Early Glycemic Control and Magnitude of HbA1c Reduction Predict Cardiovascular Events and Mortality: Population-Based Cohort Study of 24,752 Metformin Initiators

Svensson, Elisabeth; Baggesen, Lisbeth M.; Johnsen, Søren Paaske; Pedersen, Lars; Nørrelund, Helene; Buhl, Esben S.; Haase, Christiane L; Thomsen, Reimar Wernich

doi:10.2337/dc16-2271

Cited by 63 publications

(49 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Observational and database studies also provide consistent evidence of a long‐term reduction in CV risk and increased survival for people with type 2 diabetes receiving metformin compared with diet‐only, sulphonylureas, acarbose and insulin . Indeed, patients treated with metformin to achieve glycated haemoglobin (HbA1c) <48 mmol/mol (<6.5%) in their first 6 months of treatment had a lower mortality rate over the following 10 years compared with individuals who did not achieve such early control . This affirms the value of effective early use of metformin to defer CV events years later.…”

Section: Antidiabetic Drugs and CV Effectsmentioning

confidence: 87%

Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials

Bailey

2018

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

This review examines recent randomized controlled cardiovascular (CV) outcome trials of glucose-lowering therapies in type 2 diabetes and their impact on the treatment of patients with type 2 diabetes. The trials were designed to comply with regulatory requirements to confirm that major adverse cardiac events (MACE) are not detrimentally affected by such therapies. Trials involving dipeptidyl peptidase-4 (DPP-4) inhibitors did not alter a composite MACE outcome comprising CV deaths, non-fatal myocardial infarction and non-fatal stroke; however, the possibility that some members of this class might incur a small increased risk or worsening of heart failure cannot be excluded. Some studies on glucagon-like peptide-1 receptor agonists (liraglutide: LEADER trial; semaglutide: SUSTAIN-6 trial) found significant benefits for MACE, while treatment with sodium-glucose co-transporter-2 inhibitors (empagliflozin: EMPA-REG OUTCOME trial; canagliflozin: CANVAS trial) also significantly reduced MACE and reduced hospitalization for heart failure. Comparisons among trials are complicated by variance in the populations recruited, particularly CV status at randomization, and differences in trial design, data collection and analyses. A large proportion of patients recruited into these trials have previously experienced adverse CV events; thus, the therapies are mostly assessing secondary prevention of a further event. This contrasts with the overall type 2 diabetes population receiving glucose-lowering therapies, of whom the majority will not have had MACE and will be regarded as primary prevention. Overall, the trials provide reassuring evidence that new glucose-lowering medications do not adversely affect CV events and some of these agents may offer CV protection.

show abstract

Section: Antidiabetic Drugs and CV Effectsmentioning

confidence: 87%

Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials

Bailey

2018

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

show abstract

“…The so‐called mega‐trials, such as ACCORD, VADT, ADVANCE, etc, did not demonstrate a cardiovascular benefit for intensive vs moderate glycaemic control; however, a large meta‐analyses of these and other studies showed that tight glycaemic control (difference in HbA1c for active comparators vs controls of 0.9%) reduced the relative risk of coronary heart disease events by 15% and of nonfatal myocardial infarction by 17% . An observational study in a cohort of metformin initiators for type 2 diabetes showed that a larger initial fall in HbA1c and maintenance of lower HbA1c levels for the first 6 months of therapy were associated with improved cardiovascular outcomes . Such a benefit may, in principle, apply to any antihyperglycaemic agent, as long as it did not bring side effects deleterious to the cardiovascular system.…”

Section: Cardiovascular Protection With Metforminmentioning

confidence: 99%

Mechanisms of action of metformin with special reference to cardiovascular protection

Zilov

Abdelaziz

Alshammary

et al. 2019

Diabetes Metabolism Res

View full text Add to dashboard Cite

Summary Management guidelines continue to identify metformin as initial pharmacologic antidiabetic therapy of choice for people with type 2 diabetes without contraindications, despite recent randomized trials that have demonstrated significant improvements in cardiovascular outcomes with newer classes of antidiabetic therapies. The purpose of this review is to summarize the current state of knowledge of metformin's therapeutic actions on blood glucose and cardiovascular clinical evidence and to consider the mechanisms that underlie them. The effects of metformin on glycaemia occur mainly in the liver, but metformin‐stimulated glucose disposal by the gut has emerged as an increasingly import site of action of metformin. Additionally, metformin induces increased secretion of GLP‐1 from intestinal L‐cells. Clinical cardiovascular protection with metformin is supported by three randomized outcomes trials (in newly diagnosed and late stage insulin‐treated type 2 diabetes patients) and a wealth of observational data. Initial evidence suggests that cotreatment with metformin may enhance the impact of newer incretin‐based therapies on cardiovascular outcomes, an important observation as metformin can be combined with any other antidiabetic agent. Multiple potential mechanisms support the concept of cardiovascular protection with metformin beyond those provided by reduced blood glucose, including weight loss, improvements in haemostatic function, reduced inflammation, and oxidative stress, and inhibition of key steps in the process of atherosclerosis. Accordingly, metformin remains well placed to support improvements in cardiovascular outcomes, from diagnosis and throughout the course of type 2 diabetes, even in this new age of improved outcomes in type 2 diabetes.

show abstract

“…The ORIGIN trial examined the outcome of low‐dose, basal insulin compared with standard care, and the insulin arm did not reduce either all‐cause mortality or cardiovascular mortality; however, patients in the insulin group received concomitant metformin—shown to markedly attenuate mortality risk in people treated with insulin, in particular at low doses—and insulin was quite frequently used in the standard care arm. In a recent observational study characterizing the outcome of care of those exposed to metformin, where the outcome was major adverse cardiovascular events or all‐cause mortality, there was no evidence of increased adverse outcomes at low HbA1c levels . A further observational study in 2010 reported that there was no difference in all‐cause mortality across the HbA1c range, but this study was subject to immortal time bias and other limitations.…”

Section: Discussionmentioning

confidence: 84%

Impact of differing glucose‐lowering regimens on the pattern of association between glucose control and survival

Currie

Holden²,

Jenkins‐Jones³

et al. 2017

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

AimsTo characterize survival in relation to achieved glycated haemoglobin (HbA1c) level within alternative glucose‐lowering regimens with differing risks of hypoglycaemia.MethodsData were extracted from the UK Clinical Practice Research Datalink and the corresponding Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose‐lowering therapy in monotherapy or dual therapy with metformin between 2004 and 2013 were identified. Risk of all‐cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time‐dependent covariable.ResultsThere were 6646 deaths in a total follow‐up period of 374 591 years. Survival for lower (<7%) vs moderate HbA1c levels (≥7%, <8.5%) differed by cohort: metformin, adjusted hazard ratio (aHR) 1.03 (95% confidence interval [CI] 0.95‐1.12); sulphonylurea, aHR 1.11 (95% CI 0.99‐1.25); insulin, aHR 1.47 (95% CI 1.25‐1.72); combined regimens with low hypoglycaemia risk, aHR 1.02 (95% CI 0.94‐1.10); and combined regimens with higher hypoglycaemia risk excluding insulin, aHR 1.24 (95% CI 1.13‐1.35) and including insulin, aHR 1.28 (95% CI 1.18‐1.37). Higher HbA1c levels were associated with increased mortality in regimens with low hypoglycaemia risk. Post hoc analysis by HbA1c deciles revealed an elevated risk of all‐cause mortality for the lowest deciles across all cohorts, but particularly in those regimens associated with hypoglycaemia. High HbA1c was associated with no difference, or a small increase in mortality risk in regimens with increased risk of hypoglycaemia.ConclusionsThe pattern of mortality risk across the range of HbA1c differed by glucose‐lowering regimen. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia. High levels of HbA1c were associated with the expected elevated mortality risk in regimens with low hypoglycaemia risk.

show abstract

Early Glycemic Control and Magnitude of HbA1c Reduction Predict Cardiovascular Events and Mortality: Population-Based Cohort Study of 24,752 Metformin Initiators

Abstract: A large initial HbA reduction and achievement of low HbA levels within 6 months after metformin initiation are associated with a lower risk of cardiovascular events and death in patients with type 2 diabetes.

Cited by 63 publications

References 34 publications

Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials

Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials

Mechanisms of action of metformin with special reference to cardiovascular protection

Impact of differing glucose‐lowering regimens on the pattern of association between glucose control and survival

Contact Info

Product

Resources

About