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

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).

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).

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.”

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).

“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.

BMJ. Published online August 28, 2019. Full text