Some observational data have demonstrated a potential U-shaped or inverse relation- ship between glycemic levels (HbA1c) and mortality in in- dividuals with established HF and diabetes mellitus.123 125 In a study of 5815 ambulatory patients with HF receiving Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES medical treatment for diabetes mellitus treated at Vet- erans Affairs medical centers, individuals with modest glycemic control (HbA1c >7.1% 7.8%) had lower mor- tality compared with individuals with either higher or low- er HbA1c levels (Figure 4).123 In another cohort of 123 diabetic individuals with advanced HFrEF referred to a single academic medical center, patients with an HbA1c 7.0% had significantly increased mortality compared with those with an HbA1c >7.0% (adjusted HR, 2.3; 95% In a similar study of 358 patients with advanced HFrEF and diabetes mellitus, the relationship between HbA1c levels and 2-year mortality or need for urgent transplantation was assessed with the use of 7.2%; quartile 3, 7.3% 8.5%; and quartile 4, 8.6%). Two-year event-free survival was 61% and 65% in quar- The reasons for this paradoxical re- lationship have not been well established, and given the observational nature of these analyses, these studies do not necessarily imply that glucose lowering causes adverse events. The nature of the association between glucose control and outcomes in patients with HF has also not been consistent in all HF cohorts. In a subset of individuals enrolled in the CHARM trial who had HbA1c available, the relationship between HbA1c and outcomes was assessed in 2412 participants (of whom 907 par- ticipants had known diabetes mellitus).126 In the total CHARM cohort, increasing levels of HbA1c were associ- ated with increased risk of total mortality, HF hospitaliza- tion, and a composite outcome of cardiovascular death or HF hospitalization. 