Physiological monitoring of the complex multimorbid heart failure patient – diabetes and monitoring glucose control

Abstract

Heart failure (HF) is a global epidemic, particularly affecting the elderly and/or frail patients often with comorbidities. Amongst the comorbidities, type 2 diabetes mellitus (T2DM) is highly prevalent and associated with higher morbidity and mortality. We review the detection and treatment of T2DM in HF and the need to balance the risk of hypoglycaemia and overall glycaemic control. Despite large attributable risks, T2DM is often underdiagnosed in HF. Therefore there is a need for systematic monitoring (screening) for undetected T2DM in HF patients. Given that patients with HF are at greater risk for developing T2DM compared with the general population, an emphasis also has to be placed on regular reassessment of glycaemic status during follow-up. Therefore, glucose-lowering therapies (e.g. sodium-glucose cotransporter-2 inhibitors, SGLT-2 inhibitors) with a known benefit for the prevention or delay of HF hospitalization could be considered early in the course of T2DM, to optimise treatment and reduce cardiovascular (CV) risk. Although intensive glycaemic control has been shown to effectively reduce the risk of microvascular complications in T2DM, these same trials have shown either no reduction in CV outcomes, or even an increase in mortality with tight glycaemic control (i.e. targeting HbA1c levels <7.0%). More lenient glycaemic targets (e.g. HbA1c levels 7.0-8.0%) may be more appropriate for HF patients with T2DM. The 2016 ESC Guidelines for the diagnosis and treatment of HF proposed metformin as the first-line therapy, given its long-standing use and low risk of hypoglycaemia. More recently, several novel glucose lowering-medications have been introduced, including dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and SGLT-2 inhibitors. The most consistent reduction in the risk of HF hospitalisation has been shown with the three SGLT-2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) which now offer improved outcomes in patients with both HF and T2DM.

Introduction

Heart failure (HF) is a global epidemic, currently affecting ∼26 million patients worldwide.¹ The majority of HF population are elderly and/or frail patients that commonly have one or more associated comorbidities.² In addition to poorer functional status and worse outcomes, comorbidities often require more complex treatment regimens and require monitoring of treatment responses.^2,3 Amongst the comorbidities, Type 2 diabetes mellitus (T2DM) is highly prevalent (∼30–40%) and associated with higher morbidity and mortality in HF patients with either preserved ejection fraction (HFpEF) or reduced ejection fraction (HFrEF).^4–6 In addition, treatment with several glucose-lowering medications may predispose to hypoglycaemia, which is associated with a higher risk of cardiovascular (CV) events and mortality.⁷ In the present review, we will focus on the detection of undetected T2DM to ensure treatments to prevent its associated morbidity and mortality are initiated while balancing the risk of hypoglycaemia and overall glycaemic control.

Monitoring of undetected Type 2 diabetes mellitus in heart failure

The presence of T2DM nearly doubles the risk of HF independently of other clinical characteristics, and contributes to 3.1% of population-attributable risk for HF.⁸ T2DM confers the largest risk amongst the modifiable risk factors (i.e. smoking, dyslipidaemia, hypertension, and obesity), suggesting that greater use of therapies for T2DM could have a large impact on the prevention of HF and the complications of T2DM.⁹

Importantly, despite large attributable risks, T2DM is often underdiagnosed in HF.^10,11 In a large pan-European Registry of ambulatory patients with HFrEF and HFpEF, 19% had previously unknown (undetected) T2DM.¹² Similarly, one-fifth of the patients in several observational studies of HFrEF, also had previously undiagnosed T2DM.^13,14 Clinical trials suggest that 21–26% and 22%, respectively, of the HFrEF and HFpEF population may have previously unknown T2DM.^10,11 Accordingly, there is a great unmet need for the systematic monitoring (screening) for undetected T2DM in the clinical assessment of patients with HF. This could be achieved by using any of the following: overnight fasting plasma glucose levels, 2-h glucose tolerance test, or glycosylated haemoglobin A1c (HbA1c) levels, in accordance with criteria proposed by current recommendations.^4,15 Given that patients with HF are at greater risk for developing T2DM compared with the general population,¹⁶ an emphasis has to be placed on regular reassessment of glycaemic status during the long-term follow-up of HF patients. Therefore, glucose-lowering therapies (e.g. sodium-glucose cotransporter-2 inhibitors, SGLT-2 inhibitors) known to prevent or delay of HF hospitalization could be considered early in the course of T2DM, to optimize treatment and reduce CV risk, as stipulated by the European Society of Cardiology (ESC) Guidelines.^17,18

Monitoring of hypoglycaemia

Although intensive glycaemic control has been shown to effectively reduce the risk of microvascular complications in T2DM, large clinical trials have failed to demonstrate that this strategy lowers the risk of CV events or HF.^19,20 On the contrary, these trials have shown either no improvement in CV outcomes,¹⁹ or even an increase in mortality with tight glycaemic control (i.e. targeting HbA1c levels <7.0%).²⁰ All of the studies have demonstrated an increased risk of hypoglycaemic episodes with intensive glycaemic control, which in turn has been widely associated with greater mortality in observational studies.^19–21 Although the possible mechanisms by which hypoglycaemia may increase mortality are not clear, postulated mechanisms include increased sympathetic tone, abnormal cardiac repolarization (proarrhythmia), induction of cardiac and cerebral ischaemia, enhanced inflammation, and endothelial dysfunction.²²

Hypoglycaemia is frequently associated with T2DM treatment including insulin and/or insulin secretagogues (i.e. sulphonylurea and glinides), either as monotherapy or in combination with other glucose-lowering medications.²³ The risk of hypoglycaemia (in particular, severe hypoglycaemia; i.e. plasma glucose <2.8 mmol/L), is potentiated by older age, frailty, and comorbidities frequently encountered in HF, such as chronic kidney disease (CKD) and hepatic dysfunction.^22,24 In addition, decompensated HF, worsening renal function, infection and other critical illnesses, may aggravate the risk of hypoglycaemia. In some instances, concomitant use of medications intended for the treatment of HF (e.g. beta-blockers, angiotensin converting enzyme inhibitors) or concomitant disorders (e.g. fluoroquinolone antibiotics) may exacerbate the risk of hypoglycaemia,²⁵ however, their benefit far outweighs the small potential risk of hypoglycaemia. In patients with HF, hypoglycaemic episodes often remain asymptomatic and undiagnosed, thus imposing a substantial risk to the affected individuals.²⁴

Given the high risk of hypoglycaemia, current recommendations propose monitoring of plasma glucose levels in all critically ill patients with HF and T2DM, including decompensated HF, acute coronary events, serious infection, and in emergency settings.¹⁵ Self-plasma glucose monitoring could also be recommended on individual basis to improve glycaemic control and the safety of T2DM treatment.¹⁵ Dose-adjustment or even a discontinuation of a glucose-lowering agent may be required when initiating/intensifying T2DM therapy in a patient already receiving insulin/insulin secretagogues.¹⁵ Individualized therapy goals and a multidisciplinary team management (cardiologists, diabetologists, and HF nurses) merits consideration in patients in need of complex glucose-lowering therapies (two or more drugs) to reduce the risk of hypoglycaemia.

Monitoring of glucose control

Glucose control is primarily assessed with HbA1c, which is generally reliable, except in patients with comorbidities affecting erythrocyte turnover, such as severe anaemia and end-stage CKD, which may decrease diagnostic accuracy.¹⁵ Although higher levels of HbA_1c have a direct (linear) association with higher morbidity and mortality in patients with T2DM and HF, not receiving treatment with glucose-lowering drugs,²⁶ this relationship changes once treatments for T2DM have been introduced. A number of observational studies have reported either a U-shaped,^27,28 or an inverse relationship between HbA_1c levels and mortality in HF patients treated with glucose-lowering medications.^29,30 This indicates that lenient glycaemic targets (e.g. HbA1c levels 7.0–8.0%) may be more appropriate for HF patients with T2DM. This is also in line with the findings from randomized trials reporting lack of benefit (or even higher risks) with intensive glycaemic control (typically targeting HbA1c <7.0%) patients with T2DM.^19,20

Most of these studies have been conducted with traditional glucose-lowering medications (i.e. metformin, sulphonylurea, glinides, thiazolidinediones, and insulin). Despite efforts to understand the mechanisms linking intensive glycaemic control with higher CV risks, it is still uncertain whether the risk could only be attributed to hypoglycaemia, or whether effects beyond glycaemic control could have been involved. In addition to hypoglycaemia, renal sodium, and water retention (thiazolidinediones and insulin)^31,32 and weight gain (sulphonylureas, thiazolidinediones, and insulin)¹⁵ have been postulated as potential contributors to a higher HF risk with several glucose-lowering drugs.³³ The 2016 ESC Guidelines for the diagnosis and treatment of HF propose that glycaemic control in patients with T2DM and HF needs to be lenient and achieved with a preferential use of medications with confirmed safety and efficacy.¹⁸ In that respect, metformin is recommended as the first-line therapy, given its long-standing use and low risk of hypoglycaemia.¹⁸ A substantial body of observational data suggests that metformin could be safely used in complex, multimorbid patients, including those with advanced HF and/or moderate CKD or hepatic disease.^34–36 Thiazolidinediones are not recommended due to the higher risk of HF.¹⁸ Insulin and insulin secretagogues can be used, but should be done carefully, in particular, in patients prone to hypoglycaemia and while monitoring for fluid retention.

Recently, several novel glucose-lowering medications have been introduced, including dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists, and SGLT-2 inhibitors. They are all associated with a low risk of hypoglycaemia when used as monotherapy in combination with metformin. Nevertheless, when combined with insulin/secretagogues, the risk of hypoglycaemia may increase, warranting appropriate dose-adjustment and glycaemia monitoring.¹⁵ Despite low risk of hypoglycaemia, DPP-4 inhibitors have failed to show benefit in reducing CV or HF risk, whilst saxagliptin has been associated with a statistically significant 27% increase in the risk of HF hospitalization.³⁷ Glucagon-like peptide-1 receptor agonists have a neutral effect on the risk of HF, but caution is advised in patients with advanced HF, based on safety concerns from small randomized trials with liraglutide.^38,39 A consistent reduction in the risk of HF hospitalization has been shown with the three SGLT-2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin).⁴⁰ It appears that the effect on HF risk reduction with SGLT-2 inhibitors is similar across the spectrum of HbA1c levels, which may provide a safety margin for patients prone to hypoglycaemia. Hence, these drugs could be recommended for the treatment of patients with T2DM to prevent or delay HF hospitalization.⁴¹ However, monitoring of renal function and volume status in patients receiving a SGLT-2 inhibitors and in those with an estimated glomerular filtration rate <30 mL/min/m² is necessary. The mechanism of action of the SGLT-2 inhibitors in HF remains a subject of considerable scientific interest^42,43.

Conclusions

HF and diabetes are increasingly being seen together and need to be managed in concert^44,45. Recent and upcoming trials look set to expand our knowledge and treatment options for HF and diabetes⁴⁶.

Conflict of interest: none declared.