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Reducing Risk of Cardiovascular Events and Death By Lowering A1c

May 27, 2017

Study focused on type 2 diabetes patients who initiate metformin.

While much attention is given to the microvascular effects of type 2 diabetes, such as diabetic retinopathy, nephropathy, and neuropathy; and macrovascular consequences such as stroke, myocardial infarction, and peripheral vascular disease, heart failure is a seventh and more sinister complication that raises mortality.


This conclusion, based on an in-depth session entitled, “Heart Failure: The Frequent, Forgotten and Often Fatal Complication of Type 2 Diabetes,” was presented at the American Association of Clinical Endocrinology 26th Annual Scientific and Clinical Congress, by David Bell, MD; Richard E. Gilbert, MD; and Aaron I. Vinik, MD.

[Ed. note: As the paragraphs below summarize the AACE presentation, the use of “we” reflects the viewpoint of the presenters, Drs. Bell, Gilbert and Vinik.]

This was a population-based cohort study, including all metformin initiators with HbA1c tests in Northern Denmark, 2000-2012. Six months after metformin initiation, we classified patients by HbA1c achieved (<6.5% or higher) and by magnitude of HbA1c change from the pretreatment baseline. We used Cox regression to examine subsequent rates of acute myocardial infarction, stroke, or death, controlling for baseline HbA1c and other confounding factors.

They included 24,752 metformin initiators (median age 62.5 years, 55% males) with a median follow-up of 2.6 years. The risk of a combined outcome event gradually increased with rising levels of HbA1c achieved compared with a target HbA1c of <6.5%: adjusted hazard ratio (HR) 1.18 (95% CI 1.07-1.30) for 6.5-6.99%, HR 1.23 (1.09-1.40) for 7.0-7.49%, HR 1.34 (1.14-1.57) for 7.5-7.99%, and HR 1.59 (1.37-1.84) for ≥8%. Results were consistent for individual outcome events and robust by age group and other patient characteristics. A large absolute HbA1c reduction from baseline also predicted outcome: adjusted HR 0.80 (0.65-0.97) for Δ = -4, HR 0.98 (0.80-1.20) for Δ = -3, HR 0.92 (0.78-1.08) for Δ = -2, and HR 0.99 (0.89-1.10) for Δ = -1 compared with no HbA1c change (Δ = 0).

In this population-based study, 24,752 patients with type 2 diabetes who initiated metformin were enrolled to evaluate the association of early achieved HbA1c level and magnitude of HbA1c reduction with subsequent risk of cardiovascular events or death.

After a median follow-up of 2.6 years, the risk of a combined outcome event was increased with rising HbA1c levels compared with a target HbA1c of <6.5%. A large reduction in HbA1c from baseline was associated with decreased risk of cardiovascular events and death compared with no HbA1c change.

We have all been faced with the question: Does lowering the A1c level help reduce future cardiovascular (CV) events? Studies like the ACCORD trial evaluated this, but the group receiving more intensive therapy had slightly higher CV event rates. Perhaps the hypoglycemic medications caused this; but we were left lost as to whether we should be aggressive or not. Unfortunately, it is unlikely that there will be another study to tackle this issue despite the reduced risk of hypoglycemia associated with the newer medications. With no prospective studies, our only choice is to conduct observational retrospective studies.

This is one such observational study, which looked at over 24,000 patients in Denmark. The research question was when we start these patients on metformin, does the A1c level they achieve provide a hint at who will have more CV events in the future? The researchers found that patients who achieved lower A1c levels taking only metformin had the least number of CV events. They also noticed that the greater the drop in A1c, the fewer events these patients would have in the future as well.

At first glance, the conclusion would seem obvious—if a person’s disease is not that bad, a lower A1c level can be achieved and fewer CV events are likely. But, on further reflection, you need to realize it would be difficult to to tell which of the patients will have CV events or not; if we could, then we would be able to protect the higher-risk patients better.

From that perspective, this study becomes very useful. No matter what risk factors they have (that was corrected for in the study), the response to metformin can tell us which patients will do better or worse. If their metabolic derangements can be substantially corrected with metformin, as measured by a greater drop in A1c, those patients will do well.

In essence, this is a simple metabolic stress test for how the machinery is working in the patient’s body. Therefore, we need to pay attention to how much the A1c drops after starting metformin so that we can develop the best strategy for that specific patient.

In conclusion, a large initial HbA1c reduction and achievement of low HbA1c levels within 6 months after metformin initiation are associated with a lower risk of cardiovascular events and death in patients with type 2 diabetes.

Practice Pearls:

  • An initial A1c reduction within 6 months after metformin is started is associated with a lower risk of cardiovascular events and death for type 2 diabetes.
  • With all the negatives for sulfonylureas from studies, there is no reason to use them as we now have better alternatives.
  • There are more options to start patients on rather than sulfonylureas.


Presented at the American Association of Clinical Endocrinology 26th Annual Scientific and Clinical Congress. May 2017