Diabetes and Heart Failure, the Double-Edged Sword: Strategies to Conquer the Battle

Diabetes mellitus (DM) and Heart Failure (HF) are major public health problems that are increasing throughout the world. Both of these conditions often co-exist and each increases the risk of other and has an adverse impact on the prognosis of the other. In the United States, more than 30 million people have DM, and these numbers are projected to increase substantially due to high prevalence of overweight and obesity , with projections of 1 in 3 adults developing DM by 2050.¹ Globally, the number of cases of DM among adults ( 20 years or older) is about 410 million and the prevalence is increasing with the numbers projected to increase to over 640 million by the year 2040.² Atherosclerotic Cardiovascular Disease (ASCVD) including HF are the leading causes of death and disability in patients with DM. Compared with matched controls, patients with DM have significantly greater risk of ASCVD (1.5–2 times) and HF (2–4 times), both of which tend to occur at an earlier age in DM.3 Although the increased risk of ASCVD with DM is now well recognized, until recently the association of HF with DM had been largely ignored. The recent results of Cardiovascular Outcome Trials (CVOTs) with SGLT2 inhibitors showing substantial favorable impact on the HF related outcomes have highlighted the importance of HF in DM.³ Given the high prevalence of HF in DM and vice versa, and the differential effects of various newer hypoglycemic drugs on ASCVD and HF related outcomes shown in the recent CVOTs, clinicians need to familiarize themselves with the recognition of HF as an important sequel of DM and the selection of appropriate drugs in this setting. To this end, the AHA scientific Statement on Type2 Diabetes Mellitus and Heart Failure provides a timely, comprehensive review of the topic and expert opinion on the risk and management of HF in DM.4 The statement also provides a detailed overview of the risk in various settings and overall management of HF in the setting of DM, as well as it highlights the findings of the recent CVOTs and their potential impact on strategies for the future management of HF in DM.^3-4

Heart Failure and Diabetes "The Ignored Bad Companions"

The AHA scientific statement on DM and HF provides an excellent background and detailed information about the association of DM and HF as well as related pathophysiologic processes.⁴ It is important to recognize that although the association of DM with HF had been described in one of the earliest observations from the Framingham study, nearly half a century back, until recently the importance of HF in the setting of DM has been largely ignored.^5-6 The initial data from the Framingham reported that subjects with DM had 2-4-fold increased risk (more in women) of HF, these data have been subsequently confirmed in several other cohort studies. Furthermore, it has been reported that as many as half of the hospitalized patients with HF might have DM or prediabetes.

Although, the precise pathophysiologic mechanism(s) responsible for association between DM and HF remains to be established, there are several plausible explanations. First, there appears to be a bidirectional relationship between HF and insulin resistance. Second, most patients with DM have hypertension which in itself is a powerful risk factor (RF) for HF and in association with other coronary RF increases risk of ASCVD and MI, the other independent predictors of HF. Additionally, both diastolic and systolic dysfunctions of the heart have been reported without significant obstructive CAD and hypertension in what has been commonly refereed as diabetic cardiomyopathy.^7-10 Although, the mechanism responsible for diabetic cardiomyopathy remains to be established, it could be related to myocardial hypertrophy and fibrosis, defective glucose utilization and shift to free fatty acid metabolism. The production of advanced glycated end (AGEs) products, accumulation of reactive oxygen species (ROS), increased oxidative stress and inflammation could also be playing role.^7-10 At a molecular level, the increased apoptosis seen in DM, depressed myocardial function due to impaired mitochondrial function, impaired calcium handling and defective energy utilization could also be contributing. Regardless of the dominant mechanism, it is clear that DM and HF are bad companions and each has significant adverse impact on the clinical course and outcome of the other.

Strategies to Manage Diabetes and Heart Failure

The AHA Scientific statement on DM and HF provides a detailed overview of various traditional and newer approaches to apply the latest data to adequately manage HF in patents with DM.⁴ In brief, it is important to emphasize that due to the higher risk of morbidity and mortality in patients with DM and HF, the standard guideline directed medical therapies provide even greater benefit in these patients and should be always utilized. Furthermore, it is important to note that in the past, the management of patients with DM has centered around control of glucose with established hypoglycemic agents; however, the emerging data mandate that newer strategies including use of novel drugs for control of glucose and cardio-protection should be utilized.^3-4 It is known that tighter control of glucose is associated with reduction in risk of microvascular complications (i.e., retinopathy, nephropathy and neuropathy). Based on epidemiologic data, that showed some associations of higher glucose levels with macrovascular complications (i.e., MI and stroke), during the last two decades it was thought that intensive glucose control could potentially reduce this risk. Accordingly, several RCTs were conducted to examine this concept, however, these trials failed to show significant favorable impact on macrovascular events, and instead some studies revealed that intensive glucose control was associated with increased mortality, which has been thought to occur secondary to hypoglycemia due to the use multiple drugs needed to achieve tighter control.³ As a result of a mandate by FDA, several large Cardio Vascular Outcome trials (CVOTs) were conducted in the last decade to evaluate the safety of all new classes of hypoglycemic agents requiring FDA approval.^11-14 These CVOTs as summarized in the AHA Scientific statement have revealed some unexpected and surprising findings. It has been shown that some of the newer classes of drugs like SGLT2 inhibitors and GLP1 agonists are associated with reduction in the risk of MACE and HF. Specifically, the SGLT2 inhibitors have been found to substantially reduce the risk of hospitalization for HF accounting for the majority of the beneficial effects of this class of drug on CV outcomes.^3-4,11-14 An important finding about the beneficial effects of SGLT2 inhibitors on HF related outcomes is that this effect seems to be a class effect and like specific beta-blockers studies in HF there is similar degree of efficacy noted (something not universally observed with many other drugs used in HF).³ These findings have highlighted the importance of recognizing HF as an important sequala of DM and differing effects of various classes drugs on ASCVD and HF related outcomes. The beneficial effects of SGLT2 inhibitors on HF related outcomes were noted quite early and are thought to be related to the hemodynamic effects of these agents due to osmotic diuresis secondary to both glucosuria and natriuresis. This class of drugs reduces both preload (due to greater loss of interstitial volume than the loss of intravascular volume) and afterload (due to associated reduction in vascular resistance as a result of improved endothelial function and blood pressure). The SGLTs inhibitors have multitude of other effects (Table 1) both in the kidney and heart that could contribute to their beneficial effect(s).¹⁵ It has been shown that these drugs also inhibit sodium-hydrogen exchanger in both kidney and heart, the later resulting in lower cytosolic sodium and calcium concentrations and increased mitochondrial calcium concentration. Such effects could potentially be cardio-protective. In addition, long term use of SGLT2 Inhibitors is associated with increase in fatty acid oxidation stimulating ketogenesis and shifts substrate use towards fat. The resultant increased metabolism of beta-hydroxybutyrate by heart could also result in improved mitochondrial function and cardiac performance. There are a number of both experimental as well as clinical research studies that are currently going on to confirm these findings and unravel the mechanism(s) contributing to their beneficial effects in HF. Whatever the dominant mechanism(s) might be, based on the well demonstrated beneficial effects of this class of hypoglycemic agents in patients with DM and HF as stated in the AHA scientific statement as well as the 2019 ADA guidelines, this class of drugs is now recommended as preferential second line hypoglycemic agent in the management of patients with DM with HF.^4,16

Clinical Implications and Future Perspectives

Both diabetes and HF are increasing in the US and globally. There is considerable interplay of the risk between these conditions as well as some of the underlying pathophysiologic processes involved. Each has an impact on the others' prognosis and therapeutic strategies. Until recently the management of diabetes centered on glucose control as well as management of other associated risk factors like BP, lipids, and enhanced thrombotic risk to reduce the risk of MACE. Several large RCTs in the past 2 decades had revealed that tighter control of blood glucose was not associated with significant reduction in MACE. This might have been secondary to the associated increased risk of hypoglycemia.¹⁷ The recent CVOTs have clearly identified several new classes of hypoglycemic drugs that are not only safe (with lower risk of hypoglycemia) but highly effective in reducing the increased risk of MACE and HF related outcomes in DM.^3,4,11-15 The AHA Scientific Statement provides a well-balanced comprehensive review regarding DM and HF, and the impact of various therapeutic choices (including guideline directed therapy and both traditional and newer hypoglycemic drugs) available to the clinician to adequately manage these patients in an effort to reduce the devastating consequences of these frequently coexisting chronic conditions that are like the dance of two devils.