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Sulfonylureas and Risk of Falls and Fractures: A Systematic Review

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Abstract

Background

Sulfonylureas have been linked to increased risk of hypoglycemia. Hypoglycemia may lead to falls, and falls may lead to fracture. However, studies quantifying the association between sulfonylureas and fractures are sparse and yield inconsistent results.

Objective

The purpose of this article was to review the literature regarding sulfonylurea use and falls or fall-related fractures among older adults with type 2 diabetes mellitus and to delineate areas for future research.

Data Sources

We searched MEDLINE (1966–March 2012) and CINAHL (1937–March 2012) for studies of patients with type 2 diabetes mellitus living in the community or nursing homes.

Study Selection

The search algorithms combined three domains: (1) diabetic patients, (2) sulfonylurea medications, and (3) fractures or falls. We included only publications in English that pertained to human subjects. We found 9 randomized trials and 12 non-experimental studies that met the inclusion criteria.

Study Appraisal and Synthesis Methods

The guidelines provided by the Cochrane handbook or Agency for Healthcare Research and Quality (AHRQ) Methods Guide are too general to distinguish the quality of included non-experimental studies, so we developed several specific domains based on those general guidelines. These domains included study design, study population, follow-up time, comparison group, exposure definition, outcome definition, induction period, confounding adjustment, and attrition or missing data. The data were not amenable to a meta-analysis.

Results

No clinical trials included fracture as a primary endpoint. Most clinical trials excluded older adults. Most studies were not designed to evaluate the risk of sulfonylureas on fractures or falls. Studies did not show an increased risk of falls/fractures with sulfonylurea.

Limitations

The data available from existing studies suffer from methodological limitations including insufficient events, lack of primary endpoints, exclusion of older adults, and lack of clarity or inappropriate comparison groups.

Conclusion

Future studies are needed to appropriately estimate the effect of sulfonylureas on falls or fall-related fractures in older adults who are at increased risk for hypoglycemia, the hypothesized mechanism for fractures related to sulfonylurea therapy.

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Acknowledgments

This work was funded through a graduate student fellowship to Virginia Commonwealth University from US Outcomes Research/Medical Affairs Merck & Co., Inc., to Dr. Lapane.

Conflict of interest

Dr. Rajpathak is an employee of Merck, Inc. Mr. Yang, Ms. Brown, Ms. Jawahar and Dr. Pagliasotti have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Quantitative Health Science, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA

    Kate L. Lapane

  2. Department of Epidemiology and Community Health, Virginia Commonwealth University, Richmond, VA, USA

    Shibing Yang, Monique J. Brown, Rachel Jawahar & Caleb Pagliasotti

  3. US Outcomes Research/Medical Affairs Merck & Co., Inc., Whitehouse Station, New Jersey, USA

    Swapnil Rajpathak

Authors
  1. Kate L. Lapane
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  2. Shibing Yang
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Corresponding author

Correspondence to Kate L. Lapane.

Appendix

Appendix

1.1 Search Algorithms

The search algorithms combine three domains: Diabetic patients AND sulfonylurea medications AND (Fractures OR Falls).

(Diabetes mellitus [Mesh] OR Diabetes[tw] OR Diabetic[tw] OR Hyperglycemia[Mesh] OR Hyperglycemia[tw] OR Hyperglycaemia[tw] OR Insulin Resistance[mesh] OR Insulin Resistance[tw] OR non-insulin dependent[tw] OR NIDDM[tw]).

AND

(Hypoglycemic agents [Mesh] OR Hypoglycemic agent*[tw] OR Hypoglycaemic agent*[tw] OR Hypoglycemic drug* [tw] OR Hypoglycaemic drug* [tw] OR Hypoglycemic medication* [tw] OR Hypoglycaemic medication* [tw] OR Hypoglycemics [tw] OR Hypoglycaemics [tw] OR Antihyperglycemic*[tw] OR Antihyperglycaemic*[tw] OR Anti-hyperglycemic*[tw] OR Anti-hyperglycaemic*[tw] OR Hypoglycemic Effect*[tw] OR Hypoglycaemic Effect*[tw] OR Antidiabetic*[tw] OR Anti-diabetic*[tw] OR Glucose-lowering agent*[tw] OR Glucose-lowering drug*[tw] OR Glucose-lowering medication*[tw] OR OAD[tw] OR OADS[tw] OR Insulin secretagog*[tw] OR Insulin sensitizer*[tw] OR Sulfonylurea Compounds [mesh] OR Sulfonylurea*[tw] OR Sulphonylurea*[tw] OR Acetohexamide[tw] OR Dymelor[tw] OR Carbutamide[tw] OR Glucidoral[tw] OR Chlorpropamide[tw] OR Diabinese[tw] OR Tolbutamide[tw] OR Orinase[tw] OR Tolazamide[tw] OR Tolinase[tw] OR Glyburide[tw] OR Glibenclamide [tw] OR Glynase[tw] OR Diabeta[tw] OR Micronase[tw] OR Glipizide[tw] OR Glucotrol[tw] OR Glimepiride[tw] OR Amaryl[tw] OR Biguanides [mesh] OR Biguanide*[tw] OR Buformin[tw]).

AND

(Bone fracture[mesh] OR Fracture [tw] OR fractures [tw] OR Broken bone*[tw] OR Comminution[tw] OR Accidental Falls[mesh] OR Falls [tw]).

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Lapane, K.L., Yang, S., Brown, M.J. et al. Sulfonylureas and Risk of Falls and Fractures: A Systematic Review. Drugs Aging 30, 527–547 (2013). https://doi.org/10.1007/s40266-013-0081-0

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