The year in cardiovascular medicine 2022: the top 10 papers in diabetes and metabolic disorders

Graphical Abstract

BMICA, bone marrow inflammatory cell activation; CVD, cardiovascular disease; NASH, non-alcoholic steatohepatatis; MCVEs, major cardiovascular events; ASCVD, atherosclerotic cardiovascular disease.

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Haematopoiesis drives atherosclerosis

It is well-established that inflammation is an essential mediator of all stages of atherosclerosis. Experimental studies suggest that increased bone marrow (BM) haematopoietic activity may be a central link between cardiometabolic risk factors and inflammation in atherosclerosis. Numerous experiments in mice have demonstrated increased BM haematopoiesis in response to hypertension, hypercholesterolaemia, and hyperglycaemia. However, the translation from the laboratory to humans has not been fully elucidated. Indeed, human data to support the association between BM inflammatory cell activation (BMICA) and cardiovascular risk factors are sparse. Devesa et al. reported new findings from the ‘Progression of Early Subclinical Atherosclerosis’ (PESA) study that help to close this gap by showing BM activation with ¹⁸F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (¹⁸F-FDG PET/MRI) in a population of apparently healthy individuals.¹ A remarkable association between components of the metabolic syndrome including central obesity, elevated blood triglycerides, hypertension, insulin resistance, and enhanced ¹⁸F-FDG uptake in BM was observed. Interestingly, BMICA was associated with elevated numbers of leucocytes, systemic inflammation, and high arterial metabolic activity as well. In the asymptomatic PESA population, cardiovascular risk factors clustering in the metabolic syndrome determine an increase in BM activity that contributes to early atherosclerosis by increasing inflammatory cell proliferation. This is the first demonstration that BMICA is an early phenomenon in atherosclerosis development. A better understanding of the mechanisms involved in this process may unmask new targets to prevent subclinical atherosclerosis progression.

Obesity and cardiovascular disease: the effect of bariatric surgery

Although we know that bariatric surgery effectively targets CV risk factors, its effect on cardiovascular disease is not well-established. A comprehensive systematic review and meta-analysis of all cohort studies comparing bariatric surgery patients to non-surgical controls evaluated the effect of surgical intervention on CV outcomes.² This pooled analysis showed that bariatric surgery was associated with a reduction in all-cause mortality (45%) and CV mortality (41%). It remains to be elucidated whether the beneficial action of bariatric surgery is only due to absolute weight reduction or additional ancillary effects also play a role. In this perspective, bariatric surgery is defined ‘metabolic’ to highlight putative mechanisms such as different expression of gut hormones, enhanced insulin sensitivity, and changes in the gut microbiome that may contribute to its beneficial effects. Disappointingly, < 2% of eligible individuals undergo bariatric surgery. This meta-analysis strengthens the evidence that bariatric surgery as compared with standard of care reduces both all-cause and CV mortality as well as the incidence of CVD. Still, given the very profound effects of GLP-1 receptor agonists (GLP-1 RA) or novel ‘dual’ glucose-dependent insulinotropic polypeptide and GLP-1 RA, such as once-weekly tirzepatide, it needs to be assessed whether treatment with these agents should be performed before or in addition to bariatric surgery.

Polypill as CVD prevention strategy in patients with NASH

Let us now focus on a study designed to investigate the effectiveness of fixed-dose combination therapy of aspirin, atorvastatin, hydrochlorothiazide, and valsartan (polypill) for the prevention of major cardiovascular events in individuals with non-alcoholic steatohepatitis (NASH).³ It is emerging that non-alcoholic fatty liver disease (NAFLD) and its inflammatory subset NASH are common conditions affecting ∼1/4 of the adult population and are important risk factors for CVD. Indeed, fatty liver and CVD share behavioural and metabolic risk factors such as central obesity, T2D, metabolic syndrome, unhealthy diet, physical inactivity, and dyslipidaemia. This randomized controlled study from Iran tested a polypill strategy for CVD prevention in patients with NASH.³ The primary outcome were major cardiovascular events (MCVEs). According to the Zelen design of this trial, only a 17% relative risk reduction in MCVEs was obtained in the randomized population. However, a significant 39% reduction in the risk of MCVE and all-cause mortality was observed among patients who gave their consent and, hence, received the polypill. Randomization prior to trial consent and enrolment is commonly employed in trials testing the ‘real-world’ effectiveness of health promotion strategies. These results indicate that polypill exerts a cardioprotective effect in people with fatty liver and NASH where multiple cardiometabolic risk factors often co-exist. Despite these results, some important unresolved questions remain and the clinical benefit of low-dose aspirin for primary prevention must be carefully balanced against the well-known excess risk of major bleeding.

Aspirin and dementia in patients with diabetes

It is well-established that cerebrovascular events are associated with cognitive impairment and diabetes increases the rate of cognitive decline and risk of dementia. In the ASCEND trial, 15,480 people with diabetes and no history of CVD were randomized to aspirin 100 mg daily or a matching placebo for a mean of 7.4 years. Based on the rationale that aspirin may prevent cognitive impairment through the avoidance of cerebrovascular events, a pre-specified analysis by Parish et al. has investigated the effect of aspirin on dementia and cognitive decline.⁴ The primary outcome of this study was ‘broad dementia’ comprising dementia, cognitive impairment, or confusion and included the ASCEND participants with no recorded dementia prior to baseline. Aspirin did not exert any significant effect on the risk of dementia. Indeed, the broad dementia outcome occurred in a similar percentage of participants in the aspirin and placebo groups. Among other trials testing the effects of low-dose aspirin on the primary prevention of cardiovascular disease only two have been reported on dementia, ‘Aspirin in Reducing Events in the Elderly’ and the open-label ‘Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes’ trials. Both reported no statistically significant effect of aspirin. By contrast, the ASPREE trial reported higher all-cause mortality among apparently healthy older adults who received daily aspirin than among those who received a placebo. Interestingly, the authors of the ASCEND pre-specified study tested the effect of randomization to aspirin on dementia in a meta-analysis of these three trials obtaining a combined hazard ratio of 0.92 (95% CI: 0.84–1.01; P = 0.09).⁴ The role of other cardiovascular risk factors and/or the presence of established CVD for the development of dementia remains still not fully understood.

GLP-1 RA treatment in patients with type 2 diabetes

The AMPLITUDE-O trial examined the effect of efpeglenatide, a GLP-1 receptor agonist administered weekly by means of subcutaneous injection, on cardiovascular outcomes.⁵ This trial randomized efpeglenatide vs. placebo in patients with T2D and either a history of CVD or current kidney disease plus at least one other risk factor. During a medium follow-up of 1.8 years, the primary endpoint of non-fatal MI, non-fatal stroke, or death from cardiovascular or undetermined course occurred in 7% of the patients receiving efpeglenatide and 9.2% receiving placebo, leading to a significant relative risk reduction of 27%. Interestingly, 15% of all patients were treated with an SGLT2 inhibitor and subgroup analyses suggest a benefit in both, patients with and without SGLT2 inhibitor treatment.

SGLT2 inhibitors across ejection fraction and care settings

Originally conceived as diabetes medications, the SGLT2i have emerged as the gift that keeps on giving. Just 1 short year after the EMPEROR-Preserved trial provided evidence for SGLT2i benefit across the range of left ventricular ejection fraction (LVEF) further unequivocal support has been delivered by the DELIVER trial.⁶ Aside from people with HF with preserved ejection fraction (HFpEF), DELIVER also studied people with mildly reduced ejection fraction (HFmrEF) or improved (HFimpEF) ejection fraction. In brief, DELIVER found that during a median of 2.3 years of follow-up, dapagliflozin allocation culminated in an 18% reduction in worsening HF or CV death with a comparable incidence of adverse events between the dapagliflozin and placebo groups. Contrary to EMPEROR-Preserved which showed a potential loss of benefit with empagliflozin at higher LVEF, DELIVER reported improvements in its primary and secondary outcomes regardless of whether LVEF was >40% to <60% or ≥60%.⁶ By combining the datasets from DAPA-HF and DELIVER, Jhund et al.⁷ were able to examine data from over 11 000 participants who had HF with LVEF ranging from 16% to 74%. This pre-specified analysis revealed 10%–29% relative risk reductions in CV death, all-cause death, MACE, and total hospitalizations (hospitalisation for heart failure [HHF]), respectively. In that, the benefits persisted independent of LVEF is clinically meaningful and translates to the urgency to treat symptomatic HF with an SGLT2i unless there are explicit contraindications.

A meta-analysis that was published concurrently with DELIVER and included nearly 22 000 participants from DAPA-HF, DELIVER, EMPEROR-Reduced, EMPEROR-Preserved and SOLOIST-WHF uncovered a remarkable consistency in benefits across the trials with an overall 23% reduction in CV death and HHF for SGLT2 therapy vs. placebo.⁸

An important evolution of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure is the newly defined categories of heart failure that include HFrEF (LVEF ≤40%), HFimpEF (previously in HFrEF but with LVEF >40% on follow-up), HFmrEF (LVEF 41% to 49%), and HFpEF (LVEF ≥50%). The guideline additionally offers recommendations for the full spectrum of HF while also underscoring the importance of primary prevention and timely intervention. Although the guideline afforded SGLT2i, the designation of a core HF therapy, the recommendation for SGLT2i to lower hospitalization and CV death in people with HFrEF was considered Class 1a, whereas that for SGLT2i use in those with HFmrEF or HFpEF to reduce HHF and HF death was deemed class 2a. Given the results of DELIVER,⁶ the DAPA-HF-DELIVER pooled analysis⁷ and the five SGLT2i trials meta-analysis,⁸ it is anticipated that the next guideline update will provide a stronger recommendation for HFmrEF and HFpEF management and support the utilization of SGLT2i for the entire HF continuum and in diverse care settings as long as there are no overt contraindications. While the expansion of the armamentarium is welcomed, much work is still needed to narrow the gap on how applicable these trial data are to races/ethnicities that were underrepresented. Likewise, whether the benefits reported in DAPA-HF, DELIVER, EMPEROR-Reduced, EMPEROR-Preserved and SOLOIST-WHF can be reliably extended to those with cardiomyopathy, kidney disease, and other comorbidities not represented remain to be determined.

There is no argument that onboarding foundational therapies is particularly valuable in people living with HFrEF but the debate on how and when to introduce each of these therapies to optimize clinical benefits continues. In a post hoc analysis of the EMPEROR-Reduced trial, the benefit of the newly added empagliflozin therapy on CV death or HHF, as well as the total number of HHF was consistent regardless of the combinations and dosages of background pharmacotherapies.⁹ These findings although exploratory in nature do bolster confidence that SGLT2i can be used safely and efficaciously with different permutations of more established HF pharmacotherapies.

As the proportion of people who live with HF and comorbidities such as diabetes and chronic kidney disease has grown, so has the prevalence of hyperkalaemia and thus the limitations to use the bedrock RAAS inhibitors and mineralocorticoid receptor antagonists (MRAs). Using EMPEROR-pooled patient-level data, Ferreira and colleagues discovered that empagliflozin consistently lowered the risk of investigator-reported hyperkalemia or potassium binder initiation across LVEF with no excess risk of hypokalaemia compared with the placebo-assigned group.¹⁰ Whether the reduction in the incidence of hyperkalemia with SGLT2i may be attributed to the safeguarding of kidney function is unknown but it might enable more patients to attain larger doses of RAAS inhibitors, especially MRAs, to improve HF outcomes.

The very early separation of the Kaplan–Meier curves in the SGLT2i HF trials continues to beg the question of how exactly the SGLT2i are evoking their advantages. While there have been many propositions, alignment across studies focussed on decoding the same potential mechanism has been lacking.

Funding

All authors declare no funding for this contribution.

References

Author notes