Cardiovascular disease in diabetes, beyond glucose

Despite the decades-old knowledge that diabetes mellitus is a major risk factor for cardiovascular disease, the reasons for this association are only partially understood. While this association is true for both type 1 and type 2 diabetes, different pathophysiological processes may be responsible. Lipids and other risk factors are indeed important, whereas the role of glucose is less clear. This lack of clarity stems from clinical trials that do not unambiguously show that intensive glycemic control reduces cardiovascular events. Animal models have provided mechanisms that link diabetes to increased atherosclerosis, and evidence consistent with the importance of factors beyond hyperglycemia has emerged. We review clinical, pathological, and animal studies exploring the pathogenesis of atherosclerosis in humans living with diabetes and in mouse models of diabetes. An increased effort to identify risk factors beyond glucose is now needed to prevent the increased cardiovascular disease risk associated with diabetes. Despite the decades-old knowledge that diabetes mellitus is a major risk factor for cardiovascular disease, the reasons for this association are only partially understood. While this association is true for both type 1 and type 2 diabetes, different pathophysiological processes may be responsible. Lipids and other risk factors are indeed important, whereas the role of glucose is less clear. This lack of clarity stems from clinical trials that do not unambiguously show that intensive glycemic control reduces cardiovascular events. Animal models have provided mechanisms that link diabetes to increased atherosclerosis, and evidence consistent with the importance of factors beyond hyperglycemia has emerged. We review clinical, pathological, and animal studies exploring the pathogenesis of atherosclerosis in humans living with diabetes and in mouse models of diabetes. An increased effort to identify risk factors beyond glucose is now needed to prevent the increased cardiovascular disease risk associated with diabetes. The association of cardiovascular disease (CVD) and diabetes has been known for decades. Despite this, the reasons for this relationship are incompletely understood. Because treatment of hyperglycemia alters a number of factors other than circulating glucose levels, clinical and experimental data support the hypothesis that factors other than hyperglycemia are the culprit. As shown in Figure 1, clinical trials have assessed whether glycemic control or reduction of other risk factors, such as LDL-cholesterol (LDL-C), triglycerides (TGs), blood pressure, and systemic inflammation, prevents incident CVD in humans with diabetes. These trials have overwhelmingly shown a beneficial effect of LDL-C lowering, and some additional beneficial effect of targeting inflammation, while the roles of glucose reduction, TG lowering, and blood pressure control are less clear. While an important clinical goal is reduction of hyperglycemia to reduce microvascular complications, primarily disease of the eyes and kidneys, the influence of glucose reduction in atherosclerotic CVD (ASCVD) prevention remains elusive in the majority of patients with type 2 diabetes mellitus (T2DM). In this review, we will integrate the clinical and experimental data from animal models of diabetes and atherosclerosis, focusing on how diabetes alters the steps involved in atherogenesis. Before considering the clinical trial and experimental data, it is important to review the vascular pathology in patients with type 1 diabetes mellitus (T1DM) and T2DM. ASCVD in patients with diabetes differs somewhat from that in patients without diabetes, but these differences are subtle. Although greater calcification in the arterial media is found in patients with diabetes, especially T2DM (Yahagi et al., 2017Yahagi K. Kolodgie F.D. Lutter C. Mori H. Romero M.E. Finn A.V. Virmani R. Pathology of human coronary and carotid artery atherosclerosis and vascular calcification in diabetes mellitus.Arterioscler. Thromb. Vasc. Biol. 2017; 37: 191-204Crossref PubMed Scopus (196) Google Scholar) (Figure 2), in asymptomatic T2DM and T1DM patients examined by multi-slice computed tomography with similar coronary artery calcification scores, patients with T2DM had more extensive ASCVD and more non-calcified plaques than those with T1DM (Djaberi et al., 2009Djaberi R. Schuijf J.D. Boersma E. Kroft L.J. Pereira A.M. Romijn J.A. Scholte A.J. Jukema J.W. Bax J.J. Differences in atherosclerotic plaque burden and morphology between type 1 and 2 diabetes as assessed by multislice computed tomography.Diabetes Care. 2009; 32: 1507-1512Crossref PubMed Scopus (0) Google Scholar). In the CACTI (Coronary Artery Calcification in Type 1 Diabetes) study of subjects with T1DM, coronary calcification was associated with insulin resistance, a finding typically more characteristic of T2DM and poor glycemic control (Bjornstad et al., 2016Bjornstad P. Maahs D.M. Duca L.M. Pyle L. Rewers M. Johnson R.J. Snell-Bergeon J.K. Estimated insulin sensitivity predicts incident micro- and macrovascular complications in adults with type 1 diabetes over 6 years: the coronary artery calcification in type 1 diabetes study.J. Diabetes Complications. 2016; 30: 586-590Crossref PubMed Google Scholar). This suggests that insulin resistance, when present, contributes to vascular disease also in people with T1DM (Purnell et al., 2013Purnell J.Q. Zinman B. Brunzell J.D. DCCT/EDIC Research GroupThe effect of excess weight gain with intensive diabetes mellitus treatment on cardiovascular disease risk factors and atherosclerosis in type 1 diabetes mellitus: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) study.Circulation. 2013; 127: 180-187Crossref PubMed Scopus (166) Google Scholar). However, in general the lesions’ morphology appears similar, and the principal effect of diabetes is likely due to acceleration of several of the phases of atherogenesis. Unlike renal and retinal microvascular disease, there is no pathological fingerprint identifying a distinct atherosclerotic plaque in the setting of diabetes. Post-mortem coronary plaques from subjects with either T1DM or T2DM tend to have more macrophages and larger necrotic core areas, concomitant with increased plaque burden, as compared to plaques from subjects without diabetes (Yahagi et al., 2017Yahagi K. Kolodgie F.D. Lutter C. Mori H. Romero M.E. Finn A.V. Virmani R. Pathology of human coronary and carotid artery atherosclerosis and vascular calcification in diabetes mellitus.Arterioscler. Thromb. Vasc. Biol. 2017; 37: 191-204Crossref PubMed Scopus (196) Google Scholar). These studies also suggested that plaques from patients with T1DM or T2DM have more evidence of rupture and repair. Overall, these data indicate that the lesions from patients with diabetes might progress faster. Risk factors that likely drive this process will be discussed below. Animal models of diabetes often show accelerated atherogenesis. Most of these models, however, are confounded by diabetes-induced changes in circulating lipoproteins. In others, extraordinary levels of circulating cholesterol appear to “swamp out” effects of hyperglycemia or defective insulin actions. One approach to illustrate the effects of diabetes without severe hypercholesterolemia involves assessment of early lesions, assuming these represent the initiation of disease. In one model, insulin-deficient LDL receptor-deficient (Ldlr−/−) mice, a model of T1DM without marked hyperlipidemia, had more macrophage accumulation in early lesions (Renard et al., 2004Renard C.B. Kramer F. Johansson F. Lamharzi N. Tannock L.R. von Herrath M.G. Chait A. Bornfeldt K.E. Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions.J. Clin. Invest. 2004; 114: 659-668Crossref PubMed Scopus (178) Google Scholar). In the same model, diabetes promoted the incidence of hemorrhage and necrotic core expansion in advanced lesions (Johansson et al., 2008Johansson F. Kramer F. Barnhart S. Kanter J.E. Vaisar T. Merrill R.D. Geng L. Oka K. Chan L. Chait A. et al.Type 1 diabetes promotes disruption of advanced atherosclerotic lesions in LDL receptor-deficient mice.Proc. Natl. Acad. Sci. USA. 2008; 105: 2082-2087Crossref PubMed Scopus (62) Google Scholar; Kanter et al., 2019Kanter J.E. Shao B. Kramer F. Barnhart S. Shimizu-Albergine M. Vaisar T. Graham M.J. Crooke R.M. Manuel C.R. Haeusler R.A. et al.Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes.J. Clin. Invest. 2019; 129: 4165-4179Crossref PubMed Scopus (38) Google Scholar). Increased necrotic core formation, an indication of advanced plaques, also occurred in mice with loss of insulin receptors in macrophages (Han et al., 2006Han S. Liang C.P. DeVries-Seimon T. Ranalletta M. Welch C.L. Collins-Fletcher K. Accili D. Tabas I. Tall A.R. Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions.Cell Metab. 2006; 3: 257-266Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar). Greater necrotic cores could result from reduced efferocytosis (the clearance of dead cells by phagocytes), which was reported in ob/ob mice, a mouse model of T2DM (Li et al., 2009Li S. Sun Y. Liang C.P. Thorp E.B. Han S. Jehle A.W. Saraswathi V. Pridgen B. Kanter J.E. Li R. et al.Defective phagocytosis of apoptotic cells by macrophages in atherosclerotic lesions of ob/ob mice and reversal by a fish oil diet.Circ. Res. 2009; 105: 1072-1082Crossref PubMed Scopus (100) Google Scholar). Although rodent lesions are generally deficient in calcification, the combination of insulin resistance, dietary cholesterol, and saturated fat was reported to create calcification in the arterial wall (Nguyen et al., 2013Nguyen N. Naik V. Speer M.Y. Diabetes mellitus accelerates cartilaginous metaplasia and calcification in atherosclerotic vessels of LDLr mutant mice.Cardiovasc. Pathol. 2013; 22: 167-175Crossref PubMed Scopus (29) Google Scholar). Thus, animal pathology indicates that diabetes leads to faster lesion initiation and progression to more advanced lesions. Human epidemiologic and clinical trial data clearly show that improved glycemic control is associated with fewer CVD events in patients with T1DM (Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group, 2016Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research GroupIntensive diabetes treatment and cardiovascular outcomes in type 1 diabetes: the DCCT/EDIC Study 30-year follow-up.Diabetes Care. 2016; 39: 686-693Crossref PubMed Scopus (283) Google Scholar; Nathan et al., 2005Nathan D.M. Cleary P.A. Backlund J.Y. Genuth S.M. Lachin J.M. Orchard T.J. Raskin P. Zinman B. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research GroupIntensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.N. Engl. J. Med. 2005; 353: 2643-2653Crossref PubMed Scopus (3980) Google Scholar). The DCCT/EDIC study was and remains a clinical trial on improved glucose control by intensive insulin treatment versus conventional treatment in subjects with T1DM (DCCT) and a subsequent observational period (EDIC) following most of the DCCT subjects. The DCCT reported a decrease in cardiovascular events (∼40%) but this decrease was not statistically significant, likely due to the small number of events in this lower-risk population. In the EDIC observational study the decrease in cardiovascular events became statistically significant as more events accrued. However, because more intensive insulin treatment affects many parameters, these data cannot provide information on the primary cause of greater ASCVD with diabetes. For instance, studies have shown that at the 15.8-year DCCT/EDIC follow-up period the development of hypertension was decreased in the intensive insulin group (de Boer et al., 2008de Boer I.H. Kestenbaum B. Rue T.C. Steffes M.W. Cleary P.A. Molitch M.E. Lachin J.M. Weiss N.S. Brunzell J.D. Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research GroupInsulin therapy, hyperglycemia, and hypertension in type 1 diabetes mellitus.Arch. Intern. Med. 2008; 168: 1867-1873Crossref PubMed Scopus (90) Google Scholar). Moreover, early in the active phase of DCCT there were favorable changes in several inflammatory markers (soluble ICAM-1, TNF-R1) with intensive glucose control, and decreases in high-sensitivity C-reactive protein (hsCRP; a marker of systemic inflammation) in patients in the lower third of weight gain (Schaumberg et al., 2005Schaumberg D.A. Glynn R.J. Jenkins A.J. Lyons T.J. Rifai N. Manson J.E. Ridker P.M. Nathan D.M. Effect of intensive glycemic control on levels of markers of inflammation in type 1 diabetes mellitus in the diabetes control and complications trial.Circulation. 2005; 111: 2446-2453Crossref PubMed Scopus (92) Google Scholar). Epidemiologic data show that a number of risk factors other than glycemic control strongly associate with ASCVD risk in patients with diabetes, especially T2DM (Orchard et al., 2003Orchard T.J. Olson J.C. Erbey J.R. Williams K. Forrest K.Y. Smithline Kinder L. Ellis D. Becker D.J. Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes: 10-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications Study.Diabetes Care. 2003; 26: 1374-1379Crossref PubMed Scopus (358) Google Scholar). The failure of improved glycemia with insulin, sulfonylureas, and DPP4 inhibitors to reduce CVD events in patients with T2DM also implies that factors other than hyperglycemia are important, as reviewed (Schmidt, 2019Schmidt A.M. Diabetes mellitus and cardiovascular disease.Arterioscler. Thromb. Vasc. Biol. 2019; 39: 558-568Crossref PubMed Scopus (4) Google Scholar). Moreover, the observation that patients with metabolic syndrome who do not yet have an overall increase in circulating glucose—levels of glycated hemoglobin (hemoglobin A1c; HbA1c; a marker of glycemic control) are not in the currently accepted diabetic range—also have greater CVD risk has been interpreted as evidence that hypertension, obesity, dyslipidemia, thrombosis, and inflammation and not glucose levels alone drive CVD risk in patients with T2DM (Haffner et al., 2000Haffner S.M. Mykkänen L. Festa A. Burke J.P. Stern M.P. Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the prediabetic state.Circulation. 2000; 101: 975-980Crossref PubMed Google Scholar). This increased CVD might be especially profound in women (Haffner et al., 1997Haffner S.M. Miettinen H. Stern M.P. Relatively more atherogenic coronary heart disease risk factors in prediabetic women than in prediabetic men.Diabetologia. 1997; 40: 711-717Crossref PubMed Scopus (85) Google Scholar). As will be reviewed below in more detail, apart from LDL-C lowering, clinical trials have failed to provide a clear picture, either because of the many actions of drugs, the many causes of atherosclerosis, and/or differences in human response to a specific intervention. For many years, clinicians accepted that hyperglycemia explained the increased incidence of CVD in patients with diabetes. Recent epidemiological data from the Swedish National Diabetes Registry in a large cohort of patients with T1DM (n = 33,170) support the importance of improved glycemic control in reducing acute myocardial infarction, CVD death, and overall CVD risk (Matuleviciene-Anängen et al., 2017Matuleviciene-Anängen V. Rosengren A. Svensson A.M. Pivodic A. Gudbjörnsdottir S. Wedel H. Kosiborod M. Haraldsson B. Lind M. Glycaemic control and excess risk of major coronary events in persons with type 1 diabetes.Heart. 2017; 103: 1687-1695Crossref PubMed Scopus (30) Google Scholar). However, even in patients with HbA1c ≤6.9% the relative risk was 2.53, suggesting that factors other than average glucose impart vascular toxicity. Further clinical trial support for the adverse effects of hyperglycemia in T1DM was obtained in the DCCT/EDIC population and the UK Prospective Diabetes Study (UKPDS) population with recent onset of T2DM. The UKPDS was a multicenter trial of glycemic and blood pressure-lowering therapies in 5,102 patients with newly diagnosed T2DM. It ran for 20 years in 23 UK clinical sites and showed that improving blood glucose and/or blood pressure control reduced the microvascular complications of T2DM (UK Prospective Diabetes Study Group, 1998aUK Prospective Diabetes Study GroupIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18440) Google Scholar). Subsequently, all surviving patients were entered into a 10-year, open-label monitoring program. Subjects in the original intensive treatment group experienced a 15% reduction in cardiovascular events, which became statistically significant despite loss of within-trial blood glucose and antihyperglycemic therapy differences, the so-called legacy effect (Holman et al., 2008Holman R.R. Paul S.K. Bethel M.A. Matthews D.R. Neil H.A. 10-year follow-up of intensive glucose control in type 2 diabetes.N. Engl. J. Med. 2008; 359: 1577-1589Crossref PubMed Scopus (4953) Google Scholar). However, the predictive association of mean HbA1c on subsequent CVD events in both studies was partly dependent on standard risk factors (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group, 2016Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research GroupRisk factors for cardiovascular disease in type 1 diabetes.Diabetes. 2016; 65: 1370-1379Crossref PubMed Scopus (100) Google Scholar; Stevens et al., 2004Stevens R.J. Coleman R.L. Adler A.I. Stratton I.M. Matthews D.R. Holman R.R. Risk factors for myocardial infarction case fatality and stroke case fatality in type 2 diabetes: UKPDS 66.Diabetes Care. 2004; 27: 201-207Crossref PubMed Scopus (233) Google Scholar). Thus, the importance of hyperglycemia per se on CVD risk remains unclear (Figure 1, upper left). The argument that factors other than hyperglycemia fuel the greater incidence of CVD events and related mortality in patients with T1DM and T2DM is supported by several “failed” clinical trials (Laakso, 2001Laakso M. Cardiovascular disease in type 2 diabetes: challenge for treatment and prevention.J. Intern. Med. 2001; 249: 225-235Crossref PubMed Scopus (0) Google Scholar; Meigs, 2003Meigs J.B. Epidemiology of cardiovascular complications in type 2 diabetes mellitus.Acta Diabetol. 2003; 40: S358-S361Crossref PubMed Scopus (60) Google Scholar) briefly summarized in Figure 1, upper left. The open-label EDIC extension of the DCCT confirmed that better glycemic control in subjects with T1DM during the first 7 years of intensive glycemic control reduced CVD events by over 50%, and this effect was evident despite similar levels of HbA1c in the intensive versus control groups (Nathan et al., 2005Nathan D.M. Cleary P.A. Backlund J.Y. Genuth S.M. Lachin J.M. Orchard T.J. Raskin P. Zinman B. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research GroupIntensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.N. Engl. J. Med. 2005; 353: 2643-2653Crossref PubMed Scopus (3980) Google Scholar). As discussed below, the importance of glucose control in this outcome has been challenged. Of interest, in DCCT/EDIC there was an increased risk for any CVD event and major adverse cardiovascular events (MACEs) in patients on higher insulin doses, but when these data were adjusted for systolic blood pressure, pulse rate, HDL-C and LDL-C, TG, and HbA1c, there was no longer a relationship and the risk factor that explained most of this confounding was TG (Braffett et al., 2019Braffett B.H. Dagogo-Jack S. Bebu I. Sivitz W.I. Larkin M. Kolterman O. Lachin J.M. DCCT/EDIC Research GroupAssociation of insulin dose, cardiometabolic risk factors, and cardiovascular disease in type 1 diabetes during 30 years of follow-up in the DCCT/EDIC Study.Diabetes Care. 2019; 42: 657-664Crossref PubMed Scopus (0) Google Scholar). Moreover, urinary albumin excretion and sustained microalbuminuria or macroalbuminuria were associated with ∼2-fold increased risk of any CVD event and rendered the effect of HbA1c no longer significant (Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group, 2016Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research GroupIntensive diabetes treatment and cardiovascular outcomes in type 1 diabetes: the DCCT/EDIC Study 30-year follow-up.Diabetes Care. 2016; 39: 686-693Crossref PubMed Scopus (283) Google Scholar). With age, the association of mean HbA1c on subsequent CVD events was increasingly related to favorable modification of standard risk factors (Bebu et al., 2017Bebu I. Braffett B.H. Pop-Busui R. Orchard T.J. Nathan D.M. Lachin J.M. DCCT/EDIC Research GroupThe relationship of blood glucose with cardiovascular disease is mediated over time by traditional risk factors in type 1 diabetes: the DCCT/EDIC study.Diabetologia. 2017; 60: 2084-2091Crossref PubMed Scopus (43) Google Scholar). In another assessment of ASCVD in the DCCT/EDIC cohort using carotid intima-media thickness, not CVD events, fibrinogen was the best predictor for intima-media thickness progression (Hunt et al., 2015Hunt K.J. Baker N.L. Cleary P.A. Klein R. Virella G. Lopes-Virella M.F. DCCT/EDIC Group of InvestigatorsLongitudinal association between endothelial dysfunction, inflammation, and clotting biomarkers with subclinical atherosclerosis in type 1 diabetes: an evaluation of the DCCT/EDIC Cohort.Diabetes Care. 2015; 38: 1281-1289Crossref PubMed Scopus (24) Google Scholar). Thus, the benefit of improved glycemic control in the DCCT/EDIC on ASCVD appears to be multifactorial, associates with a number of changes, and fails to prove cause and effect. If glucose control were the primary driver of increased ASCVD in T2DM, then one would have expected that insulin, sulfonylureas, and the many other glucose-reducing agents to have reduced CVD events. But several large studies of T2DM have failed to prove benefits of glucose reductions in these patients (Figure 1, upper left). These trials are difficult to interpret, and the results lend themselves to multiple interpretations. One view is that failure of these trials to show CVD benefit from glucose reduction supports the hypothesis that factors other than hyperglycemia are more important accelerators of ASCVD in these patients. Unlike UKPDS, previously outlined, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study showed that tighter glycemic control actually led to more death (Gerstein et al., 2011Gerstein H.C. Miller M.E. Genuth S. Ismail-Beigi F. Buse J.B. Goff Jr., D.C. Probstfield J.L. Cushman W.C. Ginsberg H.N. Bigger J.T. et al.ACCORD Study GroupLong-term effects of intensive glucose lowering on cardiovascular outcomes.N. Engl. J. Med. 2011; 364: 818-828Crossref PubMed Scopus (806) Google Scholar). Although not a usual focus of discussion, the better-controlled subjects in ACCORD had fewer new myocardial infarctions, leading some to suggest that better glycemic control reduced atherogenesis while more hypoglycemia in the intensive treatment group with underlying CVD increased arrhythmic events and sudden death (Koska et al., 2018Koska J. Saremi A. Howell S. Bahn G. De Courten B. Ginsberg H. Beisswenger P.J. Reaven P.D. VADT InvestigatorsAdvanced glycation end products, oxidation products, and incident cardiovascular events in patients with type 2 diabetes.Diabetes Care. 2018; 41: 570-576Crossref PubMed Scopus (51) Google Scholar). Of interest, patients in ACCORD who died were those in whom reductions in glycemia by more intensive insulin management were less likely to be achieved. ADVANCE was a similar cardiovascular outcome trial (CVOT) that enrolled 11,140 T2DM patients in 215 collaborating centers in 20 countries from around the world. Sulfonylurea-based intensive glycemic therapy targeting a HbA1c ≤6.5% versus standard of care was associated with a 10% reduction in combined microvascular and macrovascular events compared with standard therapy, an effect largely driven by a 23% reduction in the risk of microvascular events, principally nephropathy (Patel et al., 2008Patel A. MacMahon S. Chalmers J. Neal B. Billot L. Woodward M. Marre M. Cooper M. Glasziou P. Grobbee D. et al.ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N. Engl. J. Med. 2008; 358: 2560-2572Crossref PubMed Scopus (41) Google Scholar). A subsequent publication by the ADVANCE group presented an additional 5.4 years of follow-up data. The group assigned to intensive glucose control still failed to demonstrate any macrovascular or mortality benefits over the standard therapy group (Zoungas et al., 2014Zoungas S. Chalmers J. Neal B. Billot L. Li Q. Hirakawa Y. Arima H. Monaghan H. Joshi R. Colagiuri S. et al.ADVANCE-ON Collaborative GroupFollow-up of blood-pressure lowering and glucose control in type 2 diabetes.N. Engl. J. Med. 2014; 371: 1392-1406Crossref PubMed Scopus (423) Google Scholar). Another large glucose reduction study, VADT, showed an overall benefit but only during the prolonged period in which the glycated hemoglobin curves were separated (Reaven et al., 2019Reaven P.D. Emanuele N.V. Wiitala W.L. Bahn G.D. Reda D.J. McCarren M. Duckworth W.C. Hayward R.A. VADT InvestigatorsIntensive glucose control in patients with type 2 diabetes - 15-year follow-up.N. Engl. J. Med. 2019; 380: 2215-2224Crossref PubMed Scopus (0) Google Scholar). In a separate analysis, patients in VADT with low coronary artery calcium had the greatest benefit (Koska et al., 2018Koska J. Saremi A. Howell S. Bahn G. De Courten B. Ginsberg H. Beisswenger P.J. Reaven P.D. VADT InvestigatorsAdvanced glycation end products, oxidation products, and incident cardiovascular events in patients with type 2 diabetes.Diabetes Care. 2018; 41: 570-576Crossref PubMed Scopus (51) Google Scholar). Could it be that glucose reduction prevents atherosclerosis in patients without severely damaged arteries, but does not prevent the final processes that lead to CVD events? Although a meta-analysis of these 4 trials did report a modest and statistically significant 9% decrease in death from CVD, non-fatal myocardial infarction, and non-fatal stroke (Turnbull et al., 2009Turnbull F.M. Abraira C. Anderson R.J. Byington R.P. Chalmers J.P. Duckworth W.C. Evans G.W. Gerstein H.C. Holman R.R. Moritz T.E. et al.Control GroupIntensive glucose control and macrovascular outcomes in type 2 diabetes.Diabetologia. 2009; 52: 2288-2298Crossref PubMed Scopus (904) Google Scholar), perhaps, with long-standing diabetes, the horse has left the barn and many years of hyperglycemic damage are mostly irreversible and not impeded. This could reflect arterial stiffness, a signature for vascular aging that in part is explained by glycation-induced accumulation of advanced glycation end products (AGEs) (Stehouwer et al., 2008Stehouwer C.D. Henry R.M. Ferreira I. Arterial stiffness in diabetes and the metabolic syndrome: a pathway to cardiovascular disease.Diabetologia. 2008; 51: 527-539Crossref PubMed Scopus (388) Google Scholar). Another issue with interpretation of these clinical trials are questions related to the method used to track glycemic control. HbA1c reflects average glucose control over a 3-month period, but this measurement does not reveal the variation in glucose levels during the day. It is argued that glucose variability and/or time in range and not average glucose leads to CVD risk. This conclusion is supported by clinical data correlating glucose variability with evidence of greater plaque vulnerability (more necrotic core) (Hirsch, 2015Hirsch I.B. Glycemic variability and diabetes complications: does it matter? Of course it does!.Diabetes Care. 2015; 38: 1610-1614Crossref PubMed Scopus (160) Google Scholar). A study of coronary calcium also associated higher score with glucose variability (Snell-Bergeon et al., 2010aSnell-Bergeon J.K. Roman R. Rodbard D. Garg S. Maahs D.M. Schauer I.E. Bergman B.C. Kinney G.L. Rewers M. Glycaemic variability is associated with coronary artery calcium in men with type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes study.Diabet. Med. 2010; 27: 1436-1442Crossref PubMed Scopus (0) Google Scholar). However, this hypothesis was not supported in PRANDIAL, a study in patients with T2DM following an acute myocardial infarction who were randomized to three premeal doses of a fast-acting insulin targeting 2 h postprandial blood glucose to <7.5 mmol/L (135 mg/dL) versus an intermediate-acting insulin twice daily or a long-acting insulin once daily targeting fasting/premeal blood glucose <6.7 mmol/L (120 mg/dL) (Raz et al., 2009Raz I. Wilson P.W. Strojek K. Kowalska I. Bozikov V. Gitt A.K. Jermendy G. Campaigne B.N. Kerr L. Milicevic Z. Jacober S.J. Effects of prandial versus fasting glycemia on cardiovascular outcome