes and microvascular complications in patients with heart failure with preserved ejection fraction. Diabetes Care 2018 Jan;41(1):150-155.
3. 3. Dei Cas A, Fonarow GC, Gheorghiade M, Butler J. Concomitant diabetes mellitus and heart failure. Curr Probl Cardiol 2015 Jan;40(1):7-43.
4. 4. From AM, Leibson CL, Bursi F, Redfield MM, Weston SA, Jacobsen SJ, et al. Diabetes in heart failure: prevalence and impact on outcome in the population. Am J Med 2006 Jul;119(7):591-599.
5. 5. Seferovic PM, Ponikowski P, Anker SD, Bauersachs J, Chioncel O, Cleland JG, et al. Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019 Oct;21(10):1169-1186.
6. 6. 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 Aug;27(8):1879-1884.
7. 7. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, et al; SAVOR-TIMI 53 Steering Committee and Investigators*. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation 2014 Oct;130(18):1579-1588.
8. 8. Sulaiman KJ, Panduranga P, Al-Zakwani I, Alsheikh-Ali A, Al-Habib K, Al-Suwaidi J, et al. Rationale, design, methodology and hospital characteristics of the first Gulf Acute Heart Failure Registry (Gulf CARE). Heart Views 2014 Jan;15(1):6-12.
9. 9. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al; Authors/Task Force Members; Document Reviewers. 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 Aug;18(8):891-975.
10. 10. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, et al; ESC Committee for Practice Guidelines (CPG). ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail 2008 Oct;10(10):933-989.
11. 11. Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007 Oct;28(20):2539-2550.
12. 12. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European society of cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012 Jul;33(14):1787-1847.
13. 13. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013 Oct;62(16):e147-e239.
14. 14. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005 Sep;112(12):e154-e235.
15. 15. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009 Jul;32(7):1327-1334.
16. 16. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974 Jul;34(1):29-34.
17. 17. Ho KK, Anderson KM, Kannel WB, Grossman W, Levy D. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation 1993 Jul;88(1):107-115.
18. 18. 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 Sep;33(9):2084-2089.
19. 19. Pazin-Filho A, Kottgen A, Bertoni AG, Russell SD, Selvin E, Rosamond WD, et al. HbA 1c as a risk factor for heart failure in persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) study. Diabetologia 2008 Dec;51(12):2197-2204.
20. 20. Matsushita K, Blecker S, Pazin-Filho A, Bertoni A, Chang PP, Coresh J, et al. The association of hemoglobin a1c with incident heart failure among people without diabetes: the atherosclerosis risk in communities study. Diabetes 2010 Aug;59(8):2020-2026.
21. 21. Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 2014 Apr;57(4):660-671.
22. 22. Held C, Gerstein HC, Yusuf S, Zhao F, Hilbrich L, Anderson C, et al; ONTARGET/TRANSCEND Investigators. Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk. Circulation 2007 Mar;115(11):1371-1375.
23. 23. MacDonald MR, Petrie MC, Varyani F, Ostergren J, Michelson EL, Young JB, et al; CHARM Investigators. 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 Jun;29(11):1377-1385.
24. 24. Targher G, Dauriz M, Laroche C, Temporelli PL, Hassanein M, Seferovic PM, et al; ESC-HFA HF Long-Term Registry investigators. In-hospital and 1-year mortality associated with diabetes in patients with acute heart failure: results from the ESC-HFA Heart Failure Long-Term Registry. Eur J Heart Fail 2017 Jan;19(1):54-65.
25. 25. Allen LA, Magid DJ, Gurwitz JH, Smith DH, Goldberg RJ, Saczynski J, et al. Risk factors for adverse outcomes by left ventricular ejection fraction in a contemporary heart failure population. Circ Heart Fail 2013 Jul;6(4):635-646.
26. 26. Vaduganathan M, Fonarow GC. Epidemiology of hospitalized heart failure: differences and similarities between patients with reduced versus preserved ejection fraction. Heart Fail Clin 2013 Jul;9(3):271-276.
27. 27. Al-Jarallah M, Rajan R, Al-Zakwani I, Dashti R, Bulbanat B, Sulaiman K, et al. Incidence and impact of cardiorenal anaemia syndrome on all-cause mortality in acute heart failure patients stratified by left ventricular ejection fraction in the Middle East. ESC Heart Fail 2019 Feb;6(1):103-110.
28. 28. Rajan R, Al Jarallah M. New prognostic risk calculator for heart failure. Oman Med J 2018 May;33(3):266-267.
29. 29. Rajan R, Al Jarallah M, Al-Zakwani I, Dashti R, Bulbanat B, Ridha M, et al. Impact of R-hf risk score on all-cause mortality in acute heart failure patients in the middle east. J Card Fail 2019;25(8):S97.
30. 30. Pocock SJ, Ariti CA, McMurray JJ, Maggioni A, Køber L, Squire IB, et al; Meta-Analysis Global Group in Chronic Heart Failure. Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies. Eur Heart J 2013 May;34(19):1404-1413.
31. 31. Davis BR, Piller LB, Cutler JA, Furberg C, Dunn K, Franklin S, et al; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Role of diuretics in the prevention of heart failure: the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation 2006 May;113(18):2201-2210.
32. 32. Kristensen SL, Mogensen UM, Jhund PS, Petrie MC, Preiss D, Win S, et al. Clinical and echocardiographic characteristics and cardiovascular outcomes according to diabetes status in patients with heart failure and preserved ejection fraction: a report from the I-PRESERVE Trial (Irbesartan in Heart Failure With Preserved Ejection Fraction). Circulation 2017 Feb;135(8):724-735.
33. 33. Das SR, Drazner MH, Yancy CW, Stevenson LW, Gersh BJ, Dries DL. Effects of diabetes mellitus and ischemic heart disease on the progression from asymptomatic left ventricular dysfunction to symptomatic heart failure: a retrospective analysis from the Studies of Left Ventricular Dysfunction (SOLVD) Prevention trial. Am Heart J 2004 Nov;148(5):883-888.
34. 34. Dries DL, Exner DV, Gersh BJ, Cooper HA, Carson PE, Domanski MJ. Racial differences in the outcome of left ventricular dysfunction. N Engl J Med 1999 Feb;340(8):609-616.
35. 35. Castagno D, Baird-Gunning J, Jhund PS, Biondi-Zoccai G, MacDonald MR, Petrie MC, et al. Intensive glycemic control has no impact on the risk of heart failure in type 2 diabetic patients: evidence from a 37,229 patient meta-analysis. Am Heart J 2011 Nov;162(5):938-948.e2.
36. 36. Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, et al; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008 Jun;358(24):2545-2559.
37. 37. Panduranga P, Al-Zakwani I, Sulaiman K, Al-Habib K, Alsheikh-Ali A, Al-Suwaidi J, et al. Comparison of Indian subcontinent and Middle East acute heart failure patients: Results from the Gulf Acute Heart Failure Registry. Indian Heart J 2016 Apr;68(Suppl 1):S36-S44.
38. 38. Kato ET, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RH, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 2019 May;139(22):2528-2536.
39. 39. Bertoni AG, Goff DC Jr, D’Agostino RB Jr, Liu K, Hundley WG, Lima JA, et al. Diabetic cardiomyopathy and subclinical cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care 2006 Mar;29(3):588-594.
40. 40. Fitchett D, Butler J, van de Borne P, Zinman B, Lachin JM, Wanner C, et al; EMPA-REG OUTCOME® trial investigators. 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 Feb;39(5):363-370.
41. 41. Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ 2016 Feb;352:i610.
42. 42. Al-Jarallah M, Rajan R, Al-Zakwani I, Dashti R, Bulbanat B, Ridha M, et al. Impact of diabetes on mortality and rehospitalization in acute heart failure patients stratified by ejection fraction. ESC Heart Fail 2019 Dec.
43. 43. Strawbridge RJ, van Zuydam NR. Shared Genetic Contribution of Type 2 Diabetes and Cardiovascular Disease: Implications for Prognosis and Treatment. Curr Diab Rep 2018 Jun;18(8):59.
44. 44. Soman SO, Vijayaraghavan G, Natarajan R, Karta CC, Nair RR, Pillai HR. Genetic markers in hypertensive hypertrophic cardiomyopathy. Ann Clin Cardiol 2019;1:20-23.