Heart Failure in T2DM: Ready for Prime Time?

Although not the most prevalent comorbid condition in patients with T2DM, heart failure was the most fatal in a 17-year long nationwide real-life cohort study. 

The risk of developing heart failure (HF) in patients with T2DM is double for men and triple for women compared to patients without T2DM.^1,2  In 2008, the FDA introduced new guidelines that required cardiovascular (CV) safety studies for T2DM medications. Major atherosclerotic coronary events were the primary focus of these studies.³ It is noteworthy that structural heart disease, including HF, was not included as a primary outcome in these guidelines. Although still not an original primary endpoint, reducing HF hospitalizations is now recognized as an essential safety outcome in diabetes trials.⁴  

Determining which CV outcomes are associated with poor prognosis in patients with T2DM is an important clinical consideration and the basis behind Zareini et al., 17-year long Danish nationwide registry study. Eligible adults were required to have a new diagnosis of T2DM, determined by first-time fill of a prescription for non-insulin diabetes medication. Patients were excluded if they had a prior diagnosis of HF, ischemic heart disease (IHD), stroke, chronic kidney disease (CKD), peripheral artery disease (PAD), or gestational diabetes mellitus. The primary outcome was all-cause death. Patients were followed until they left Denmark, died, or completed the study. A landmark approach was used to minimize the risk of immortality bias; subjects still alive at landmark years (any year 0-10 during follow-up) were grouped according to CV or renal disease diagnosis. The diagnosis was assigned according to discharge records and contact information in the patient registry. Patients without a diagnosis served as a reference for calculating the relative risk (RR) and average time lost. The Kaplan Meier estimates ratio was used to calculate RR, and the area under the Kaplan Meier curves was used to determine the average time lost per year.⁵ 

One hundred fifty-three thousand four hundred five subjects were enrolled between January 1998 and December 2015 and followed for a median of 9.7 years. During the follow-up period, approximately 45% of subjects received a diagnosis of CV or renal disease. In these patients, 62.3% received one, 25% received two, and 12.6% had greater than three diagnoses. The most common comorbid condition upon enrollment was hypertension (10.9%). Permitted medications included antihypertensives, statins, aspirin, and diuretics. By the end of the study, the most common diagnosis was IHD (0.6%-8.0%), and the least common was HF (0.4%-4.5%). In patients with two diagnoses, the most frequent combination was IHD and HF.⁵ 

In patients with a single diagnosis of CV or renal disease, still alive 5-years after a diagnosis of T2DM, the highest 5-year risk of death was seen in patients diagnosed with HF (47.6%), compared to less than 35% in patients who developed IHD, stroke, CKD, or PAD. Compared to patients without the corresponding single diagnosis, the 5-year risk of death was highest for HF with a 3-fold increase, and lowest for IHD with a 1.3 fold increase. The average time lost within these five years was highest for HF (11.7 months) and the weakest for IHD (1.6 months).⁵ 

In patients with greater than one CV or renal diagnosis, the risk of death 5-years after T2DM diagnosis was over 50% in patients with HF in combination with stroke (54%) or CKD (63.7%), and less than 50% in patients with HF in combination with PAD (48.4%) or IHD (45.5%). The average time lost during these five years was highest in patients diagnosed with HF and stroke (16.2 months) or HF and CKD (18.2 months) and lowest in patients diagnosed with HF and PAD (14.3 months) or HF and IHD (11 months). According to age, sex, enrollment year, and comorbid conditions upon enrollment, subgroup analyses per landmark year did not differ from the main results. Study limitations include a lack of microvascular complications and clinical data necessary to determine the severity of HF and T2DM. ⁵  

In this real-world registry study, IHD was the most frequent CV diagnosis in patients with new-onset T2DM. However, HF alone, or with other CV or renal disease was the diagnosis associated with the highest risk of death and the most considerable reduction in life expectancy. These findings highlight the importance of structural heart and atherosclerotic risk assessments when treating patients with T2DM. 

Practice Pearls: 

• Patients with T2DM are at an increased risk of developing HF.
• In patients with T2DM, HF is associated with a higher mortality rate than atherosclerotic events.  
• When caring for patients with T2DM, evaluate their risk of developing structural heart and atherosclerotic disease.

References for “Heart Failure in T2DM: Ready for Prime Time?”:

1. Wilkinson, Michael J, et al. “Heart Failure and Diabetes Mellitus: Defining the Problem and Exploring the Interrelationship.“ The American Journal of Medicine vol. 132,10 (2019): S3-S12. doi: 10.1016/j.amjmed.2019.08.004 
2. Bell, David S. “Heart Failure.“ Diabetes Care vol. 26,8 (2003): 2433-2441; doi: 10.2337/diacare.26.8.2433 
3. Butler Javed. Heart Failure Endpoints in Cardiovascular Outcome Trials of Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Type 2 Diabetes Mellitus.“ Circulation vol. 140 (2019): 2108-2118. doi:10.1161/circulationaha.119.042155    
4. Cefalu, William T et al. “Cardiovascular Outcomes Trials in Type 2 Diabetes: Where Do We Go from Here? Reflections From a Diabetes Care Editors’ Expert Forum.“ Diabetes care vol. 41,1 (2018): 14-31. doi:10.2337/dci17-0057 
5. Zareini, Bochra, et al. “Type 2 Diabetes Mellitus and Impact of Heart Failure on Prognosis Compared to Other Cardiovascular Diseases.“ Circ Cardiovasc Qual vol. 13 (2020): e006260. doi:10.1161/circoutcomes.119.006260 

Louise Brown, PharmD Candidate, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences 

See more about heart failure and T2DM in our cardiology center.