No Benefit Found for HbA1c Below 6.5% in Type 1 Diabetes

Miriam E. Tucker

September 06, 2019

A target HbA1c level of 6.5%-6.9% may be preferable to aiming below 6.5% in adults and children with type 1 diabetes, new research suggests. 

The findings, from more than 10,000 children and adults with type 1 diabetes diagnosed between 1998 and 2017 from the Swedish National Diabetes Registry, were published online August 28 in the BMJ by Marcus Lind, MD, PhD, professor of diabetology at the Institute of Medicine, University of Gothenburg, Sweden, and colleagues.

From diagnosis through 2017, among individuals who achieved HbA1c < 6.5% (< 48 mmol/mol) compared with 6.5%-6.9% (48-52 mmol/mol), there was no reduction in risk of diabetic retinopathy or nephropathy, but there was a significantly increased risk of hypoglycemia at levels < 6.5%.

Severe complications most commonly occurred at much higher HbA1c levels, above 8.6% (> 70 mmol/mol), and milder complications began to increase above 7.0% (53 mmol/mol).

Overall, Lind and colleagues write: "The current findings support a general target of HbA1c < 7.0% in people with type 1 diabetes. People who achieve HbA1c levels < 6.5% should be vigilant about not spending too much time in hypoglycemia and achieve a good diabetes-related quality of life."

The new information is important because HbA1c target guidelines vary worldwide. In the United States, the American Diabetes Association Standards of Care recommend an HbA1c of < 7.5% (< 58 mmol/mol) for children and < 7.0% (< 53 mmol/mol) for adults. In the UK, the National Institute for Health and Care Excellence advises an HbA1c < 6.5% (< 48 mmol/mol) for both children and adults, and Swedish guidelines recommend an HbA1c < 6.5% for children and < 7.0% for adults. 

And the International Society for Pediatric and Adolescent Diabetes has recently lowered their HbA1c target from < 7.5% (< 58 mmol/mol) to < 7.0% (< 53 mmol/mol). 

Pinpointing Exact Target Difficult, but HbA1c 6.5%-7% "Reasonable"

In an interview with Medscape Medical News, Lind said that a major reason for the divergent targets is "that the evidence is not totally clear. It is very clear that reducing HbA1c from high levels is critical for reducing complications. But for small HbA1c differences at low levels, where fewer complications exist, the data are more limited." 

Given these new data, Lind said, "I think a unified target goal of HbA1c 6.5%-7.0% (48-52 mmol/mol) seems reasonable for both children and adults. In cases with very little time in hypoglycemia and good diabetes-related quality of life at lower HbA1c levels, I think certain patients can remain on such an HbA1c level."

Asked to comment, Gregory P. Forlenza, MD, assistant professor of pediatrics at the Barbara Davis Center for Childhood Diabetes Pediatric Endocrinology, University of Colorado, Denver, agreed.

"I think this is a very interesting and compelling article, especially as it pertains to conversations with patients about their goals. Some patients feel compelled to target normal glycemia or blood sugar levels in the range of someone without type 1 diabetes. They often feel like they're failing if they can't get their HbA1c as low as possible and feel like an HbA1c in the 5[%]s is better than an HbA1c in the 6[%]s," he said.

"This article supports my longstanding belief that such an approach is past the point of diminishing returns, even arguing that it's harmful due to the risk of severe hypoglycemia with increasingly low targets," he continued.

However, Forlenza also pointed to recent data showing that less than 20% of patients with type 1 diabetes across the United States are currently meeting the ADA targets and that average HbA1c levels are actually rising in nearly all age groups, suggesting "overly aggressive targets are not the primary concern in the US type 1 diabetes population."

Is Time-in-Range a Better Metric Than HbA1c?

Forlenza also said that a shift in focus from HbA1c to "time-in-range," enabled by the use of continuous glucose monitoring (CGM), could provide a better approach to diabetes management.

"Suggesting a time in range of > 70% as a goal allows for minimization of both hypo- and hyperglycemia percentages without necessarily promoting a focus on extremely low blood glucose values. Many patients with type 1 diabetes have expressed that time-in-range has quality of life implications that are not well captured by HbA1c."

And, he noted, available and emerging automated insulin delivery systems — the Medtronic 670G, Tandem Control-IQ, and Insulet Horizon — have been shown to enable patients to achieve 70%-80% of time in range with less than 3% of time spent in hypoglycemia.

But Lind has a different view of time in range, noting that he recently had two patients, both with an HbA1c of 6.8% (50 mmol/mol) and similar time in range, but one had 18% time in hypoglycemia while the other had just 2%.

"Time in range is essential but I would advocate an even greater focus on time in hypoglycemia as a complement to HbA1c," he said.

"If a patient has good HbA1c I think it is still the most reliable measure for complications...What I like to look at is how much time in hypoglycemia a patient has with a good HbA1c. Glycemic variability measures are also essential as well as identifying certain patterns for treatment improvements," he noted.

Complication Rates Weren't Improved at HbA1c < 6.5% vs 6.5%-7.0%

The study population was comprised of 10,398 children and adults (mean age at first visit, 14.7 years) diagnosed between 1998 and 2017 with a mean type 1 diabetes duration at last follow-up of 11.9 years. Most (56.6%) were male.

Overall, 33.3% had a retinopathy event, 3.0% had preproliferative retinopathy, and 1.1% had proliferative retinopathy.

After adjustment for age, sex, duration of diabetes, blood pressure, blood lipid levels, body mass index (BMI), and smoking, the risk of any retinopathy for mean HbA1c < 6.5% (< 48 mmol/mol) compared with 6.5-6.9% (48-52 mmol/mol) didn't differ (odds ratio [OR], 0.77; P = .10).

The risk began to increase with HbA1c levels 7.0%-7.4% (53-57 mmol/mol), with an adjusted OR of 1.31, compared with HbA1c 6.5%-6.9% (P = .02).

At even higher HbA1c levels of 7.5%-8.6% (58-70 mmol/mol), the retinopathy risk more than doubled compared with HbA1c 6.5%-6.9% (adjusted OR, 2.05; P < .001) and nearly quadrupled at an HbA1c > 8.6% (> 70 mmol/mol) (3.72; P < .001).

For preproliferative retinopathy or worse, the risk actually increased at HbA1c < 6.5% as well as at higher levels compared with HbA1c 6.5%-6.9%, with an adjusted OR of 3.29 (P = .05) for HbA1c < 6.5%, 3.98 for 7.5%-8.6% (P = .008), and 13.77 for > 8.6% (P < .001).  

The authors write, "It seems unlikely that low HbA1c levels indicating glucose levels close to normal should be harmful in themselves; however, preclinical studies have indicated that microvascular complications might be promoted by frequent hypoglycemia, as is possibly the case with rapid glucose fluctuations that can be related to hypoglycemia."

For microalbuminuria/macroalbuminuria, again, the risks didn't differ between the two lowest HbA1c categories, with an adjusted OR of 0.98 for HbA1c < 6.5% compared with 6.5%-6.9% (P = .95). The risk increased at HbA1c 7.0%-7.4% (OR, 1.55; P = .03) and > 8.6% (OR, 2.64; P < .001).

The risk of macroalbuminuria alone more than tripled at HbA1c levels > 8.6% (OR, 3.43; P = .03).

Severe Hypoglycemia Risk Increased With HbA1c < 6.5%

Compared with HbA1c 6.5%-6.9%, the risk of severe hypoglycemia was significantly increased at HbA1c < 6.5% (OR, 1.34; P = .005) and that risk was halved at HbA1c > 8.6% (OR, 0.53; P < .001). 

Lind commented, "Overall, the HbA1c goal needs to be individualized for patients relating to factors such as complex biological fluctuating diabetes, current social situation, mental status/motivation, and other factors."

"But since we found less complications at HbA1c 6.5%-7.0% than above 7.0%, I think it should be the general treatment target window," especially because "we did not find any lower risks for complications below HbA1c 6.5% but [there were] 30% more severe hypoglycemias with unconsciousness or seizures."

At the same time, he commented, "We have shifted the HbA1c curve from being very high 30 to 40 years ago to moderately high on a population level."

"We therefore also must continue focusing to reduce HbA1c and how to do it in patients with very high HbA1c levels > 8.5%...If they could be reduced to moderate levels, such as < 8.0%, we should avoid a lot of severe complications," he said.

Forlenza adds, "I believe that we can see artificial pancreas systems meet the necessary requirements for glycemic control. Our next rounds of development in these areas will focus on improved usability, burden reduction, enhanced automation, and reduced costs."

Lind has reported receiving grants from AstraZeneca, Dexcom, Novo Nordisk, and Pfizer, and consulting fees from AstraZeneca, Dexcom, Eli Lilly, MSD, Novo Nordisk, and Rubin Medical. Forlenza has reported receiving research support from Abbott, Beta Bionics, Dexcom, Insulet, Medtronic, Tandem, and Type Zero. He has served as a speaker/consultant for Dexcom, Medtronic, and Tandem.

BMJ. Published online August 28, 2019. Full text

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