Research Original Investigation
Hypoglycemia After Antimicrobial Prescription
27. Perry CM, Scott LJ. Cefdinir: a review of its use in the management of mild-to-moderate bacterial infections. Drugs. 2004;64(13):1433-1464. 28. Broekhuysen J, Deger F, Douchamps J, et al. Pharmacokinetic study of cefuroxime in the elderly. Br J Clin Pharmacol. 1981;12(6):801-805. 29. AHRQ Quality Indicators. http://www .qualityindicators.ahrq.gov/. Assessed March 14, 2014. 30. Klabunde CN, Potosky AL, Legler JM, Warren JL. Development of a comorbidity index using physician claims data. J Clin Epidemiol. 2000;53 (12):1258-1267. 31. Ginde AA, Blanc PG, Lieberman RM, Camargo CA Jr. Validation of ICD-9-CM coding algorithm for improved identification of hypoglycemia visits. BMC Endocr Disord. 2008;8:4. doi:10.1186/1472-6823-8-4. 32. Koroukian SM, Xu F, Murray P. Ability of Medicare claims data to identify nursing home patients: a validation study. Med Care. 2008;46(11): 1184-1187. 33. RED BOOK Select Extracts. Ann Arbor, MI: Truven Health Analytics; 2011. http://sites.truvenhealth.com /redbook/. Accessed November 25, 2013. 34. Austin PC. Absolute risk reductions, relative risks, relative risk reductions, and numbers needed
to treat can be obtained from a logistic regression model. J Clin Epidemiol. 2010;63(1):2-6. 35. Myrand SP, Sekiguchi K, Man MZ, et al. Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations. Clin Pharmacol Ther. 2008;84(3):347-361. 36. Zhang Y, Steinman MA, Kaplan CM. Geographic variation in outpatient antibiotic prescribing among older adults. Arch Intern Med. 2012;172(19):1465-1471. 37. Tan A, Holmes HH, Kuo Y-F, Raji M, Goodwin JS. Co-administration of co-trimoxazole with sulfonoureas: hypoglycemic events and patterns of use [published online May 24, 2014]. J Gerontol A Biol Sci Med Sci. doi:10.1093/gerona/glu072. 38. Kurose K, Sugiyama E, Saito Y. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab Pharmacokinet. 2012;27(1):9-54. 39. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004;329(7456):15-19.
40. Mallet L, Spinewine A, Huang A. The challenge of managing drug interactions in elderly people. Lancet. 2007;370(9582):185-191. 41. Gurwitz JH, Field TS, Harrold LR, et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA. 2003;289(9):1107-1116. 42. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365 (21):2002-2012. 43. ePocrates. Watertown, MA: Athenahealth; 2013. http://www.epocrates.com/. Accessed November 25, 2013. 44. Lipska KJ, Ross JS, Wang Y, et al. National trends in US hospital admissions for hyperglycemia and hypoglycemia among Medicare beneficiaries, 1999 to 2011 [published online May 17, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014.1824. 45. Redberg RF. Editor’s Note: hospital admissions for hypoglycemia new exceed those for hyperglycemia in Medicare beneficiaries [published online May 17, 2014]. JAMA Intern Med. doi:10.1001 /jamainternmed.2014.2192.
Invited Commentary
Improving Safety of Diabetes Mellitus Management Kasia J. Lipska, MD, MHS
Older adults experience adverse drug events (ADEs) far more often than younger persons. The reasons for this include agerelated decline in kidney and liver function, comorbidities, and the use of multiple medications. Oral glucose-lowering Related article page 1605 agents and insulin are implicated in one-quarter of emergency hospitalizations for ADEs among older US adults.1 Nearly all of these diabetes mellitus (DM)-related drug events are for hypoglycemia. Among oral agents, sulfonylureas lead to most hospital visits for hypoglycemia. Although rates of DM complications have improved over the past 2 decades in the United States,2 serious hypoglycemic events are on the rise.3 Among older adults, especially those with longer duration of DM, severe hypoglycemic events are more common than many of the complications that glucoselowering treatment is intended to prevent.4 Despite these trends, current performance metrics and surveillance systems do not measure or evaluate severe hypoglycemia occurring during DM treatment. It is time to improve the safety of DM management. The Department of Health and Human Services recently drafted a National Action Plan for Adverse Drug Event Prevention focused on glucose-lowering agents as 1 of 3 classes of medications (the others include anticoagulants and opioids).5 The draft plan proposes 4 strategies for reducing ADEs: surveillance, prevention, incentives and oversight, and research. As a first step in improving safety, clinicians and patients need to better understand which medications, and in 1612
which types of patients, pose the highest risk for hypoglycemia. Based on data from randomized clinical trials, insulin and sulfonylureas are well known to increase this risk. However, limited data exist on the magnitude of this risk among older adults, especially when glucose-lowering agents are used in combination or together with commonly prescribed therapies, such as antibiotics, β-blockers, or opioids. This is because trials often exclude older, frail adults with complex health problems or those with acute exacerbations of underlying comorbidities that require concomitant treatments. In this issue of JAMA Internal Medicine, Parekh et al6 bring us a step closer to a better understanding of severe hypoglycemia risk among older adults. The researchers examined interactions between commonly prescribed antibiotics and sulfonylureas and the risk for serious hypoglycemia. Using Texas Medicare claims data for older patients using glipizide or glyburide, the investigators calculated rates of emergency department or hospital admissions for hypoglycemia within 14 days of prescription fill for 1 of 16 antibiotics; 7 of these antibiotics were previously implicated in causing hypoglycemia, while 9 had no clear mechanism or evidence linking them to these ADEs. After adjustment for demographic characteristics, comorbidities, prior health care utilization, and hypoglycemia, and the indication for the antibiotic, they found that clarithromycin, levofloxacin, sulfamethoxazole/trimethoprim, metronidazole, and ciprofloxacin were significantly associated with increased odds of severe hypoglycemia. The numbers needed to harm were 71 for clarithromycin and 334
JAMA Internal Medicine October 2014 Volume 174, Number 10
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 06/05/2015
jamainternalmedicine.com
Hypoglycemia After Antimicrobial Prescription
Original Investigation Research
for ciprofloxacin, with numbers needed to harm ranging from 131 to 187 for the other antibiotics. Concomitant use of these antibiotics with sulfonylureas was very common. Among patients using glipizide or glyburide, 28% had overlapping prescriptions for 1 of the 5 interacting antibiotics. As a result, 13% of all hypoglycemic events among patients taking sulfonylureas occurred in the context of using 1 of the interacting antibiotics. When Parekh et al6 examined ADEs, they hypothesized that several specific antimicrobial agents would result in clinically significant interactions. On the one hand, such deductive inquiries, grounded in the understanding of drug mechanisms, physiology, or prior information about possible harms, may be less likely to lead to spurious associations. On the other hand, many drug-drug interactions are not easy to predict. Since polypharmacy has become ubiquitous, better surveillance for drug-drug interactions is needed—both for interactions that may be suspected a priori, but also for those that are unexpected. Applying inductive reasoning and pattern recognition to “big data” with the use of advanced analytical techniques may aid in the detection of these interactions.7 One limitation of the study is that acute illness requiring an antibiotic may have largely contributed to severe hypoglycemia. For example, a urinary tract infection in an older woman may have resulted in a prescription for levofloxacin. The patient may have experienced mild fever and anorexia, leading to a skipped meal, which, in turn, precipitated a hypoglycemic reaction. However, the use of other antibiotics as a control group in the study mitigates this concern to some extent. Confirmation of these findings using other data sets would further increase the confidence in these associations. Although randomized clinical trials to corroborate the study’s results would not be feasible, the findings suggest that collection of data on concomitant medication use, including short-term prescriptions for acute conditions, may be useful to assess the safety of therapies during ongoing trials. ARTICLE INFORMATION Author Affiliation: Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut. Corresponding Author: Kasia J. Lipska, MD, MHS, Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, 333 Cedar St, PO Box 208020, New Haven, CT 06520-8020 (kasia [email protected]). Published Online: September 1, 2014. doi:10.1001/jamainternmed.2014.3290. Conflict of Interest Disclosures: None reported. Funding/Support: Dr. Lipska receives support from the Centers for Medicare & Medicaid Services (CMS) to develop publicly reported quality measures. Dr Lipska is also supported by the Pepper Center Career Development Award (P30 AG21342), the Grants for Early Medical/Surgical Specialists’ Transition to Aging Research (R03 AG045086) from the National Institute on Aging and the American Diabetes Association/Association for Specialty Professors, and the Yale Center for Investigation Scholar Award. This publication was
jamainternalmedicine.com
The findings by Parekh et al6 underscore that the risk of hypoglycemia associated with glucose-lowering medications may be modified by ongoing chronic and short-term therapies, which may potentially interact with DM agents. In turn, the magnitude of the risk of hypoglycemia may substantially alter the expected health gains associated with glycemic control for individual patients.8 To enhance safe prescribing, clinicians and patients need to carefully consider the expected benefits and harms of glucose-lowering agents, in the context of each patient’s values and preferences. Serious hypoglycemia substantially lowers health-related quality of life for many patients and, therefore, shifts the balance of benefits and harms. An older patient with a hemoglobin A1c level of less than 9% of total hemoglobin (0.09 proportion of total hemoglobin) and at high risk for hypoglycemia, for whom this complication results in a small loss in quality of life, may experience net harm from treatment with glucose-lowering agents other than metformin.8 In such a patient, the decision to avoid an offending antibiotic may lower the risk of hypoglycemia; in addition, the decision to use glucose-lowering treatments that are viewed as burdensome to the patient (because they lead to hypoglycemic reactions or other side effects) warrants reconsideration. But better understanding of hypoglycemia risk, even with the knowledge about drug-drug interactions and higherquality decision making in practice, may not be enough to ensure safety. As noted in the National Action Plan,5 surveillance, oversight, and incentives are also needed to reduce ADEs. Without active surveillance, it is difficult to develop and target risk reduction strategies to patients, clinicians, and health systems that need them the most. Future quality measures that assess ADEs can help incentivize and inform implementation of strategies to reduce hypoglycemia. In turn, appropriate medication management that minimizes the risk of harm in this population is likely to improve health outcomes and lower costs of care.
made possible by Clinical and Translational Science Award grant No. UL1 TR000142 from the National Center for Advancing Translational Science, a component of the National Institutes of Health (NIH). Disclaimer: The contents are solely the responsibility of the author and do not necessarily represent the official view of the NIH. REFERENCES 1. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365 (21):2002-2012. 2. Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014;370(16):1514-1523. 3. Lipska KJ, Ross JS, Wang Y, et al. National trends in us hospital admissions for hyperglycemia and hypoglycemia among Medicare beneficiaries, 1999 to 2011. JAMA Intern Med. 2014;174(7):1116-1124. 4. Huang ES, Laiteerapong N, Liu JY, John PM, Moffet HH, Karter AJ. Rates of complications and
mortality in older patients with diabetes mellitus: the diabetes and aging study. JAMA Intern Med. 2014;174(2):251-258. 5. US Department of Health and Human Services, Office of Disease Prevention and Health Promotion. National Action Plan for Adverse Drug Event Prevention. http://www.Health.Gov/hai/pdfs/ade -action-plan.Pdf. Accessed June 23, 2014. 6. Parekh TM, Raji M, Lin Y-L, Tan A, Kuo Y-F, Goodwin JS. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas [published online September 1, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014.3293. 7. Krumholz HM. Big data and new knowledge in medicine: the thinking, training, and tools needed for a learning health system. Health Aff (Millwood). 2014;33(7):1163-1170. 8. Vijan S, Sussman JB, Yudkin JS, Hayward RA. Effect of patients' risks and preferences on health gains with plasma glucose level lowering in type 2 diabetes mellitus [published online June 30, 2014]. JAMA Intern Med. doi: 10.1001/jamainternmed.2014 .2894.
JAMA Internal Medicine October 2014 Volume 174, Number 10
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 06/05/2015
1613
Hypoglycemia After Antimicrobial Prescription
27. Perry CM, Scott LJ. Cefdinir: a review of its use in the management of mild-to-moderate bacterial infections. Drugs. 2004;64(13):1433-1464. 28. Broekhuysen J, Deger F, Douchamps J, et al. Pharmacokinetic study of cefuroxime in the elderly. Br J Clin Pharmacol. 1981;12(6):801-805. 29. AHRQ Quality Indicators. http://www .qualityindicators.ahrq.gov/. Assessed March 14, 2014. 30. Klabunde CN, Potosky AL, Legler JM, Warren JL. Development of a comorbidity index using physician claims data. J Clin Epidemiol. 2000;53 (12):1258-1267. 31. Ginde AA, Blanc PG, Lieberman RM, Camargo CA Jr. Validation of ICD-9-CM coding algorithm for improved identification of hypoglycemia visits. BMC Endocr Disord. 2008;8:4. doi:10.1186/1472-6823-8-4. 32. Koroukian SM, Xu F, Murray P. Ability of Medicare claims data to identify nursing home patients: a validation study. Med Care. 2008;46(11): 1184-1187. 33. RED BOOK Select Extracts. Ann Arbor, MI: Truven Health Analytics; 2011. http://sites.truvenhealth.com /redbook/. Accessed November 25, 2013. 34. Austin PC. Absolute risk reductions, relative risks, relative risk reductions, and numbers needed
to treat can be obtained from a logistic regression model. J Clin Epidemiol. 2010;63(1):2-6. 35. Myrand SP, Sekiguchi K, Man MZ, et al. Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations. Clin Pharmacol Ther. 2008;84(3):347-361. 36. Zhang Y, Steinman MA, Kaplan CM. Geographic variation in outpatient antibiotic prescribing among older adults. Arch Intern Med. 2012;172(19):1465-1471. 37. Tan A, Holmes HH, Kuo Y-F, Raji M, Goodwin JS. Co-administration of co-trimoxazole with sulfonoureas: hypoglycemic events and patterns of use [published online May 24, 2014]. J Gerontol A Biol Sci Med Sci. doi:10.1093/gerona/glu072. 38. Kurose K, Sugiyama E, Saito Y. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab Pharmacokinet. 2012;27(1):9-54. 39. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004;329(7456):15-19.
40. Mallet L, Spinewine A, Huang A. The challenge of managing drug interactions in elderly people. Lancet. 2007;370(9582):185-191. 41. Gurwitz JH, Field TS, Harrold LR, et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA. 2003;289(9):1107-1116. 42. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365 (21):2002-2012. 43. ePocrates. Watertown, MA: Athenahealth; 2013. http://www.epocrates.com/. Accessed November 25, 2013. 44. Lipska KJ, Ross JS, Wang Y, et al. National trends in US hospital admissions for hyperglycemia and hypoglycemia among Medicare beneficiaries, 1999 to 2011 [published online May 17, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014.1824. 45. Redberg RF. Editor’s Note: hospital admissions for hypoglycemia new exceed those for hyperglycemia in Medicare beneficiaries [published online May 17, 2014]. JAMA Intern Med. doi:10.1001 /jamainternmed.2014.2192.
Invited Commentary
Improving Safety of Diabetes Mellitus Management Kasia J. Lipska, MD, MHS
Older adults experience adverse drug events (ADEs) far more often than younger persons. The reasons for this include agerelated decline in kidney and liver function, comorbidities, and the use of multiple medications. Oral glucose-lowering Related article page 1605 agents and insulin are implicated in one-quarter of emergency hospitalizations for ADEs among older US adults.1 Nearly all of these diabetes mellitus (DM)-related drug events are for hypoglycemia. Among oral agents, sulfonylureas lead to most hospital visits for hypoglycemia. Although rates of DM complications have improved over the past 2 decades in the United States,2 serious hypoglycemic events are on the rise.3 Among older adults, especially those with longer duration of DM, severe hypoglycemic events are more common than many of the complications that glucoselowering treatment is intended to prevent.4 Despite these trends, current performance metrics and surveillance systems do not measure or evaluate severe hypoglycemia occurring during DM treatment. It is time to improve the safety of DM management. The Department of Health and Human Services recently drafted a National Action Plan for Adverse Drug Event Prevention focused on glucose-lowering agents as 1 of 3 classes of medications (the others include anticoagulants and opioids).5 The draft plan proposes 4 strategies for reducing ADEs: surveillance, prevention, incentives and oversight, and research. As a first step in improving safety, clinicians and patients need to better understand which medications, and in 1612
which types of patients, pose the highest risk for hypoglycemia. Based on data from randomized clinical trials, insulin and sulfonylureas are well known to increase this risk. However, limited data exist on the magnitude of this risk among older adults, especially when glucose-lowering agents are used in combination or together with commonly prescribed therapies, such as antibiotics, β-blockers, or opioids. This is because trials often exclude older, frail adults with complex health problems or those with acute exacerbations of underlying comorbidities that require concomitant treatments. In this issue of JAMA Internal Medicine, Parekh et al6 bring us a step closer to a better understanding of severe hypoglycemia risk among older adults. The researchers examined interactions between commonly prescribed antibiotics and sulfonylureas and the risk for serious hypoglycemia. Using Texas Medicare claims data for older patients using glipizide or glyburide, the investigators calculated rates of emergency department or hospital admissions for hypoglycemia within 14 days of prescription fill for 1 of 16 antibiotics; 7 of these antibiotics were previously implicated in causing hypoglycemia, while 9 had no clear mechanism or evidence linking them to these ADEs. After adjustment for demographic characteristics, comorbidities, prior health care utilization, and hypoglycemia, and the indication for the antibiotic, they found that clarithromycin, levofloxacin, sulfamethoxazole/trimethoprim, metronidazole, and ciprofloxacin were significantly associated with increased odds of severe hypoglycemia. The numbers needed to harm were 71 for clarithromycin and 334
JAMA Internal Medicine October 2014 Volume 174, Number 10
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 06/05/2015
jamainternalmedicine.com
Hypoglycemia After Antimicrobial Prescription
Original Investigation Research
for ciprofloxacin, with numbers needed to harm ranging from 131 to 187 for the other antibiotics. Concomitant use of these antibiotics with sulfonylureas was very common. Among patients using glipizide or glyburide, 28% had overlapping prescriptions for 1 of the 5 interacting antibiotics. As a result, 13% of all hypoglycemic events among patients taking sulfonylureas occurred in the context of using 1 of the interacting antibiotics. When Parekh et al6 examined ADEs, they hypothesized that several specific antimicrobial agents would result in clinically significant interactions. On the one hand, such deductive inquiries, grounded in the understanding of drug mechanisms, physiology, or prior information about possible harms, may be less likely to lead to spurious associations. On the other hand, many drug-drug interactions are not easy to predict. Since polypharmacy has become ubiquitous, better surveillance for drug-drug interactions is needed—both for interactions that may be suspected a priori, but also for those that are unexpected. Applying inductive reasoning and pattern recognition to “big data” with the use of advanced analytical techniques may aid in the detection of these interactions.7 One limitation of the study is that acute illness requiring an antibiotic may have largely contributed to severe hypoglycemia. For example, a urinary tract infection in an older woman may have resulted in a prescription for levofloxacin. The patient may have experienced mild fever and anorexia, leading to a skipped meal, which, in turn, precipitated a hypoglycemic reaction. However, the use of other antibiotics as a control group in the study mitigates this concern to some extent. Confirmation of these findings using other data sets would further increase the confidence in these associations. Although randomized clinical trials to corroborate the study’s results would not be feasible, the findings suggest that collection of data on concomitant medication use, including short-term prescriptions for acute conditions, may be useful to assess the safety of therapies during ongoing trials. ARTICLE INFORMATION Author Affiliation: Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut. Corresponding Author: Kasia J. Lipska, MD, MHS, Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, 333 Cedar St, PO Box 208020, New Haven, CT 06520-8020 (kasia [email protected]). Published Online: September 1, 2014. doi:10.1001/jamainternmed.2014.3290. Conflict of Interest Disclosures: None reported. Funding/Support: Dr. Lipska receives support from the Centers for Medicare & Medicaid Services (CMS) to develop publicly reported quality measures. Dr Lipska is also supported by the Pepper Center Career Development Award (P30 AG21342), the Grants for Early Medical/Surgical Specialists’ Transition to Aging Research (R03 AG045086) from the National Institute on Aging and the American Diabetes Association/Association for Specialty Professors, and the Yale Center for Investigation Scholar Award. This publication was
jamainternalmedicine.com
The findings by Parekh et al6 underscore that the risk of hypoglycemia associated with glucose-lowering medications may be modified by ongoing chronic and short-term therapies, which may potentially interact with DM agents. In turn, the magnitude of the risk of hypoglycemia may substantially alter the expected health gains associated with glycemic control for individual patients.8 To enhance safe prescribing, clinicians and patients need to carefully consider the expected benefits and harms of glucose-lowering agents, in the context of each patient’s values and preferences. Serious hypoglycemia substantially lowers health-related quality of life for many patients and, therefore, shifts the balance of benefits and harms. An older patient with a hemoglobin A1c level of less than 9% of total hemoglobin (0.09 proportion of total hemoglobin) and at high risk for hypoglycemia, for whom this complication results in a small loss in quality of life, may experience net harm from treatment with glucose-lowering agents other than metformin.8 In such a patient, the decision to avoid an offending antibiotic may lower the risk of hypoglycemia; in addition, the decision to use glucose-lowering treatments that are viewed as burdensome to the patient (because they lead to hypoglycemic reactions or other side effects) warrants reconsideration. But better understanding of hypoglycemia risk, even with the knowledge about drug-drug interactions and higherquality decision making in practice, may not be enough to ensure safety. As noted in the National Action Plan,5 surveillance, oversight, and incentives are also needed to reduce ADEs. Without active surveillance, it is difficult to develop and target risk reduction strategies to patients, clinicians, and health systems that need them the most. Future quality measures that assess ADEs can help incentivize and inform implementation of strategies to reduce hypoglycemia. In turn, appropriate medication management that minimizes the risk of harm in this population is likely to improve health outcomes and lower costs of care.
made possible by Clinical and Translational Science Award grant No. UL1 TR000142 from the National Center for Advancing Translational Science, a component of the National Institutes of Health (NIH). Disclaimer: The contents are solely the responsibility of the author and do not necessarily represent the official view of the NIH. REFERENCES 1. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365 (21):2002-2012. 2. Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014;370(16):1514-1523. 3. Lipska KJ, Ross JS, Wang Y, et al. National trends in us hospital admissions for hyperglycemia and hypoglycemia among Medicare beneficiaries, 1999 to 2011. JAMA Intern Med. 2014;174(7):1116-1124. 4. Huang ES, Laiteerapong N, Liu JY, John PM, Moffet HH, Karter AJ. Rates of complications and
mortality in older patients with diabetes mellitus: the diabetes and aging study. JAMA Intern Med. 2014;174(2):251-258. 5. US Department of Health and Human Services, Office of Disease Prevention and Health Promotion. National Action Plan for Adverse Drug Event Prevention. http://www.Health.Gov/hai/pdfs/ade -action-plan.Pdf. Accessed June 23, 2014. 6. Parekh TM, Raji M, Lin Y-L, Tan A, Kuo Y-F, Goodwin JS. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas [published online September 1, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014.3293. 7. Krumholz HM. Big data and new knowledge in medicine: the thinking, training, and tools needed for a learning health system. Health Aff (Millwood). 2014;33(7):1163-1170. 8. Vijan S, Sussman JB, Yudkin JS, Hayward RA. Effect of patients' risks and preferences on health gains with plasma glucose level lowering in type 2 diabetes mellitus [published online June 30, 2014]. JAMA Intern Med. doi: 10.1001/jamainternmed.2014 .2894.
JAMA Internal Medicine October 2014 Volume 174, Number 10
Copyright 2014 American Medical Association. All rights reserved.
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