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Severe hypoglycemia increases fracture risk more than hyperglycemia among adults with type 2 diabetes
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Among adult men and postmenopausal women with type 2 diabetes, those who have experienced severe hypoglycemia are at elevated risk for fracture, with risk increasing with greater number of severe hypoglycemic events, according to findings from a study in Japan.
Researchers also found that among those who have never had severe hypoglycemia, higher HbA1c increased fracture risk only for men.
“Episodes of severe hypoglycemia were significant risk factors for both men and postmenopausal women, whereas very poor glycemic control was a risk only for men after adjustment for potential confounders,” Masanori Iwase, MD, PhD, of the department of medicine and clinical science at the Graduate School of Medical Sciences of Kyushu University and the Diabetes Centre of Hakujyuji Hospital in Fukuoka, Japan, and colleagues wrote. “In addition, the impact of episodes of severe hypoglycemia on fractures appeared to be independent of HbA1c in both men and postmenopausal women.”
Iwase and colleagues analyzed data from 4,706 adult men and postmenopausal women with type 2 diabetes from the Fukuoka Diabetes Registry (mean age, 66 years; 41.5% postmenopausal women). Participants self-reported severe hypoglycemic events and fractures every year, and the researchers recorded HbA1c during a median of 5.3 years of follow-up.
In fully adjusted models, participants who reported at least two severe hypoglycemic events experienced 71.2 fractures per 1,000 person-years and had an HR of 2.11 (95% CI, 1.41-3.14) for a fracture vs. those who did not report a severe hypoglycemic event and had an HbA1c less than 53 mmol/mol — the refence group. The researchers noted that both postmenopausal women (HR = 1.84; 95% CI, 1.07-3.15) and men (HR = 2.46; 95% CI, 1.37-4.43) who reported at least two hypoglycemic events were at significantly higher risk for fracture vs. the reference group.
Participants who reported one severe hypoglycemic event experienced 43.1 fractures per 1,000 person-years and had an HR of 1.48 (95% CI, 1.02-2.15) for a fracture vs. the reference group. Although men who reported one severe hypoglycemic event were at significantly greater risk (HR = 2.04; 95% CI, 1.18-3.55), postmenopausal women who reported one severe hypoglycemic event were not, according to the researchers. Similarly, participants with an HbA1c of 75 mmol/mol or more with no reported severe hypoglycemic events experienced 40.5 fractures per 1,000 person-years and had an HR of 1.45 (95% CI, 1.06-1.98) for fracture vs. the reference group, but this finding remained significant only among men (HR = 1.86; 95% CI, 1.11-3.12).
The researchers also found that for every 10.9 mmol/mol increase in baseline HbA1c, there was a 10% rise in fracture risk (HR = 1.1; 95% CI, 1.01-1.19) and that those with a baseline HbA1c of at least 75 mmol/mol had an HR of 1.34 (95% CI, 1.001-1.79) for fracture vs. those with a baseline HbA1c of less than 75 mmol/mol. Significance did not hold when examining updated mean HbA1c and most recent HbA1c, according to the researchers.
“Our study demonstrated that both severe hypoglycemia and poor glycemic control were significantly related to an increased risk of fractures in people with type 2 diabetes,” the researchers wrote. “This study suggests that the glycemic target to prevent fractures may be HbA1c < 75 mmol/mol, which is far higher than that used to prevent microvascular complications, and higher than that for older adults with type 2 diabetes.” – by Phil Neuffer
Disclosures: The authors report no relevant financial disclosures.
Perspective
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Nelson B. Watts, MD
It’s clear that fracture risk is increased in patients with type 2 diabetes. It’s also pretty clear that multiple factors are involved, which makes it unlikely that any study will provide a simple answer. Patients with hypoglycemic events are more likely to fall — and falls are likely to result in fractures. Patients with poor control probably have changes in the bone constituents (advanced glycosylation end products) that affect bone quality. Other factors that are probably important include peripheral neuropathy, postural hypotension and poor vision. Duration of diabetes 10 years or more seems to be implicated.
Optimal glucose control and minimal risk of hypoglycemia are reasonable goals for all patients with type 2 diabetes. For older patients, someone should be assessing fracture risk and, if risk is high, offering measures to reduce the chance of fractures. FRAX, the risk-assessment tool, does not account for the additional risk from type 2 diabetes, but that can be adjusted for by either ticking the box for “rheumatoid arthritis,” which essentially mimics the fracture risk associated with type 2 diabetes, or by reducing the T-score by 0.5 T-score units (eg, if the patient is –1.9, putting in –2.4 instead). Although firm data is lacking for diabetes, it’s reasonable to assume that the medications used for long-term treatment of postmenopausal osteoporosis (alendronate, risedronate, zoledronic acid and denosumab) would be effective.
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