The Association of Clinical Symptomatic Hypoglycemia with Cardiovascular Events and Total Death in Type 2 Diabetes Mellitus A nationwide population-based study Pai-Feng Hsu M.D. Shao-Yuan Chuang PhD Taipei Veteran General Hospital, Taiwan National Yang-Ming University National Health Research Institutes, Taiwan
Declaration of Conflicts of Interest None
Hypoglycemia in type 2 diabetes Hypoglycemia symptoms are common in type 2 diabetes Incidence of mild episodes is 2-10 per patient/year; severe episodes is 0.1-0.7 per patient/year 1 Associated with: Reduced quality of life Reduced treatment satisfaction Reduced therapy adherence More common at HbA1c < 7% Increased long term morbidity and mortality? 1. UK hypoglycaemia study group. Diabetologia. 2007;50:1140-1147
Immediate Cardiovascular Complications of Severe Hypoglycemia Increased Risk of Cardiac Arrhythmia 1 Abnormal prolonged cardiac repolarization QTc Sudden death Increased Risk of Ischemic Heart 2 Sympathetic surge Destabilized atherosclerotic plaque Increased platelet aggregation 1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299 307. 2. Wright RJ, et al. Diabetes Metab Res Rev. 2008; 24:353-363
Serious Clinical Outcomes After a Hypoglycemic Episode in Hospitalized Patients with Diabetes Study No of Subjects Comparison Groups Time of Outcome All Cause Death HR (95% CI) CV Death HR (95% CI) Svensson et al (2005) Kosiborod et al (2008) 684 Hypo vs Norm in acute MI admission 2 years 1.93 (1.18 3.17) 4916 Hypo vs Norm in hospitalization for acute MI DIGAMI-2 trial 1253 Symptomatic hypoglycemia vs no hypoglycemia during the first 24 h of hospitalization for acute MI CREATE-ECLA and OASIS-6 trials 5440 Hypo vs norm on admission for acute MI Hypo vs norm 24 h after an acute MI Length of hospitalization NA 6.5* NA 2.1 years 1.09 (0.64 1.87) 30 d 2.13 (1.01 4.49) 30 d 1.58 (0.77 3.24) *Adjusted odds ratio in the subgroup of patients with diabetes was estimated from a graph. 1.20 (0.69 2.09) NA NA Natalia Yakubovich et al, Circulation 2011, 123:342-348
Increased Risk of Hypoglycemic Episodes by Aggressive Intervention dose not Necessarily Increase the Risk of Coronary Heart Disease Events Meta-analysis: impact of intensive glucose control on coronary heart disease* events Intensive treatment/standard treatment Participants Events Odds ratio (95% CI) Odds ratio (95% CI) UKPDS 3,071/1549 426/259 0.75 (0.54 1.04) PROactive 2,605/2633 164/202 0.81 (0.65 1.00) ADVANCE 5,571/5,569 310/337 0.92 (0.78 1.07) VADT 892/899 77/90 0.85 (0.62 1.17) ACCORD 5,128/5123 205/248 0.82 (0.68 0.99) Overall 17,267/15,773 1,182/1,136 0.85 (0.77 0.93) 0.6 Intensive treatment better 1.0 2.0 Standard treatment better *Included non-fatal myocardial infarction and death from all cardiac mortality. Ray KK, et al. Lancet 2009; 373:1765 1772.
Severe Hypoglycemia is Strongly Associated with Increased Risks of Adverse Clinical Outcomes Events 11,140 patients with type 2 diabetes participated in ADVANCE study Severe Hypoglycemia n=231 No Severe Hypoglycemia n=10,909 No of patients with events (%) Hazard Ratio* (95% CI) Hazard Ratio* (95% CI) Macro vascular 33 (15.9) 1114 (10.2) 3.53 (2.41-5.17) Micro vascular 24 (11.5) 1107 (10.1) 2.19 (1.40-3.45) Total Death 45 (19.5) 986 (9.0) 3.27 (2.29-4.65) CVD 22 (9.5) 520 (4.8) 3.79 (2.36-6.08) Non-CVD 23 (10.0) 466 (4.3) 2.80 (1.64-4.79) *All in adjusted models 0.1 1.0 10.0 Zoungas et al, NEJM 2010;363;1410-1418
Gaps The impact of clinical outpatient hypoglycemic episodes in type 2 diabetes mellitus patients on long term cardiovascular outcome remains unclear. Whether the hypoglycemia episodes are a risk factor or marker for future cardiovascular events remains debatable.
Objective To investigate the associations of outpatient and inhospital hypoglycemic episodes with long term outcome, including cardiovascular events and allcause mortality in treated type 2 diabetes patients. To explore the temporal relationship between hypoglycemia episodes and events.
Research Design and Methods The study population, identified from the one million patients in the nationally representative sample dataset (National Health Insurance Research Database) released by the Taiwan National Health Research Institutes during 1998-2009. A total of 77,611 newly diagnosed diabetes were identified with more than 3 times of diabetes [ICD-9: 250.XX] diagnosis.
Research Design and Methods We designed a prospective cohort, consisting of hypoglycemic type 2 diabetes patients with randomly selected and age, sex, diabetes duration matched cases without hypoglycemia. Severe hypoglycemia Diabetic patients with hypoglycemia [ICD-9-CM: 251.2X] identified from the hospital claims dataset. Mild hypoglycemia Diabetic patients with hypoglycemia identified from the outpatient claims dataset.
Research Design and Methods We investigated the relations of hypoglycemia to total mortality, and cardiovascular events including stroke, coronary heart disease, cardiovascular diseases (CVD) and hospitalization from all causes.
Flow chart of study population 77,611 diabetic patients ( 3 times diabetes diagnosis) from the 1 million insured individuals who were newly diagnosed during 1998-2009 2,000 DM without hypoglycemia were matched to 500 DM with hypoglycemia with regard to age, gender and duration of DM 500 DM with hypoglycemia were identified by hospital claims dataset 1,344 DM with hypoglycemia were identified by outpatient claims dataset 5,376 DM without hypoglycemia were matched to 1,344 DM with hypoglycemia with regard to age, gender and duration of DM Stroke, coronary heart disease, cardiovascular events and total mortality
Characteristics of Diabetic Patients with Hypoglycemia and Matches without Hypoglycemia (1) Severe Hypoglycemia (n = 500) No Hypoglycemia (n = 2,000) p-value Mild Hypoglycemia (n = 1,344) No Hypoglycemia (n = 5,376) p-value Age, yrs 65.2 ± 9.2 65.2 ± 9.2 1.0000 62.6 ± 9.6 62.6 ± 9.6 1.0000 Male sex 233 46.60% 932 46.60% 1.0000 573 42.63% 2292 42.63% 1.0000 Duration, yrs 3.75 ± 2.8 3.75 ± 2.8 1.0000 5.41 ± 3.1 5.41 ± 3.1 1.0000 Hypertension 318 63.60% 1023 51.15% <0.0001 895 66.59% 2600 48.36% <0.0001 Atrial fibrillation 6 1.20% 14 0.70% 0.2616 27 2.01% 45 0.84% 0.0002 Dyslipidemia 85 17.00% 433 21.65% 0.0218 408 30.36% 1351 25.13% <0.0001 Liver cirrhosis 15 3.00% 26 1.30% 0.0074 32 2.38% 78 1.45% 0.0162 Renal disease 87 17.40% 103 5.15% <0.0001 226 16.82% 286 5.32% <0.0001 Stroke 75 15.00% 80 4.00% <0.0001 150 11.16% 176 3.27% <0.0001 Heart disease 66 13.20% 72 3.60% <0.0001 132 9.82% 203 3.78% <0.0001 Other drugs: other oral diabetic medications; Good compliance of treatment: Proportion of Days Covered (PDC) more than 80 percentage High social economic status: the insured salary more than median (16500 new Taiwan dollars)
Characteristics of Diabetic Patients with Hypoglycemia and Matches without Hypoglycemia (2) Severe Hypoglycemia (n = 500) No Hypoglycemia (n = 2,000) p-value Mild Hypoglycemia (n = 1,344) No Hypoglycemia (n = 5,376) p-value Mental disease 107 21.40% 250 12.50% <0.0001 262 19.49% 688 12.80% <0.0001 Cancer 40 8.00% 48 2.40% <0.0001 84 6.25% 130 2.42% <0.0001 High social economic status Good compliance 214 42.80% 937 46.85% 0.1041 700 52.08% 2854 53.09% 0.5094 142 28.40% 529 26.45% 0.3788 302 22.47% 866 16.11% <0.0001 Insulin 121 24.20% 87 4.35% <0.0001 460 34.23% 400 7.44% <0.0001 Sulfonylureas 339 67.80% 1099 54.95% <0.0001 912 67.86% 2467 45.89% <0.0001 Other drugs 307 61.40% 940 47.00% <0.0001 894 66.52% 2404 44.72% <0.0001 High social economic status: the insured salary more than median (16500 new Taiwan dollars) Good compliance of treatment: Proportion of Days Covered (PDC) more than 80 percentage Other drugs: other oral diabetic medications;
Association between hypoglycemia and hospitalization caused by stroke, coronary heart disease, cardiovascular diseases and all-causes mortality in multivariate model Stroke CHD CVD Death Variables HR (95% C.I.) HR (95% C.I.) HR (95% C.I.) HR (95% C.I.) Mild hypoglycemia 1.92 (1.60-2.31) 1.76 (1.46-2.13) 2.21 (1.98-2.47) 2.70 (2.19-3.33) Severe hypoglycemia 1.64 (1.29-2.07) 1.63 (1.28-2.08) 2.26 (1.93-2.65) 2.18 (1.66-2.88) Adjusted for hypertension, atrial fibrillation, dyslipidemia, liver cirrhosis, renal, mental disease, cancer, previous stroke, heart disease, social economic status, drug compliance, and insulin, sulfonylurea uses.
Propensity Score Matched Analysis for Cardiovascular Diseases and Hospitalization Hypoglycemia (n=257) No Hypoglycemia (n=257) Cardiovascular diseases Event rate, per 1000 PYs 283.11 125.23 HR (95% CI) 2.09 (1.63-2.67) Reference Any cause hospitalization Event rate, per 1000 PYs 494.98 167.24 HR (95% CI) 2.51 (2.00-3.16) Reference Total mortality Event rate, per 1000 PYs 33.63 13.51 HR (95% CI) 2.48 (1.41-4.38) Reference After PS matched age, sex, DM duration, hypertension, Af, dyslipidemia, liver, renal, mental disease, previous stroke, heart disease, social economic status, and drug compliance.
Survival rate Association Between Hypoglycemia and Hospitalization From Any Cause 1.0 0.8 0.6 P<0.001 None Mild Severe 0.4 0.2 0.0 0 2 4 6 8 10 12 Years
1.0 0.9 (A) Hypoglycemia and stroke P<0.001 1.0 0.9 (B) Hypoglycemia and CHD P<0.001 Survival 0.8 0.7 Survival 0.8 0.7 None 0.6 0.6 Mild Severe 0.5 0.5 0 2 4 6 8 10 0 2 4 6 8 10 (C) Hypoglycemia and CVD (D) Hypoglycemia and total mortality 1.0 P<0.001 1.0 P<0.001 0.8 0.9 Survival 0.6 0.4 Survival 0.8 0.7 0.2 0.6 0.0 0.5 0 2 4 6 8 10 0 2 4 6 8 10 Time Time
Conclusions Hypoglycemic episodes in outpatient clinically treated type 2 DM patients, both mild and severe are strongly associated with subsequent major cardiovascular events, including stroke, CHD, and CVD, any causes of hospitalization and even allcause mortality. Diabetes patients who are vulnerable to hypoglycemia have more comorbidities including hypertension, liver disease, renal disease, mental disease, cancer and previous stroke or heart diseases.
Conclusions Medications, including insulin, and sulfonylurea are also important factors that promote hypoglycemic episodes. Once outpatient-treated diabetes patients have hypoglycemic episodes, cardiovascular and hospitalization events occur most frequently in the first year after the event regardless of whether the hypoglycemia was mild or severe.
Acknowledgement Taiwan Society of Cardiology Co-authors Shih-Hsien Sung, Hao-Min Cheng, Jong-Shiuan Yeh Wen-Ling Liu Wan-Leong Chan Chen-Huan Chen, Pesus Chou