A1C: Episode 3

There are many numbers to keep in mind when we help people with diabetes manage their condition. Some are diagnosis criteria, others are therapeutic targets, and still others are related to specific treatments. Although these numbers may seem random or arbitrary to some of our patients, they are evidence-based and derived from data related to diabetes pathophysiology and the prevention of complications. This article is part of a series explaining some of the key numbers related to diabetes management and summarizing the evidence underpinning them.

A1C: Episode 3

Because A1C is foundational to nearly all facets of diabetes care, the first two articles in this series focused on A1C (1,2). However, there are too many A1C-related numbers discussed in the American Diabetes Association’s (ADA’s) Standards of Care in Diabetes—2024 to be adequately covered in just two articles. Thus, this is the third and final article exploring A1C-related numbers. Future articles in this series will focus on other numbers related to diabetes management.

≤8%

Significance of this A1C value

An A1C ≤8% is suggested by some institutions as the A1C goal for elective surgery whenever possible.

Supporting evidence

Surgical stress and counterregulatory hormones can have negative impacts on surgical outcomes, including increased mortality risks, infection rates, and lengths of stay. Although there are scarce data to guide the care of people with diabetes during the perioperative period, some institutions suggest an A1C cutoff value and an A1C optimization program to achieve the A1C goal before surgery. Some studies have shown an association between preoperative A1C values >7–8% and higher rates of wound complications, infections, and mortality (3–5).

8.5%

Significance of this A1C value

This A1C value serves as a treatment guide for new-onset diabetes in youth with overweight or obesity with a clinical suspicion of type 2 diabetes. It is recommended that initial treatment for youth with an A1C <8.5% should be metformin alone, whereas those with an A1C ≥8.5% should be started on insulin with or without metformin.

Supporting evidence

Insulin should be used as the initial treatment when A1C is ≥8.5% and the distinction between type 1 and type 2 diabetes is not clear in youth with new-onset diabetes (6). When insulin is not required as the initial treatment, initiation of metformin is recommended. In the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study, half of the participants had durable glycemic control (A1C <8%) for 6 months with metformin alone (7).

9%

Significance of this A1C value

Initiating insulin treatment in individuals admitted to the hosptial with an A1C of >9% is one of the successful strategies to prevent readmission.

Supporting evidence

The hospital readmission rate in people with diabetes is 14–20%, which is nearly twice of that in people without diabetes. Although there is no standard to prevent readmissions in people with diabetes, several successful strategies have been reported to identify high-risk individuals and initiate interventions. One of these strategies is to start insulin therapy for individuals with an admission A1C >9% (8).

>10%

Significance of this A1C value

It is common practice to initiate insulin treatment when a patient has severe hyperglycemia, especially with evidence of catabolism such as weight loss, hypertriglyceridemia, and ketosis. An A1C >10% is commonly considered indicative of severe hyperglycemia, when insulin therapy should be initiated.

Supporting evidence

Insulin has the advantage of being more effective than noninsulin therapies when glucose toxicity intensifies insulin resistance; it lowers glucose in a dose-dependent manner and thus can address almost any level of blood glucose. When glucose toxicity resolves, it is often possible to change to a noninsulin therapy. However, some studies show that, in some people, poorly managed type 2 diabetes can be effectively treated with a sulfonylurea, glucagon-like peptide 1 (GLP-1) receptor agonist, or dual gastric inhibitory polypeptide (GIP)/GLP-1 receptor agonist such as tirzepatide (9–11). GLP-1 receptor agonists and tirzepatide have additional benefits over sulfonylureas and insulin, including lowering hypoglycemia risk and promoting weight loss. GLP-1 receptor agonists also provide cardiovascular and kidney benefits.

>1.5% Above Target

Significance of this A1C value

Dual combination therapy or a more potent glucose-lowering agent is usually required for individuals with an A1C 1.5% above their individualized A1C target.

Supporting evidence

Combination therapy has many benefits, including increased durability of glycemic control, simultaneous targeting of multiple pathophysiological processes of type 2 diabetes, and positive impacts on medication burden, medication-taking behavior, and treatment persistence, as well as complementary clinical benefits such as weight loss and cardiovascular and kidney protection (12). Studies suggest that A1C reductions of 0.7–1% can result when each new class of noninsulin therapy is added to metformin, and reductions of 1–2% can be expected when a GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist is added (9,13,14) (13–15). A study looking at the combination of metformin with a sodium–glucose cotransporter 2 (SGLT2) inhibitor showed A1C reductions of 1.98–2.05% (15).

0.3–0.4% Reduction in A1C

Significance of this range

Using injectable and oral glucose-lowering agents as an adjunct to insulin treatment in people with type 1 diabetes has shown to yield modest reductions in A1C of ∼0.3–0.4% from baseline.

Supporting evidence

Although insulin replacement therapy is essential in people with type 1 diabetes who have absent or near-absent β-cell function, noninsulin therapy has been shown to be effective in reducing A1C, excess weight, and insulin doses. Clinical trials of the β-cell peptide amylin (pramlintide) have shown A1C reductions of 0.3–0.4% (16). About the same degree of reduction (∼0.4%) has been seen with liraglutide 1.8 mg daily (17,18). SGLT2 inhibitors have been studied in people with type 1 diabetes and yielded similar improvement; however, the use of SGLT2 inhibitors was associated with an increased rate of diabetic ketoacidosis (19).

Nonspecific A1C-Related Numbers and Their Effects on Complications

Rapid reduction of A1C and retinopathy

Studies have shown that rapid reductions of A1C can be associated with initial worsening of retinopathy. In pregnant women with preexisting type 1 or type 2 diabetes who also have retinopathy, rapid implementation of intensive glycemic management is associated with early worsening of retinopathy (20). Intensification of glucose-lowering therapy such as GLP-1 receptor agonists in the setting of retinopathy can also be associated with initial worsening of retinopathy. A 0.1% increase in the degree of A1C reduction was associated with increased progression of retinopathy (21).

Near-normoglycemia and complication rates

Large, prospective randomized trials have shown that intensive diabetes management with the goal of achieving near-normoglycemia (A1C ∼7%) is associated with prevention and/or delay in onset and progression of retinopathy, reduction in the need for future ocular surgery, and potentially improved self-reported visual function (22–26). Early achievement of near-normoglycemia in people with type 1 diabetes has been shown to effectively delay or prevent the development of diabetic peripheral neuropathy and cardiovascular autonomic neuropathy (27–30). The benefit of achieving near-normoglycemia in people with type 2 diabetes is not as strong as in those with type 1 diabetes. Some studies have shown a modest slowing of progression of neuropathy without reversal of neuronal loss (31,32).

Elevated A1C

One of the criteria when considering metabolic surgery in adolescence is elevated A1C and/or serious complications despite lifestyle modification and pharmacological intervention. According to the executive summary of a joint statement by international diabetes organizations (33), metabolic surgery is recommended in people with type 2 diabetes who have class II obesity (BMI 35.0–39.9 kg/m²) with inadequately controlled hyperglycemia despite lifestyle change and optimal medical therapy, and metabolic surgery should be considered in those with class I obesity (BMI 30.0–34.9 kg/m²) and inadequately controlled hyperglycemia despite optimal medical treatment by either oral or injectable medications (including insulin).

Although no randomized trials to date have compared the effectiveness and safety of surgery to those of conventional treatment options in adolescents, small retrospective analyses and a prospective multicenter, nonrandomized study (34) suggest that bariatric or metabolic surgery has benefits in adolescents with obesity and type 2 diabetes similar to those observed in adults, including similar degrees of weight loss, diabetes remission, and improvement of cardiometabolic risk factors for at least 3 years after surgery.