Heart failure with insulin degludec versus glargine U100 in patients with type 2 diabetes at high risk of cardiovascular disease: DEVOTE 14

Type 2 diabetes (T2D) is becoming increasingly prevalent worldwide and is one of the leading causes of death in the United States [1, 2]. Patients with diabetes are two to three times more likely to have cardiovascular disease (CVD) compared with those without diabetes [3], and CVD is the leading cause of death among these patients [4]. The increased risk of CVD in patients with T2D may be mediated in part through sub-optimal glycemic control, especially chronic hyperglycemia [5, 6], but also hypoglycemia. With respect to the latter, a clear association has been established, although a direct causal relationship remains unclear [7‐12]. As T2D progresses, maintaining glycemic control becomes more challenging, and many patients require treatment intensification using insulin. Insulin-treated T2D increases the risk of severe hypoglycemia [13], which is associated with an increased rate of cardiovascular (CV) events [14, 15] and the possible risk of hospitalization for heart failure (HF) [16‐22].

T2D is an independent risk factor for the development of HF [16]. Indeed, HF has emerged as one of the most common CV complications of T2D [23, 24]. It is estimated that 6.5 million Americans have HF [25], and of these, approximately 40% are reported to have T2D [26]. HF is associated with a poor prognosis; 30–40% of those diagnosed with HF die within 1 year and from then on, mortality rates remain high at 9% per year [27]. Not surprisingly, patients with HF and diabetes have an increased risk of mortality compared with patients with diabetes and no HF [28]. With the prevalence of T2D and HF predicted to increase in the foreseeable future, the coexistence of HF and T2D will become even more pronounced [25].

Recognizing the importance of HF as a complication of T2D, it has been suggested to include HF in a broader 5-point major adverse CV event (MACE) definition when performing T2D CV outcomes trials (CVOTs) [29‐31]. A recent feasibility study using the Medical Dictionary for Regulatory Activities (MedDRA)-based endpoints suggested that these MedDRA query-derived endpoints may have utility as they closely approximate the adjudicated estimates reported in CVOTs [32].

Insulin degludec (degludec) is a basal insulin with an ultra-long duration of action, which has been shown to lead to lower rates of overall confirmed, nocturnal confirmed and severe hypoglycemia compared with insulin glargine 100 units/mL (glargine U100) across different patient populations, including the general diabetes population, elderly patients and patients with type 1 diabetes [33‐40]. In the CVOT Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE), the CV safety of degludec versus glargine U100 was assessed in patients with T2D at high risk of CV events [38]. The primary analysis of DEVOTE showed that degludec was non-inferior to glargine U100 in terms of a 3-point MACE composite endpoint (CV death, non-fatal myocardial infarction [MI] and non-fatal stroke) (hazard ratio [HR] 0.91 [0.78; 1.06]_{95% CI}) [38]. A 4-point MACE composite endpoint that included hospitalization for unstable angina demonstrated similar results. In addition, treatment with degludec, compared with glargine U100, resulted in a lower rate of both severe and nocturnal severe hypoglycemia (HR 0.60 [0.48; 0.76]_{95% CI} and 0.47 [0.31; 0.73]_{95% CI}, respectively; both p < 0.001). In a pre-specified secondary analysis of DEVOTE, a temporal association between severe hypoglycemia and all-cause mortality was identified [11].

DEVOTE presents an opportunity to investigate the risk of HF in a large patient cohort (n = 7637) with T2D at high risk of CV events and treated with insulin. The aims of this pre-specified secondary analysis were to investigate baseline factors and treatment differences that are associated with an increased risk of hospitalization for HF (hHF), and to gain a better understanding of the possible association between severe hypoglycemia and the subsequent increased risk of hHF.

The results from this pre-specified secondary analysis of DEVOTE demonstrated that there was no significant difference in the risk of experiencing hHF with degludec versus glargine U100.

Prior HF at baseline was the strongest predictive factor for experiencing hHF during the trial. Other baseline factors associated with hHF during the trial included hepatic impairment, lower eGFR, atrial fibrillation, higher total insulin dose at week 1, prior MI, macular edema, higher A1C, proteinuria and higher systolic blood pressure. Furthermore, severe hypoglycemia during the trial increased the risk of subsequent hHF. These baseline characteristics are all hallmark characteristics of long-standing diabetes as well as both hepatic impairment and atrial fibrillation potentially being signs of established HF. In particular, a recent survey highlighted that patients with T2D with high blood glucose levels (> 11.1 mmol/L) admitted to hospital with HF had an increased mortality risk [47]. Furthermore, glycemic variability has also been shown to be independently related to an increased risk of all-cause mortality in patients with T2D and HF [48]. When simultaneously considering other baseline variables, diabetes duration was not a strong predictor of hHF. Likewise, age was significantly associated with hHF during the trial in a single-factor analysis, but when considering other predictors of hHF simultaneously this association was no longer significant. Therefore, suggesting that it is the complications associated with age and diabetes duration, and not the age or diabetes duration in itself, leading to an increased risk of hHF.

In this study, 58.9% of patients who experienced hHF had a diagnosis of HF before the trial, compared with 15.3% of patients who did not experience hHF. A greater proportion of patients who experienced hHF during the trial were using β-blockers and diuretics at baseline compared with those who did not experience hHF during the trial. This was expected, as these treatments are standard of care for patients with a prior diagnosis of HF.

Treatment with insulin increases the risk of severe hypoglycemia [13], which is associated with an increased risk of all-cause mortality and CV events, including stroke, coronary heart disease, CV disease and all-cause hospitalization (including heart failure) [16‐22]. In a previous secondary analysis of DEVOTE, it was demonstrated that there was a significant association as well as a temporal association between severe hypoglycemia and all-cause mortality [11]. These results are similar to those observed in the LEADER trial, where it was demonstrated that patients experiencing severe hypoglycemia were more likely than those without severe hypoglycemia to experience MACE, CV death and all-cause mortality [8]. Analyses from the Veterans Affairs Diabetes Trial (VADT) also demonstrated that a severe hypoglycemic event was an independent predictor of death at 90 days [44, 49]. Furthermore, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, patients who had one or more severe hypoglycemic episodes had higher rates of death than those who did not experience such episodes [50]. In the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, severe hypoglycemia increased the risk of arrhythmic death, all-cause death and CV death [10]. In addition, in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), severe hypoglycemia was associated with an increased risk of CV events, all-cause death and CV death [12]. In the current analysis, patients who experienced severe hypoglycemia were at a significantly higher risk of subsequently experiencing hHF than those who did not experience severe hypoglycemia. A strong temporal relationship (with the highest risk observed within a week of the event) further supports this hypothesis. Furthermore, such an association was also demonstrated in LEADER. The relatively weaker strength of an association when adjusting for baseline covariates suggests that the association may partly be explained by more frail patients suffering from comorbidities and complications, which in itself are risk factors of both severe hypoglycemia and hHF [12, 51]. Furthermore, although the hazard ratio for hHF did not reach statistical significance, the point estimate was in favor of degludec. This is consistent with the significantly lower rates of severe hypoglycemia with degludec versus glargine U100 observed in the primary DEVOTE trial [38, 41], and the significantly higher risk of hHF following an occurrence of severe hypoglycemia observed in this secondary analysis. The reason for the hazard ratio for hHF not reaching statistical significance, despite the other two strong significant associations, may be because factors other than treatment may affect the risk of severe hypoglycemia. Furthermore, the trial was not powered to detect a significant treatment effect for hHF. It is also important to note that our investigation into the possible association between severe hypoglycemia and subsequent hHF is relatively novel in that, aside from the TECOS and EMPA-REG OUTCOME trials, this association has not been explored by other trials [12, 52]. In TECOS, a significant association between severe hypoglycemia and subsequent hHF was not identified [12]. However, a post hoc exploratory analysis of the EMPA-REG OUTCOME trial demonstrated that hypoglycaemia was associated with an increased risk of subsequent hHF [52]. Our results are in line with those from EMPA-REG OUTCOME trial as well as LEADER, which had a similar patient population to DEVOTE. However, it is currently unclear whether there is a direct pathophysiological link between severe hypoglycemia and hHF, or whether severe hypoglycemia is primarily a marker of vulnerability for patients at risk of hHF. Overall, our results support an association between severe hypoglycemia and subsequent hHF even when adjusting for potential confounders and it is most likely that hypoglycemia is just a single contributory factor to hHF events in a much larger multifactorial landscape.

This study has a number of limitations. This was a pre-specified secondary analysis from a trial that was not powered to compare differences in the risk of hHF when treated with different basal insulin. It was also not designed or powered to compare the difference in risk of experiencing hHF based on HF prior to the trial or indeed the relationship between severe hypoglycemia and risk of hHF. However, the findings support those from other trials and therefore, this analysis supports and adds to the existing body of evidence.

Furthermore, the inclusion criteria of this trial were designed to recruit a cohort who were at a high CV risk, so the different outcomes observed may not be generalizable to the wider T2D population or to those not fulfilling the inclusion criteria. A further limitation is that hHF events were not adjudicated by an EAC in this trial. However, the sensitivity analysis based on LEADER adjudicated probabilities demonstrated similar results to analyses without adjudication.

Strengths of this study include the large sample size, the double-blind active-control design and the independent adjudication of severe hypoglycemic events. The prospective design and international multicenter nature of this trial, as well as the high levels of patient follow-up are additional strengths. Robustness was also increased through the use of a MedDRA search matched with LEADER EAC criteria, as well as use of the SMQ definition.

This secondary analysis from DEVOTE of patients with T2D at high risk of CV events, treated with basal insulin (degludec or glargine U100) demonstrated no treatment differences with degludec versus glargine U100 in terms of hHF, that prior HF was the strongest predictor of future hHF events, and that there was an association between severe hypoglycemia and subsequent hHF, which was further supported by the similar results from LEADER.