Associations of hypoglycemia, glycemic variability and risk of cardiac arrhythmias in insulin-treated patients with type 2 diabetes: a prospective, observational study

Andreas Andersen, Jonatan I Bagger, Samuel K Sørensen, Maria P A Baldassarre, Ulrik Pedersen-Bjergaard, Julie L Forman, Gunnar Gislason, Tommi B Lindhardt, Filip K Knop, Tina Vilsbøll, Andreas Andersen, Jonatan I Bagger, Samuel K Sørensen, Maria P A Baldassarre, Ulrik Pedersen-Bjergaard, Julie L Forman, Gunnar Gislason, Tommi B Lindhardt, Filip K Knop, Tina Vilsbøll

Abstract

Background: Insulin-treated patients with type 2 diabetes (T2D) are at risk of hypoglycemia, which is associated with an increased risk of cardiovascular disease and mortality. Using a long-term monitoring approach, we investigated the association between episodes of hypoglycemia, glycemic variability and cardiac arrhythmias in a real-life setting.

Methods: Insulin-treated patients with T2D (N = 21, [mean ± SD] age 66.8 ± 9.6 years, BMI 30.1 ± 4.5 kg/m2, HbA1c 6.8 ± 0.4% [51.0 ± 4.8 mmol/mol]) were included for a one-year observational study. Patients were monitored with continuous glucose monitoring ([mean ± SD] 118 ± 6 days) and an implantable cardiac monitor (ICM) during the study period.

Results: Time spend in hypoglycemia was higher during nighttime than during daytime ([median and interquartile range] 0.7% [0.7-2.7] vs. 0.4% [0.2-0.8]). The ICMs detected 724 episodes of potentially clinically significant arrhythmias in 12 (57%) participants, with atrial fibrillation and pauses accounting for 99% of the episodes. No association between hypoglycemia and cardiac arrhythmia was found during daytime. During nighttime, subject-specific hourly incidence of cardiac arrhythmias tended to increase with the occurrence of hypoglycemia (incident rate ratio [IRR] 1.70 [95% CI 0.36-8.01]) but only slightly with increasing time in hypoglycemia (IRR 1.04 [95% CI 0.89-1.22] per 5 min). Subject-specific incidence of cardiac arrhythmias during nighttime increased with increasing glycemic variability as estimated by coefficient of variation whereas it decreased during daytime (IRR 1.33 [95% CI 1.05-1.67] and IRR 0.77 [95% CI 0.59-0.99] per 5% absolute increase, respectively).

Conclusions: Cardiac arrhythmias were common in insulin-treated patients with T2D and were associated with glycemic variability, whereas arrhythmias were not strongly associated with hypoglycemia.

Trial registration: NCT03150030, ClinicalTrials.gov, registered May 11, 2017. https://ichgcp.net/clinical-trials-registry/NCT03150030.

Keywords: Cardiac arrhythmias; Glycemic variability; Hypoglycemia; Insulin treatment; Type 2 diabetes.

Conflict of interest statement

AA, MPAB, SKS, TBL and GG declare no conflicts of interest. JIB has received lecture fee from Novo Nordisk. UPB has served on advisory boards for AstraZeneca/Bristol Myers Squibb, Sanofi Aventis, Novo Nordisk and Zealand Pharma and has received lecture fee and research grant from Novo Nordisk. FKK has served on scientific advisory panels and/or been part of speaker’s bureaus for, served as a consultant to and/or received research support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi and Zealand Pharma. TV has served on scientific advisory panels, been part of speaker’s bureaus for, served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gilead, GSK, Mundipharma, MSD/Merck, Novo Nordisk, Sanofi and Sun Pharmaceuticals.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Individual time in range and arrhythmic event count. Individual time in range and arrhythmic event count for each participant displayed according to insulin regimen: (1) basal insulin only, (2) combination therapy with basal and bolus insulin, and (3) premixed basal and bolus insulin in a fixed ratio. Glycemic ranges defined as: (1) hypoglycemia ( 10.0 mmol/L). Event counts are displayed on an antilog scale
Fig. 2
Fig. 2
Glucose profiles during episodes of level 2 hypoglycemia. A Daytime and B nighttime plasma glucose profiles during episodes of level 2 hypoglycemia (plasma glucose nadir < 3.0 mmol/L). Time 0 is the time of plasma glucose nadir defined as first measurement equal to the minimum measured plasma glucose value during the hypoglycemic episode
Fig. 3
Fig. 3
Hypoglycemia, glycemic variability and risk of cardiac arrhythmias. Incident rate ratio (95% CI) for cardiac arrhythmia (as defined by the study protocol) according to within-subject change in glycemic summaries (generalized linear mixed model). Note that no arrhythmias were detected during daytime hypoglycemia. *Risk of arrhythmia during an hour with occurrence of hypoglycemia defined as plasma glucose

Fig. 4

Hyperglycemia and risk of cardiac…

Fig. 4

Hyperglycemia and risk of cardiac arrhythmias. Incident rate ratio (95% CI) for cardiac…

Fig. 4
Hyperglycemia and risk of cardiac arrhythmias. Incident rate ratio (95% CI) for cardiac arrhythmia (as defined by the study protocol) according to within-subject change in glycemic summaries of hyperglycemia (generalized linear mixed model). *Risk of arrhythmia during an hour with occurrence of hyperglycemia defined as plasma glucose > 10.0 mmol/L compared with an hour of euglycemia with plasma glucose 3.9–10.0 mmol/L
Fig. 4
Fig. 4
Hyperglycemia and risk of cardiac arrhythmias. Incident rate ratio (95% CI) for cardiac arrhythmia (as defined by the study protocol) according to within-subject change in glycemic summaries of hyperglycemia (generalized linear mixed model). *Risk of arrhythmia during an hour with occurrence of hyperglycemia defined as plasma glucose > 10.0 mmol/L compared with an hour of euglycemia with plasma glucose 3.9–10.0 mmol/L

References

    1. Tancredi M, Rosengren A, Svensson A-M, Kosiborod M, Pivodic A, Gudbjörnsdottir S, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med. 2015;373:1720–1732.
    1. Raghavan S, Vassy JL, Ho Y-L, Song RJ, Gagnon DR, Cho K, et al. Diabetes mellitus-related all-cause and cardiovascular mortality in a national cohort of adults. J Am Heart Assoc. 2019;8:e011295.
    1. Andersen A, Jørgensen PG, Knop FK, Vilsbøll T. Hypoglycaemia and cardiac arrhythmias in diabetes. Ther Adv Endocrinol Metab. 2020;11:2042018820911803.
    1. Association AD 6. Glycemic targets: standards of medical care in diabetes—2020. Diabetes Care. 2020;43:S66–76.
    1. Amiel SA, Aschner P, Childs B, Cryer PE, de Galan BE, Frier BM, et al. Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol. 2019;7:385–396.
    1. Tattersall RB, Gill GV. Unexplained deaths of type 1 diabetic patients. Diabet Med J Br Diabet Assoc. 1991;8:49–58.
    1. Fitzpatrick C, Chatterjee S, Seidu S, Bodicoat DH, Ng GA, Davies MJ, et al. Association of hypoglycaemia and risk of cardiac arrhythmia in patients with diabetes mellitus: a systematic review and meta-analysis. Diabetes Obes Metab. 2018;20:2169–2178.
    1. Chow E, Bernjak A, Williams S, Fawdry RA, Hibbert S, Freeman J, et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes. 2014;63:1738–1747.
    1. Pistrosch F, Ganz X, Bornstein SR, Birkenfeld AL, Henkel E, Hanefeld M. Risk of and risk factors for hypoglycemia and associated arrhythmias in patients with type 2 diabetes and cardiovascular disease: a cohort study under real-world conditions. Acta Diabetol. 2015;52:889–895.
    1. Middleton TL, Wong J, Molyneaux L, Brooks BA, Yue DK, Twigg SM, et al. Cardiac effects of sulfonylurea-related hypoglycemia. Diabetes Care. 2017;40:663–670.
    1. Novodvorsky P, Bernjak A, Chow E, Iqbal A, Sellors L, Williams S, et al. Diurnal differences in risk of cardiac arrhythmias during spontaneous hypoglycemia in young people with type 1 diabetes. Diabetes Care. 2017;40:655–662.
    1. Riddle MC, Miller ME. Scientific exploration with continuous monitoring systems: an early assessment of arrhythmias during hypoglycemia. Diabetes Care. 2018;41:664–666.
    1. Grant AK, Golden L. Technological advancements in the management of type 2 diabetes. Curr Diab Rep. 2019;19:163.
    1. Tomson TT, Passman R. Current and emerging uses of insertable cardiac monitors: evaluation of syncope and monitoring for atrial fibrillation. Cardiol Rev. 2017;25:22–29.
    1. Rodbard D. Continuous glucose monitoring: a review of successes, challenges, and opportunities. Diabetes Technol Ther. 2016;18:S2-3–13.
    1. Sakhi R, Theuns DAMJ, Szili-Torok T, Yap S-C. Insertable cardiac monitors: current indications and devices. Expert Rev Med Devices. 2019;16:45–55.
    1. Bailey TS, Ahmann A, Brazg R, Christiansen M, Garg S, Watkins E, et al. Accuracy and acceptability of the 6-day enlite continuous subcutaneous glucose sensor. Diabetes Technol Ther. 2014;16:277–283.
    1. Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, et al. International consensus on use of continuous glucose monitoring. Diabetes Care. 2017;40:1631–1640.
    1. Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, et al. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. Diabetes Care. 2019;42:1593–1603.
    1. Sarkar S, Ritscher D, Mehra R. A detector for a chronic implantable atrial tachyarrhythmia monitor. IEEE Trans Biomed Eng. 2008;55:1219–1224.
    1. Fitzmaurice GM, Laird NM, Ware JH. Applied longitudinal analysis, chapter 9. 2. Hoboken: Wiley; 2011.
    1. Ceriello A, Monnier L, Owens D. Glycaemic variability in diabetes: clinical and therapeutic implications. Lancet Diabetes Endocrinol. 2019;7:221–230.
    1. Lee DY, Han K, Park S, Yu JH, Seo JA, Kim NH, et al. Glucose variability and the risks of stroke, myocardial infarction, and all-cause mortality in individuals with diabetes: retrospective cohort study. Cardiovasc Diabetol. 2020;19:144.
    1. Barzegar N, Ramezankhani A, Tohidi M, Azizi F, Hadaegh F. Long-term glucose variability and incident cardiovascular diseases and all-cause mortality events in subjects with and without diabetes: tehran lipid and glucose study. Diabetes Res Clin Pract. 2021;178:108942.
    1. Yang CD, Shen Y, Ding FH, Yang ZK, Hu J, Shen WF, et al. Visit-to-visit fasting plasma glucose variability is associated with left ventricular adverse remodeling in diabetic patients with STEMI. Cardiovasc Diabetol. 2020;19:131.
    1. Ito T, Nakasuka K, Fujita H, Yokoi M, Nakayama T, Sugiura T et al. Impact of glucose variability on coronary plaque vulnerability in patients with dysglycemia: a whole coronary analysis with multislice computed tomography. J Cardiol. 2021. . Accessed 25 Oct 2021.
    1. Okada K, Hibi K, Gohbara M, Kataoka S, Takano K, Akiyama E, et al. Association between blood glucose variability and coronary plaque instability in patients with acute coronary syndromes. Cardiovasc Diabetol. 2015;14:111.
    1. Zhang J, He L, Cao S, Yang Q, Yang S, Zhou Y. Effect of glycemic variability on short term prognosis in acute myocardial infarction subjects undergoing primary percutaneous coronary interventions. Diabetol Metab Syndr. 2014;6:76.
    1. Gerbaud E, Darier R, Montaudon M, Beauvieux M-C, Coffin-Boutreux C, Coste P, et al. Glycemic variability is a powerful independent predictive factor of midterm major adverse cardiac events in patients with diabetes with acute coronary syndrome. Diabetes Care. 2019;42:674–681.
    1. Nusca A, Tuccinardi D, Proscia C, Melfi R, Manfrini S, Nicolucci A, et al. Incremental role of glycaemic variability over HbA1c in identifying type 2 diabetic patients with high platelet reactivity undergoing percutaneous coronary intervention. Cardiovasc Diabetol. 2019;18:147.
    1. Zhou Z, Sun B, Huang S, Zhu C, Bian M. Glycemic variability: adverse clinical outcomes and how to improve it? Cardiovasc Diabetol. 2020;19:102.
    1. Gula LJ, Krahn AD, Skanes AC, Yee R, Klein GJ. Clinical relevance of arrhythmias during sleep: guidance for clinicians. Heart. 2004;90:347–352.
    1. Shusterman V, Warman E, London B, Schwartzman D. Nocturnal peak in atrial tachyarrhythmia occurrence as a function of arrhythmia burden. J Cardiovasc Electrophysiol. 2012;23:604–611.
    1. Black N, D’Souza A, Wang Y, Piggins H, Dobrzynski H, Morris G, et al. Circadian rhythm of cardiac electrophysiology, arrhythmogenesis, and the underlying mechanisms. Heart Rhythm. 2019;16:298–307.
    1. Chow E, Bernjak A, Walkinshaw E, Lubina-Solomon A, Freeman J, Macdonald IA, et al. Cardiac autonomic regulation and repolarization during acute experimental hypoglycemia in type 2 diabetes. Diabetes. 2017;66:1322–1333.
    1. Jun JE, Jin S-M, Baek J, Oh S, Hur KY, Lee M-S, et al. The association between glycemic variability and diabetic cardiovascular autonomic neuropathy in patients with type 2 diabetes. Cardiovasc Diabetol. 2015;14:70.
    1. Tang X, Zhong J, Zhang H, Luo Y, Liu X, Peng L, et al. Visit-to-visit fasting plasma glucose variability is an important risk factor for long-term changes in left cardiac structure and function in patients with type 2 diabetes. Cardiovasc Diabetol. 2019;18:50.
    1. Zick R, Petersen B, Richter M, Haug C, SAFIR Study Group Comparison of continuous blood glucose measurement with conventional documentation of hypoglycemia in patients with type 2 diabetes on multiple daily insulin injection therapy. Diabetes Technol Ther. 2007;9:483–92.
    1. Kawaguchi Y, Sawa J, Sakuma N, Kumeda Y. Efficacy and safety of insulin glargine 300 U/mL vs insulin degludec in patients with type 2 diabetes: a randomized, open-label, cross-over study using continuous glucose monitoring profiles. J Diabetes Investig. 2019;10:343–351.
    1. UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet. 1998;352:837–53.
    1. Action to Control Cardiovascular Risk in Diabetes Study Group. Gerstein HC, Miller ME, Byington RP, Goff DC, Bigger JT, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.
    1. ADVANCE Collaborative Group Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.
    1. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–139.
    1. ORIGIN Trial Investigators. Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–28.
    1. Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340:b4909.
    1. Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363:1410–1418.
    1. Frier BM. Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol. 2014;10:711–722.
    1. Tsujimoto T, Sugiyama T, Noda M, Kajio H. Intensive glycemic therapy in patients with type 2 diabetes on β-blockers. Diabetes Care. 2016;39:1818–1826.
    1. Bonora BM, Raschi E, Avogaro A, Fadini GP. SGLT-2 inhibitors and atrial fibrillation in the Food and Drug Administration adverse event reporting system. Cardiovasc Diabetol. 2021;20:39.
    1. Li H-L, Lip GYH, Feng Q, Fei Y, Tse Y-K, Wu M, et al. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and cardiac arrhythmias: a systematic review and meta-analysis. Cardiovasc Diabetol. 2021;20:100.
    1. Zelniker TA, Bonaca MP, Furtado RHM, Mosenzon O, Kuder JF, Murphy SA, et al. Effect of dapagliflozin on atrial fibrillation in patients with type 2 diabetes mellitus. Circulation. 2020;141:1227–1234.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다