DiRECT and indirect paths to reducing cardiovascular risk in diabetes: insights from Diabetes UK 2019

The 2019 Diabetes UK conference in Liverpool was notable for the range of home-grown innovative research – much of which had clinical translational relevance – on display. Examples ranged from updates on the potential utility of pharmacogenomics through advances in the diagnosis and care of patients with monogenic forms of diabetes to an intriguing demonstration of the potential value of current assays of C-peptide to reclassify diabetes subtypes. Other presentations at the conference also served to illustrate the gathering momentum of precision medicine in diabetes. This brief review focuses on two very different approaches to reducing the excess risk of cardiovascular disease in diabetes. The first concerns inducing remission of obesity-associated type 2 diabetes using an approach that builds on the experimental and translational clinical studies of Professor Roy Taylor (Newcastle University, UK) and Professor Mike Lean (University of Glasgow, UK). Whether the surrogate biomarkers of cardiovascular risk induced by supervised weight reduction will ultimately lead to reductions in cardiovascular morbidity and mortality await confirmation in longer-term follow-up studies. For now, the impact on cardiovascular biomarkers appears encouraging. By way of contrast, in an illuminating perspective Professor Simon Heller of the University of Sheffield reminded the audience of the threat to the cardiovascular health of patients with diabetes posed by iatrogenic hypoglycaemia. The highly-anticipated follow-up results of the DiRECT open-label cluster-randomized controlled trial using a structured reduced calorie regimen in a UK primary care setting were well received. The 2-year results of DiRECT confirmed that type 2 diabetes is potentially reversible by weight loss in many cases. DiRECT recruited individuals with type 2 diabetes not receiving insulin aged 20–65 years with less than 6 years’ known duration of disease and a body mass index of 27–45 kg/m2. The coprimary outcomes at 24 months were a reduction in bodyweight ≥15 kg and remission of diabetes, defined as haemoglobin (Hb)A1c <6.5% (<48 mmol/mol) after withdrawal of glucose-lowering medication at baseline (independent of status at 12 months). At 24 months, 11% of intervention participants and 2% of control participants had weight loss of at least 15 kg (P = 0·0023) and 36% of intervention participants and 3% of control participants had remission of diabetes (P < 0·0001). At 24 months, 70% of those who maintained a weight loss of more than 15 kg remained in remission [1]. Glucose-lowering medications were used by only 40% of intervention participants at 24 months (75% at baseline), compared to 84% of control participants (77% at baseline). Various practical aspects of the trial were presented. For example, strategies were in place for management of weight regain (>2 kg) or relapse to diabetes. The DiRECT investigators also provided a cost-effectiveness analysis that demonstrated lower cost per type 2 diabetes remission compared with the current average cost of management. Of note in the context of this trial, Diabetes UK, the European Association for the Study of Diabetes, and the American Diabetes Association are collaborating to define an international consensus for remission of type 2 diabetes. Discussing the DiRECT data, co-lead investigator Professor Roy Taylor of Newcastle University argued for a new term of ‘post-diabetes’ to describe patients in remission reflecting improvements in pathophysiology and lower risk. As for the impact of the intervention on cardiovascular risk factors, at 24 months the DiRECT intervention was associated with a statistically significant reduction in systolic blood pressure despite lower use of antihypertensive drugs in concert with a reduction in plasma triglyceride concentrations. For participants in remission at 24 months, improvements were observed in 10-year cardiovascular event risk (Q-RISK score) and calculated heart age along with HbA1c. Although the clinical implications of these benefits remain to be more reliably determined a post-hoc analysis of DiRECT suggested a positive impact on cardiovascular events and cancer. Dr. Ahmad Al-Mrabeh of Newcastle University, UK presented data from a sub-study (the DiRECT Mechanistic Study) designed to investigate Professor Taylor’s twin cycle hypothesis. In susceptible people, Professor Taylor postulates that obesity leads to fat in the pancreas and β-cell dysfunction, reducing insulin secretion and exacerbating insulin resistance in a vicious cycle. Hepatic steatosis is not only associated with insulin resistance but may promote the development of coronary artery disease. In terms of therapeutic interventions, it is hypothesized the cycle can be interrupted by weight reduction with restoration of hepatic and pancreatic function. Participants were divided into responders, relapsers and non-responders. Hepatic and pancreatic lipid, quantified using magnetic resonance imaging, differed between responders, non-responders and participants who relapsed. Isotopically-determined hepatic production of very-low-density lipoprotein aligned with hepatic imaging data. As for the pancreas, the reduction in intra-pancreatic lipid in the responder group was greater than in the non-responder group. Islet β-cell function (defined as first-phase and maximal insulin response using glucose and arginine stimulation methodologies) was restored in responders but not in the other groups; rapid improvement in first-phase insulin response was followed by improvements in maximal insulin secretion over 12 months. In his Banting Lecture address, Professor Heller thoughtfully reviewed the history of insulin-induced hypoglycaemia to provide a perspective across the decades. Frederick Banting of the University of Toronto described insulin-induced hypoglycaemia in 1923. This observation was followed in 1941 by Professor RD Lawrence’s description of reduced symptomatic awareness of hypoglycaemia. Later, mechanistic studies demonstrated impaired sympathoadrenal and glucagon counter-regulatory responses as a function of increasing duration of type 1 diabetes; glucagon secretion was found to be significantly reduced after around 5 years, and after 15 years the responses of both glucagon and adrenaline were impaired. This complex clinical picture of risks and benefits was expanded with the demonstration (a) that tight glycaemic control is associated with reduced counter-regulatory hormonal responses and (b) the confirmation that episodes of hypoglycaemia impair these protective responses, research to which Professor Heller has made notable personal contributions. Current evidence supporting a role for hypoglycaemia as a cause of cardiac dysfunction in susceptible individuals was also considered in detail. The clinical implications of this hypothesis are relevant to the controversy concerning the inconsistent results of a series of large trials of intensive glucose-lowering strategies in patients with type 2 diabetes and the long-feared ‘dead in bed’ syndrome in patients with type 1 diabetes which was first described in detail by Tattersall and Gill [2]. The continuous glucose monitoring record of a patient who died during nocturnal severe hypoglycaemia provided a powerful reminder of the risk posed to susceptible patients. Severe hypoglycaemia was shown to predict mortality in the aforementioned trials in patients with type 2 diabetes. A multiplicity of potential mechanisms postulated to provide a causal link between hypoglycaemia and fatal cardiovascular events were reviewed [3]. Unrecognized nocturnal hypoglycaemia may cause an elongation of the electrocardiographic QT interval which may in turn heighten the risk of cardiac arrhythmias. Alterations in markers of thrombosis may be evident several days following an episode of hypoglycaemia. Hypoglycaemia may also induce bradycardia. Whether severe hypoglycaemia directly influenced adverse outcomes via cardiovascular mechanisms in intensive therapy trials in type 2 diabetes or whether hypoglycaemia represented a marker for mortality in vulnerable patients remains unclear. Such uncertainties notwithstanding, in 2019 – nearly a century since the inception of insulin therapy – it was apposite to re-emphasize that scrupulous avoidance of severe hypoglycaemia in pursuit of tight glycaemic targets remains a major clinical challenge.

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