Data from epidemiological and randomized controlled trials on the benefits of HbA1c reduction have been contradictory and therefore confusing for health care practitioners. The publication of numerous differing guideline recommendations on glycemic control has also caused confusion among health care professionals who have questioned the usefulness of lowering HbA1c. This is likely a major reason for the failure to achieve guideline-recommended risk factor targets in routine clinical practice (1). It is therefore timely that an article in this issue of Diabetes Care by Cahn et al. (2) reports analysis from the Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58) on the association of baseline HbA1c with cardiovascular and kidney outcomes. This post hoc analysis of 17,160 participants with type 2 diabetes in the DECLARE-TIMI 58 trial, who were randomized to dapagliflozin or placebo and followed up for a median of 4.2 years, demonstrated that in the whole population, increasing HbA1c was associated with higher risk of cardiovascular death or hospitalization for heart failure, major adverse cardiovascular events (MACE), and cardiorenal outcomes. The risk of MACE and cardiorenal outcomes was significantly higher with increasing HbA1c in the group with multiple risk factors compared with the population with atherosclerotic cardiovascular disease (ASCVD). Interestingly, baseline HbA1c was not associated with risk of hospitalization for heart failure. However, dapagliflozin led to a decrease in all outcomes with no heterogeneity by baseline HbA1c, a finding seen in other studies.
Association of hyerglycemia and cardiovascular outcomes in observational studies. A meta-analysis of 46 observational studies in people with diabetes showed an increased risk of all-cause mortality and cardiovascular mortality associated with glycemic control, with an optimal HbA1c level of 6% for reduction in all-cause and cardiovascular mortality (3). Another meta-analysis of 26 prospective cohort studies reported that the pooled relative risk association of a 1% increase in glycated hemoglobin in people with type 2 diabetes was 1.15 (95% CI 1.11–1.20) for all-cause mortality, 1.17 (95% CI 1.12–1.23) for cardiovascular disease, 1.15 (95% CI 1.10–1.20) for coronary heart disease, 1.11 (95% CI 1.05–1.18) for heart failure, 1.11 (95% CI 1.06–1.17) for stroke, and 1.29 (95% CI 1.18–1.40) for peripheral arterial disease (4). A meta-analysis of 39 studies with 532,799 participants showed that every 1% increase in HbA1c was associated with a 17% (hazard ratio [HR] 1.17, 95% CI 1.09–1.25) increase in the first-ever occurrence of a stroke in people with diabetes (5).
Association of hyperglycemia and cardiovascular outcomes in RCTs. The UK Prospective Diabetes Study (UKPDS) of people newly diagnosed with type 2 diabetes was the first to demonstrate risk reduction for myocardial infarction and death from all causes at 10 years posttrial follow-up (6). A meta-analysis of intensive glucose-lowering trials, Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), Veterans Affairs Diabetes Trial (VADT), and UKPDS, also reported a 9% reduction for risk of MACE (HR 0.91, 95% CI 0.84–0.99) and 15% (HR 0.85, 95% CI 0.76–0.94) for myocardial infarction (7). Meta-regression in a recent meta-analysis of 18 cardiovascular trials with 161,156 participants reported that HbA1c lowering was associated with reduction of MACE that explained 97% of between-study variance (8). The meta-analysis also showed that heart failure and all-cause death were not associated with improvement in glycemic control in these cardiovascular outcome trials (CVOTs) (8). The risk reduction for MACE was greater for sodium–glucose cotransporter 2 inhibitors (SGLT2i) than for dipeptidyl peptidase 4 inhibitors for the same level of HbA1c reduction, suggesting that SGLT2i have additional benefits irrespective of HbA1c levels.
Surprisingly, although heart failure is one of the most common complications of type 2 diabetes, the benefits of glucose lowering in patients with heart failure have not been conclusively defined. A meta-analysis of 12 cardiovascular outcome trials in people with type 2 diabetes found no association between the degree of HbA1c reduction and risk of heart failure (8). Another meta-analysis of 30 trials reported no overall effect of glucose-lowering interventions on the risk of heart failure (risk ratio 0.98, 95% CI 0.90–1.08), with high heterogeneity between drug classes (9). However, an analysis from the Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS), in which participants had good glycemic control, showed that glycated hemoglobin exhibited a U-shaped association with cardiovascular outcomes in people with type 2 diabetes and ASCVD, with the lowest risk at an HbA1c around 7% (10).
Reasons for differences in observational and interventional studies. A forward-thinking aspect of the DECLARE-TIMI 58 study was that 59% of the participants did not have established ASCVD but had multiple risk factors, and it was adequately powered with long follow-up (4.2 years) to separately assess outcomes for those with ASCVD and those with multiple risk factors. However, there may be a number reasons for the differences observed in various observational and interventional studies. Although these CVOTs determined the safety of new glucose-lowering therapies with recommendations for the placebo arm to have glycemic equipoise with intervention arms, many trials reported worse glycemic control in the placebo arm (8). These conflicting results may be due to the different background therapies that were used. A meta-analysis of 10 randomized controlled trials of 92,400 participants with type 2 diabetes of glucose-lowering therapies with low risk of hypoglycemia demonstrated that a 1% reduction in HbA1c was associated with a significant 30% (95% CI 17–40%) reduced risk for MACE outcomes (11). However, trials using conventional glucose-lowering agents with a higher risk of hypoglycemia failed to demonstrate any benefits (11). The beneficial effects observed in CVOTs irrespective of HbA1c reduction could also be due to pleiotropic properties of SGLT2i and glucagon-like protein 1 receptor agonists (GLP-1RA) (12). Further explanatory factors include higher baseline prevalence of coronary heart disease in CVOTs, potentially reducing the beneficial effects of glycemic control. In the DECLARE-TIMI 58 trial, people with ASCVD were more likely to be on cardioprotective therapies at baseline (13), and it is plausible that the results are driven by background therapies in people with established ASCVD.
Implementing findings into routine clinical practice. Although the beneficial effects of reduction in microvascular complications by improving glycemic control are well established, the benefits to cardiovascular outcomes still remain uncertain, except for those in patients who are targeted early in the course of disease, as seen in the UKPDS. Early management of other risk factors, including lipids and blood pressure, can also lead to improved microvascular and macrovascular complications, particularly in the context of early control of multiple risk factors (14). Novel therapies using SGLT2i and GLP-1RA have advanced the treatment paradigm for those with established or at high risk of ASCVD, chronic kidney disease, or heart failure, although most of these CVOTs have been in patients much later in the course of diabetes (duration of diabetes ∼11–13 years) (15). Whether earlier introduction of these novel therapies will have long-term benefits is unknown.
Recent epidemiological evidence demonstrates a substantial reduction in cardiovascular complications over the last two decades (16) but an increase in the incidence of microvascular complications globally (17). We have made much progress in improving macrovascular complications over the last two decades, and we need to continue implementing novel therapies, including SGLT2i and GLP-1RA, for prevention of cardiovascular disease in high-risk patients. However, as 80% of people with type 2 diabetes live in low- to middle-income countries, the key priority should be the implementation of multiple risk factor control from diagnosis using affordable glucose-lowering therapies to reduce the increasing microvascular and macrovascular burden in people with and without established ASCVD and to advance early therapy (Fig. 1). The growing increase in prevalence of diabetes globally will further escalate the burden of complications in the coming decades, and therefore early glycemic and control of multiple risk factors need to be prioritized.
See accompanying article, p. 938.
Article Information
Funding. K.K. is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration East Midlands and the NIHR Leicester Biomedical Research Centre.
The views expressed are those of the authors and not necessarily those of the NIHR, National Health Service, or the Department of Health and Social Care.
Duality of Interest. K.K. has acted as a consultant or speaker or has received grants for investigator-initiated studies for AstraZeneca, Novartis, Novo Nordisk, Sanofi, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, Bayer, Berlin-Chemie AG/Menarini Group, Janssen, and Napp Pharmaceuticals. V.R.A. has served as a consultant for Applied Therapeutics, Fractyl Health, Novo Nordisk, Pfizer, and Sanofi. V.R.A.’s spouse is an employee of Janssen. V.R.A. has received institutional research contracts from Applied Therapeutics, Eli Lilly, Fractyl, Novo Nordisk, and Sanofi. No other potential conflicts of interest relevant to this article were reported.
