Insulin Does Not Increase Fracture Risk Over Oral Diabetes Agents

Commentary by Karel Kostev, PhD and Jakob Starup-Linde, MD, PhD

Data from more than 100,000 people with type 2 diabetes did not show an increased risk of fracture among those taking insulin versus oral antidiabetes agents, according to a long-term study published in Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. In fact, insulin use was linked to a lower risk of fractures, although this difference was not statistically significant.

“Hypoglycemic events are associated with an increased risk of falling, and hypoglycemia is more common in people treated with insulin compared to oral antidiabetics like metformin or also incretins,” said lead author Karel Kostev, PhD, Senior Manager Epidemiology Research, IMS Health. “On the other hand, sulfonylurea therapy also is known to be associated with hypoglycemia.” This investigation found that insulin was not associated with a significant difference in fracture risk compared with oral antidiabetes agents, Dr Kostev said.

Man fallen off of ladder

“The study by Pscherer et al highlights that the observed increased fracture risk in patients with type 2 diabetes cannot be explained by a specific antidiabetic drug,” commented Jakob Starup-Linde, MD, PhD, Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark. “However, prevention of hypoglycemic events may decrease fracture risk within these individuals. Furthermore, besides a possible reducing effect on hypoglycemic events by insulin glargine, it also may cause a more stable blood glucose level. Diabetes is a condition with low bone turnover, and fluctuations in blood glucose (with high plasma glucose levels) is associated with a decreased bone turnover. These fluctuations may have detrimental effects on bone strength.”

Retrospective Data Review
The authors retrospectively studied data from the German Disease Analyzer database, which includes information entered by general practitioners throughout Germany. The sample included data from 24,250 patients with type 2 diabetes given at least 1 insulin prescription per 180 days between January 2000 and August 2014, and 81,710 patients with type 2 diabetes prescribed any oral antidiabetes agent, but not insulin, during the same period.

Key Findings
Overall, patients prescribed insulin had a slightly lower rate of incident fractures compared with patients prescribed oral antidiabetes agents (3.5% vs. 4.3%; odds ratio [OR] 0.87; P=0.1744). The findings were not statistically significant at least in part due to relative few fracture cases and short observation times, the authors noted.

“We found no significant difference in the fracture rates among patients with type 2 diabetes taking insulin versus oral antidiabetic drugs,” said Dr. Kostev. However, since patients with diabetes are at increased risk for fracture compared with the general population, the study authors recommend that “bone density tests should be ordered in patients with diabetes to detect osteoporosis before a bone fracture or to estimate a risk of bone fractures.”

Multivariate analysis showed that men were significantly less likely than women to have any fractures (OR, 0.59; P<0.0001). In contrast, patients with heart failure (OR, 1.31; P=0.0330), peripheral arterial disease (OR, 1.48; P=0.0069), or older age (1.04; P<0.0001) were more likely to have fractures. Use of sulfonylureas was linked to a significantly increased risk of fracture (OR, 1.86; P=0.0320)

The Effects of Insulin Choice on Fracture Risk
Conventional insulin treatment (ie, premixed short and long-acting insulin) was linked to an increased fracture risk compared with basal-supported oral therapy, but this difference was not statistically significant (OR, 1.59; P=0.1194). In addition, insulin glargine was linked to a lower risk of any fracture compared to Neutral Protamine Hagedorn (NPH) basal insulin; however, this finding only reached statistical significance after at least 2 years of follow-up (OR: 0.69; P=0.0264). No significant difference in fracture risk was found among the various types of basal insulins.

“The findings of the study by Pscherer et al suggest that the choice of insulin therapy may affect fracture risk in patients with diabetes,” Dr. Starup-Linde said. “The observed effect is most likely to be caused by differences in the number of hypoglycemic events and thus falls causing fracture. However, it is still unknown whether the observed results could be due to confounding by indication thus users of glargine insulin and NPH insulin may differ in characteristics.”

A 2016 study coauthored by Dr. Starup-Linde “showed no specific effects of glucose-lowering drugs on fracture risk. Insulin use was neutral in terms of fracture risk in patients with type 2 diabetes similar to the results of Psherer et al.”

“Besides the neutral results of glucose-lowering drugs, we observed a signal with increased fracture among patients with type 2 diabetes and very low LDL-cholesterol levels,” Starup-Linde said. “Thus, a huge suppression of LDL-cholesterol may be detrimental in terms of bone health.”

Overall Fracture Risk in Patients With Type 2 Diabetes
Dr. Kostev noted that a 10-year study by Rathmann et al showed that patients with type 2 diabetes have an increased risk of fractures overall compared with the general population, and also that type 2 diabetes patients more frequently experienced hip, spine, and upper arm and shoulder fractures. The study showed no significant differences between different antihyperglycaemic therapies regarding fracture risk, Dr. Kostev said.

“Again, in patients with diabetes, bone density tests should be ordered to detect osteoporosis before a bone fracture or to estimate a risk of bone fractures,” Dr. Kostev told EndocrineWeb. “In the case when bone density is low, orthopedists should be consulted to initiate [appropriate] therapy.”

March 22, 2016

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