A revolution in diabetes care: novel drugs and new recommendations

For the podcast associated with this article, please visit https://academic. oup.com/eurheartj/pages/Podcasts. Diabetes is the cancer of the blood vessels.1 Indeed, today diabetics of both sexes do not die from diabetes, but from myocardial infarction, renal failure, and stroke, despite the availability of glucose-lowering drugs.2–4 Chronically elevated blood sugar levels may cause an array of molecular changes in the endothelium, smooth muscle, and circulating blood cells, which all trigger the typical diffuse atherosclerotic disease of diabetics. While traditionally the management of diabetes was glucocentric, more recent drugs such as sodium–glucose transport inhibitors type 2 (SGLT25–7) and glucagon-like peptide agonists8,9—that for the first time change cardiovascular outcomes—made the treatment cardiocentric.10,11 Of note, antidiabetics may induce hypoglycaemia which in patients with type 2 diabetes treated aggressively is associated with an increased risk for cardiovascular events.12 In contrast, SGLT2 inhibitors reduce the risk of cardiovascular death and/or heart failure hospitalization, while decreasing HbA1c without increasing hypoglycaemia. This is further evaluated in the FAST TRACK ‘Relationship between hypoglycaemia, cardiovascular outcomes, and empagliflozin treatment in the EMPA-REG OUTCOME® trial’, by David Fitchett and colleagues from the University of Toronto in Ontario, Canada.13 A total of 7020 patients with type 2 diabetes were treated with empagliflozin, 10 or 25 mg, or placebo and followed for a median of 3 years. The relationship between on-trial hypoglycaemia and cardiovascular outcomes, and effects of empagliflozin on outcomes by incidence of hypoglycaemia were investigated. Overall, in 28%, some form of hypoglycaemia occurred. In the placebo group, hypoglycaemia was associated with an increased risk of heart failure hospitalization and an increased risk of myocardial infarction. However, empagliflozin reduced cardiovascular outcomes, regardless of occurrence of hypoglycaemia (Figure 1). Thus, while hypoglycaemia was associated with an increased risk of heart failure hospitalization and infarction, the cardio-protective effects of empagliflozin were evident regardless of the development of hypoglycaemia. These novel findings are further discussed in an Editorial by Carolina Solis-Herrera and colleagues from the University of Texas Health Science Center at San Antonio in the USA.14 Relationship between occurrence and non-occurrence of hypoglycaemia and select outcomes in the placebo group of EMPA-REG OUTCOME. Lower panel: effect of empagliflozin on select outcomes in the total population and by occurrence of hypoglycaemia in EMPA-REG OUTCOME. Hypoglycaemia is defined as symptomatic hypoglycaemia with plasma glucose (PG) ≤70 mg/dL, any hypoglycaemia with PG <54 mg/dL, or severe hypoglycaemia from (Fitchett D, Inzucchi SE, Wanner C, Mattheus M, George JT, Vedin O, Zinman B, Johansen OE. Relationship between hypoglycaemia, cardiovascular outcomes, and empagliflozin treatment in the EMPA-REG OUTCOME® trial. See pages 209–217). Obesity is a major risk factor for the development of diabetes, but is also associated with a number of cardiovascular conditions such as hypertension, atrial fibrillation,15 coronary artery disease,16 abdominal aortic aneurysms,17 cardiomyopathy,18 and heart failure.19 However, whether this association is causal or accidental in nature is still unclear. In their article entitled ‘Body mass index and body composition in relation to 14 cardiovascular conditions in UK Biobank: a Mendelian randomization study’, Susanna Larsson and colleagues from the Karolinska Institutet in Stockholm, Sweden used the Mendelian randomization design to investigate the associations of body mass index (BMI) with 13 cardiovascular diseases and arterial hypertension.20 Single nucleotide polymorphisms associated with BMI and fat mass and fat-free mass indices were used as instrumental variables to estimate the associations with the cardiovascular conditions among 367 703 UK Biobank participants. After correcting for multiple testing, genetically predicted BMI was positively associated with outcomes, such as with decreasing magnitude, aortic valve stenosis, heart failure, deep vein thrombosis, arterial hypertension, peripheral artery disease, coronary artery disease, atrial fibrillation, and pulmonary embolism. The odds ratio per 1 kg/m2 increase in BMI ranged from 1.06 for pulmonary embolism to 1.13 for aortic valve stenosis (Figure 2). There was suggestive evidence of positive associations of genetically predicted fat mass index with nine outcomes. The strongest magnitude was with aortic valve stenosis, with an odds ratio per 1 kg/m2 increase in fat mass of 1.46, while there was an inverse associations of fat-free mass index with atrial fibrillation, ischaemic stroke, and abdominal aortic aneurysm. Thus, higher BMI and, in particular, fat mass index are associated with increased risk of aortic valve stenosis and most other cardiovascular conditions. This manuscript is accompanied by an Editorial by Aroon Hingorani and colleagues from the University College London in the UK.21 Associations of genetically predicted 1 kg/m2 increase in BMI with 14 cardiovascular conditions in UK Biobank. The total number of individuals is 367 703 from (Larsson SC, Bäck M, Rees JMB, Mason AM, Burgess S. Body mass index and body composition in relation to 14 cardiovascular conditions in UK Biobank: a Mendelian randomization study. See pages 221–226). Another marker of cardiovascular outcomes is resting heart rate.22 In diabetics, this is of particular interest because of autonomic neuropathy and increased vascular vulnerability.23 In their contribution ‘Resting heart rate and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk: analysis from the ONTARGET/TRANSCEND trials’ Michael Böhm and colleagues from the Uniklinikum des Saarlandes in Homburg, Germany examined 30 937 patients aged 55 years or older at high cardiovascular risk or with a history of myocardial infarction, stroke, or peripheral vascular disease from the ONTARGET and TRANSCEND trials. Of these, around one-third had diabetes.24 In diabetics, the mean resting heart rate was 72 and in non-diabetics 67. Those with a mean resting heart rate of 75 to <80 had an even greater incidence of death infarction, and stroke, with a hazard ratio of 1.26 in diabetics and 1.16 in non-diabetics. Those with a resting heart rate of 80 or higher were at even higher risk. Similar results with higher event rates in diabetics were obtained for hospitalization for heart failure and all-cause death, while the effect of resting heart rate on myocardial infarction was less pronounced and was absent for stroke. Of note, no harm was observed on lower the resting heart rate. Thus, resting heart rates above 75 are associated with increased cardiovascular outcomes except for stroke, particularly in diabetics. Heart rate lowering in such patients should be studied in future prospective trials to determine if it will reduce outcomes in diabetic and non-diabetic patients at high cardiovascular risk. Proprotein convertase subtilisin/kexin type-9 or PCSK9, a molecular determinant of LDL receptor fate, has emerged as an important therapeutic target for atherosclerotic cardiovascular diseases,25,26 also recommended in the most recent 2019 ESC Guidelines for the management of dyslipidaemias.27 However, the precise mechanism by which PCSK9 regulates the internalization and lysosomal degradation of LDL receptors is unknown. In their Basic Science article entitled ‘Cyclase-associated protein 1 is a binding partner of proprotein convertase subtilisin/kexin type-9 and is required for the degradation of low-density lipoprotein receptors by proprotein convertase subtilisin/kexin type-9’, Hyo-Soo Kim and colleagues from the Seoul National University College of Medicine in the Republic of South Korea investigated this question further.28 Adenylyl cyclase-associated protein 1 or CAP-1 is a receptor for human resistin whose globular C-terminus is structurally similar to the C-terminal cysteine-rich domain (CRD) of PCSK9. Therefore, they investigated the role of CAP1 in PCSK9-mediated lysosomal degradation of LDL receptors and plasma LDL cholesterol (LDL-C) levels. The direct binding between PCSK9 and CAP1 was confirmed by immunoprecipitation assay, far-western blot, biomolecular fluorescence complementation, and surface plasmon resonance assay. Fine mapping revealed that the C-terminal cysteine-rich domain of PCSK9 binds with the Src homology 3 domain of CAP-1. Two loss-of-function polymorphisms found in human PCSK9 (i.e. S668R and G670E in the C-terminal cysteine-rich domain) were attributed to a defective interaction with CAP-1. Small interfering RNA (siRNA) against CAP1 reduced the PCSK9-mediated degradation of LDL receptors in vitro. The viable heterozygous CAP-1 knockout mice had higher protein levels of LDL receptors and lower LDL-C levels in liver and plasma than controls. Mechanistic analysis revealed that PCSK9-induced endocytosis and lysosomal degradation of LDL receptors were mediated by caveolin but not by clathrin, and they were dependent on binding between CAP1 and caveolin-1. Thus, CAP-1 is a new binding partner of PCSK9 and a key mediator of caveolae-dependent endocytosis and lysosomal degradation of LDL receptors. Their findings will change LDL receptor degradation biology from a PCSK9-centric view to a broader approach as further outlined in an thoughtful Editorial by Robert A. Hegele and colleagues from the Western University at London, ON in the Canada.29 This issue also contains the third set of Guidelines produced by the ESC in collaboration with the EASD, i.e. the ‘2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD)’ by Francesco Cosentino and colleagues from the ESC Scientific Document Group.30 The interval between the 2013 ESC Guidelines31 and the current one has seen an unprecedented increase in the evidence base for the management of diabetics, in particular due to a number of new drugs that for the first time improve cardiovascular outcomes. The ESC Guidelines now recommend the novel antidiabetics, i.e. the SGLT2 inhibitors and glucagon-like peptide agonists agonists, as first-line drugs in diabetics with atherosclerotic cardiovascular disease rather than metformin—a true revolution in diabetes care. The issue is also complemented by various Discussion Forum contributions. In a first piece entitled ‘The possible role of insulin and glucagon in patients with heart failure and type 2 diabetes’ Marko Skelin and colleagues from the General Hospital Sibenik in Šibenik, Croatia comment on the recently published article ‘Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association–European Society of Cardiology’ by Stephane Heymans and colleagues from the Maastricht University Hospital in the Netherlands.32,33 Maack et al. respond in their comment.34 In another Discussion Forum entitled ‘Comments on the 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases’ Anders Jorsal and colleagues from the Aarhus University Hospital in Denmark comment on the most recent ESC Guidelines.30,35 A similar Discussion Forum entitled ‘Treatment algorithm in patients with type 2 diabetes and atherosclerotic cardiovascular disease or high/very high cardiovascular risk’ by Giovanni Targher and colleagues from the Ospedale Civile Maggiore in Verona, Italy also comments on the ESC Guidelines.36 Francesco Cosentino on behalf of the ESC Guidelines Task Force responds to both comments in his contribution.37 The editors of the European Heart Journal hope that this issue will be of interest to its readers. With thanks to Amelia Meier-Batschelet for help with compilation of this article.