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Table 1.  Characteristics of the Study Sample by Object Drug
Characteristics of the Study Sample by Object Drug
Table 2.  Adjusted Rate Ratios for Serious Hypoglycemia With vs Without Use of Calcium-Channel Blockers in Insulin Secretagogue or Metformin Users
Adjusted Rate Ratios for Serious Hypoglycemia With vs Without Use of Calcium-Channel Blockers in Insulin Secretagogue or Metformin Users
1.
Shehab  N, Lovegrove  MC, Geller  AI, Rose  KO, Weidle  NJ, Budnitz  DS.  US emergency department visits for outpatient adverse drug events, 2013-2014.   JAMA. 2016;316(20):2115-2125. doi:10.1001/jama.2016.16201 PubMedGoogle ScholarCrossref
2.
Guseva  N, Phillips  D, Mordes  JP.  Successful treatment of persistent hyperinsulinemic hypoglycemia with nifedipine in an adult patient.   Endocr Pract. 2010;16(1):107-111. doi:10.4158/EP09110.CRR PubMedGoogle ScholarCrossref
3.
Koklu  E, Ozkan  KU, Sayar  H, Koklu  S, Keskin  M.  Treatment of hyperinsulinemic hypoglycemia because of diffuse nesidioblastosis with nifedipine after surgical therapies in a newborn.   J Pediatr Endocrinol Metab. 2013;26(11-12):1153-1156. doi:10.1515/jpem-2013-0091 PubMedGoogle ScholarCrossref
4.
Cook  DL, Ikeuchi  M, Fujimoto  WY.  Lowering of pHi inhibits Ca2+-activated K+ channels in pancreatic B-cells.   Nature. 1984;311(5983):269-271. doi:10.1038/311269a0 PubMedGoogle ScholarCrossref
5.
Nam  YH, Brensinger  CM, Bilker  WB, Leonard  CE, Han  X, Hennessy  S.  Serious hypoglycemia and use of warfarin in combination with sulfonylureas or metformin.   Clin Pharmacol Ther. 2019;105(1):210-218. doi:10.1002/cpt.1146 PubMedGoogle ScholarCrossref
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    1 Comment for this article
    Calcium Channel Blockers Blunt Hypoglycemia; Will they Reduce Insulin Sensitivity?
    Arvind Joshi, MBBS MD FCGP FAMS FICP | Our Own Discussion Group Mumbai PIN 400028, Ruchi Diagnostic Center and Ruchi Clinical Laboratory Kharghar PIN 410210
    While the authors have noted a reduced incidence of severe hypoglycemia in patients concomitantly receiving calcium channel blockers and insulin secretagogues, it remains to be seen if this effect is due to decreased insulin sensitivity.
    CONFLICT OF INTEREST: None Reported
    Views 6,252
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    Research Letter
    Diabetes and Endocrinology
    September 2, 2021

    Association Between Serious Hypoglycemia and Calcium-Channel Blockers Used Concomitantly With Insulin Secretagogues

    Author Affiliations
    • 1Therapeutics Research and Infectious Disease Epidemiology (TIDE), Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts
    • 2Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
    • 3Endocrinology Service, Department of Subspecialty Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
    JAMA Netw Open. 2021;4(9):e2124443. doi:10.1001/jamanetworkopen.2021.24443
    Introduction

    Serious hypoglycemia is a major, potentially fatal adverse event caused by insulin secretagogues.1 Previous case reports suggested that calcium-channel blockers (CCBs) might reduce the risk of serious hypoglycemia in patients with hyperinsulinemic hypoglycemia.2,3 However, the association of serious hypoglycemia and CCBs used with insulin secretagogues has remained unclear. Because insulin secretion by the pancreas is mediated by calcium influx in beta cells through calcium channels,4 we conducted a population-based observational study on the hypothesis that concomitant use of CCBs may be associated with reduced rates of serious hypoglycemia in insulin secretagogue users.

    Methods

    This self-controlled case series study was approved by the institutional review board of the University of Pennsylvania, which waived the requirement for informed consent because the use or disclosure of the protected health information involved no more than minimal risk to the privacy of individuals, and the research could not practicably be conducted without the waiver or alteration and without access to and use of the protected health information. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. We used claims data from the Medicaid programs of 5 US states (California, Florida, New York, Ohio, and Pennsylvania, encompassing more than a third of the nationwide Medicaid population), supplemented with Medicare claims for dual enrollees, from January 1, 1999, to December 31, 2011, and used the self-controlled case series design. Our methods were described in detail in a previous study.5 Users (aged ≥18 years) of insulin secretagogues (glimepiride, glipizide, glyburide, nateglinide, and repaglinide; object drugs) or metformin (negative-control object drug) who were enrolled in Medicaid for at least 180 days immediately before the first object drug–specific observation time (eFigure 1 in the Supplement), who were free of an enrollment gap and dispensing of that object drug, and who experienced at least 1 outcome event during the observation time were eligible (flowchart in eFigure 2 in the Supplement). The exposure was active prescription for a CCB (amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, and verapamil; precipitant drugs) during the observation time. The outcome was serious hypoglycemia ascertained by International Classification of Diseases, Ninth Revision, Clinical Modification discharge diagnosis codes appearing in principal position on inpatient hospital claims or any position on emergency department claims (positive predictive value of approximately 78%-89%).5 The self-controlled case series design inherently controls for all time-invariant confounders, and we further controlled for time-varying potential confounders (eTables 1 and 2 in the Supplement) at the person-day level. We computed confounder-adjusted rate ratios (RRs) and 95% CIs for outcome occurrence during precipitant-exposed vs -unexposed time using conditional Poisson regression, and we performed sensitivity analyses. Statistical analysis was conducted from April 8, 2018, to August 30, 2018.

    Results

    The number of individuals who met inclusion criteria and the patient characteristics for each object drug–specific sample are presented in Table 1. The median age at the start of observation ranged from 63.2 years (interquartile range [IQR], 50.0-73.8 years) for metformin to 72.8 years (IQR, 63.2-80.8 years) for repaglinide, and the proportion of women and men ranged from 7100 women (63.8%) and 4036 men (36.2%) for glipizide to 4362 women (67.7%) and 2080 men (32.3%) for glimepiride. Adjusted RRs (95% CIs) for serious hypoglycemia with (vs without) concomitant CCB use were reduced with glimepiride (0.79; 0.70-0.89), glipizide (0.86; 0.79-0.94), glyburide (0.81; 0.73-0.90), and metformin (0.91; 0.86-0.96). Adjusted RRs (95% CIs) with nateglinide and repaglinide were 0.74 (0.55-1.00) and 0.84 (0.69-1.02), respectively (Table 2). Adjusted RRs (95% CIs) for sensitivity analyses 1 and 2, respectively, were similar: glimepiride 0.79 (0.71-0.89) and 0.82 (0.70-0.95), glipizide 0.86 (0.79-0.94) and 0.80 (0.71-0.90), glyburide 0.81 (0.73-0.89) and 0.81 (0.71-0.92), nateglinide 0.69 (0.52-0.93) and 0.76 (0.52-1.09), repaglinide 0.89 (0.73-1.07) and 0.78 (0.61-0.98), and metformin 0.91 (0.86-0.96) and 0.91 (0.84-0.99) (Table 2).

    Discussion

    Calcium-channel blockers used concomitantly with insulin secretagogues were associated with reduced rates of serious hypoglycemia compared with the use of insulin secretagogues without CCBs. Although the reduced RRs for metformin suggest an inherent effect of CCBs rather than a drug interaction, further studies are needed to elucidate the mechanism. Limitations of this study include lack of data on actual intake of drugs, lifestyle, and health behaviors; however, such factors would have introduced bias only if they were varying within persons across the CCB-exposed and -unexposed time and associated with both CCB use and serious hypoglycemia. Generalizability beyond the Medicaid population needs further investigation. Our findings may help clinicians with cardiovascular drug choice for patients treated with insulin secretagogues. Our findings also suggest that it may be important to monitor whether glycemic control is sufficient without dose adjustments when patients receiving glucose-lowering agents are coadministered a CCB.

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    Article Information

    Accepted for Publication: July 7, 2021.

    Published: September 2, 2021. doi:10.1001/jamanetworkopen.2021.24443

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Nam YH et al. JAMA Network Open.

    Corresponding Author: Sean Hennessy, PhD, PharmD, Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology and Informatics, Perelman of School of Medicine, University of Pennsylvania, 423 Guardian Dr, 803 Blockley Hall, Philadelphia, PA 19104-4865 (hennessy@upenn.edu).

    Author Contributions: Ms Brensinger had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Nam, Hennessy.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Nam.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Brensinger, Bilker.

    Obtained funding: Hennessy, Leonard, Flory.

    Administrative, technical, or material support: Hennessy.

    Supervision: Hennessy.

    Conflict of Interest Disclosures: Dr Leonard reported being an executive committee member of the University of Pennsylvania’s Center for Pharmacoepidemiology Research and Training, which receives funds from Pfizer and Sanofi to support pharmacoepidemiology education; and reported receiving honoraria from the American College of Clinical Pharmacy Foundation and the University of Florida outside the submitted work. Dr Hennessy reported receiving support through his employer from Pfizer, Sanofi, and Johnson & Johnson; consulting for Merck, the Medullary Thyroid Carcinoma (MTC) Registry Consortium (Novo Nordisk, AstraZeneca, GlaxoSmithKline, and Eli Lilly), and Eli Lilly, all outside the submitted work. No other disclosures were reported.

    Funding/Support: This study was supported by the National Institutes of Health (R01DK102694, R01AG025152, and R01AG060975), American Diabetes Association (1-18-ICTS-097), and Patient-Centered Outcomes Research Institute (CER-2017C3-9230).

    Role of the Funder/Sponsor: The National Institutes of Health, American Diabetes Association, and Patient-Centered Outcomes Research Institute had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: The authors thank Qing Liu, BS, and Min Du, MS, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, for their assistance with biostatistics computer programming. Neither one received any additional compensation beyond usual salary for her contributions.

    References
    1.
    Shehab  N, Lovegrove  MC, Geller  AI, Rose  KO, Weidle  NJ, Budnitz  DS.  US emergency department visits for outpatient adverse drug events, 2013-2014.   JAMA. 2016;316(20):2115-2125. doi:10.1001/jama.2016.16201 PubMedGoogle ScholarCrossref
    2.
    Guseva  N, Phillips  D, Mordes  JP.  Successful treatment of persistent hyperinsulinemic hypoglycemia with nifedipine in an adult patient.   Endocr Pract. 2010;16(1):107-111. doi:10.4158/EP09110.CRR PubMedGoogle ScholarCrossref
    3.
    Koklu  E, Ozkan  KU, Sayar  H, Koklu  S, Keskin  M.  Treatment of hyperinsulinemic hypoglycemia because of diffuse nesidioblastosis with nifedipine after surgical therapies in a newborn.   J Pediatr Endocrinol Metab. 2013;26(11-12):1153-1156. doi:10.1515/jpem-2013-0091 PubMedGoogle ScholarCrossref
    4.
    Cook  DL, Ikeuchi  M, Fujimoto  WY.  Lowering of pHi inhibits Ca2+-activated K+ channels in pancreatic B-cells.   Nature. 1984;311(5983):269-271. doi:10.1038/311269a0 PubMedGoogle ScholarCrossref
    5.
    Nam  YH, Brensinger  CM, Bilker  WB, Leonard  CE, Han  X, Hennessy  S.  Serious hypoglycemia and use of warfarin in combination with sulfonylureas or metformin.   Clin Pharmacol Ther. 2019;105(1):210-218. doi:10.1002/cpt.1146 PubMedGoogle ScholarCrossref
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