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Predictors and Consequences of Severe Hypoglycemia in Adults with Diabetes – Systematic Review of the Evidence Evidence-Based Synthesis Program

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Predictors and Consequences of Severe Hypoglycemia in Adults with Diabetes – Systematic Review of the Evidence Evidence-Based Synthesis Program Predictors and Consequences of Severe Hypoglycemia in Adults with Diabetes – Systematic Review of the Evidence Evidence-based Synthesis Program Table 3. Incidence of Severe Hypoglycemia by Treatment Arms Table 3a. Intensive versus Standard Glycemic Control Studies Study Intervention Hypoglycemia Risk ratio Study and year Study type duration Control Incidence % (n/N) [95% CI] Duckworth (VADT) Intensive control 8.5 (76/892) RCT 5.6 yrs 2.74 [1.79 to 4.18] 20095 Standard control 3.1 (28/899) Intensive control 16.6 (849/5128) ACCORD 20083 RCT 3.5 yrs 3.10 [2.72 to 3.53] Standard control 5.3 (274/5123) Intensive control 2.7 (150/5571) ADVANCE 20084 RCT 5 yrs 1.88 [1.44 to 2.46] Standard control 1.5 (81/5669) Intensive control 1.1 (33/3071) UKPDS 33 1998*21 RCT 10 yrs 1.53 [0.71 to 3.30] Standard control 0.7 (8/1138) Abraira (VA- Intensive control 6.7 (5/75) RCT 2.3 yrs 2.60 [0.52 to 12.99] CSDM) 199530 Standard control 2.6 (2/78) Intensive control 7.6 (1113/14737) Totals 2.40 [1.76 to 3.27] Standard control 3.0 (393/12907) *Data obtained from Hemmingsen B, Lund SS, Gluud C, Vaag A, Almdal T, Hemmingsen C,Wetterslev J. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2011, Issue 6. Art. No.: CD008143. DOI: 10.1002/14651858.CD008143.pub2. Table 3b. Insulin Studies Hypoglycemia Study Intervention(s) Study and year Study type Incidence % duration Control (n/N) A. Regular insulin and Lispro studies: fast-short acting Anderson, 199747 Regular human insulin phase 0.6 (4/722) RCT 26 wks (crossover study) Insulin lispro phase 0.1 (1/722) B. Insulin aspart studies: rapid-acting Prandial insulin aspart 2.1 (5/239) Holman, 200943 RCT 3 yrs Biphasic insulin aspart 2.6 (6/235) (4T study) Insulin detemir (basal) 0.9 (2/234) C. Biphasic insulin: intermediate- and fast-acting mixture Berntorp, 201115 Prospective cohort 26 wks Biphasic insulin aspart 0.2 (2/1154) Insulin lispro 75/25 mix 4.2 (20/473) Buse, 201136 RCT 2.5 yrs Insulin glargine (long-acting) 2.9 (12/419) Biphasic insulin aspart 2.6 (6/235) Holman 200943 RCT 3 yrs Prandial insulin aspart 2.1 (5/239) (4T study) Insulin detemir (basal) 0.9 (2/234) Biphasic insulin aspart 0/178 Liebl, 200948 RCT Insulin detemir and insulin aspart 0.9 (5/537) 0.13 (69/52,419) Valensi Prospective cohort 26 wks Biphasic insulin aspart 0.008 events (IMPROVE) 200922 per patient-year D. Mixed fast and long-acting insulins studies Insulin detemir and insulin aspart 0.9 (5/537) Liebl, 200948 RCT 26 wks Biphasic insulin aspart 0/178 Regular human insulin + NPH 1.6 (7/442) Rayman, 200645 RCT 26 wks Insulin glulisine + NPH 0.5 (2/448) Regular human insulin + NPH 1.2 (5/441) Dailey, 200446 RCT 26 wks Insulin glulisine + NPH 1.4 (6/435) E. NPH insulin studies: intermediate acting 110 Predictors and Consequences of Severe Hypoglycemia in Adults with Diabetes – Systematic Review of the Evidence Evidence-based Synthesis Program Hypoglycemia Study Intervention(s) Study and year Study type Incidence % duration Control (n/N) Rosenstock, NPH insulin 11.1 (55/504) RCT 5 yrs 200935 Insulin glargine 7.6 (38/513) NPH (basal therapy) + regular human insulin 1.6 (7/442) Rayman, 200745 RCT 26 wks NPH (basal therapy) + insulin glulisine 0.5 (2/448) Insulin detemir <2% both arms Haak, 200533 RCT 26 wks (numbers not NPH insulin given) NPH (basal therapy) + regular human 1.2 (5/441) Dailey, 200446 RCT 26 wks insulin NPH (basal therapy) + insulin glulisine 1.4 (6/435) NPH insulin + glimepiride (G) 3 mg 2.6 (6/232) Fritsche, 200344 RCT 24 wks Bedtime Insulin glargine + G 1.8 (4/227) Morning Insulin glargine + G 2.1 (5/236) Adjunct NPH insulin to 1-2 oral antiglycemic agents (sulfonylurea, 1.8 (7/389) metformin, or glitazone) Riddle, 200341 RCT 24 wks Adjunct Insulin glargine to 1-2 oral antiglycemic agents (sulfonylurea, 2.5 (9/367) metformin, or glitazone) Rosenstock, NPH insulin 2.3 (6/259) RCT 28 wks 200139 Insulin glargine 0.4 (1/259) F. Insulin detemir studies: long-acting Insulin detemir (basal) 0.9 (2/234) Holman, 2009 RCT 3 yrs Insulin aspart (prandial) 2.1 (5/239) (4T study)43 Biphasic insulin aspart 2.6 (6/235) Insulin detemir and insulin aspart 0.9 (5/537) Liebl, 200948 RCT 26 wks Biphasic insulin aspart 0/178 Rosenstock, Insulin detemir 1.7 (5/291) RCT 52 wks 200840 Insulin glargine 2.7 (8/291) 0.26 events per Meneghini Insulin detemir - Algorithm care patient years (PREDICTIVE) RCT 26 wks 0.20 events per 2007176 Insulin detemir - Standard care patient years Insulin detemir <2% in both Haak, 200533 RCT 26 wks arms NPH insulin (numbers NR) Marre (PREDICTIVE) Prospective cohort 52 wks Insulin detemir 0.3 (4/1129) 200918 G. Insulin glargine studies: long-acting 2.5 yrs Insulin glargine (long-acting) 2.9 (12/419) Buse, 201136 RCT follow-up Insulin lispro 75/25 mix 4.2 (20/473) Insulin glargine (long-acting) 7.6 (38/513) Rosenstock, 200935 RCT 5 yrs NPH insulin (intermediate acting) 11.1 (55/504) Insulin glargine (long-acting) added to 0/232 metformin and sulfonylurea) Russell-Jones, Liraglutide added to metformin and RCT 26 wks 2.2 (5/230) 200954 sulfonylurea) Placebo added to metformin and 0/114 sulfonylurea) 111 Predictors and Consequences of Severe Hypoglycemia in Adults with Diabetes – Systematic Review of the Evidence Evidence-based Synthesis Program Hypoglycemia Study Intervention(s) Study and year Study type Incidence % duration Control (n/N) Rosenstock, Insulin glargine 2.7 (8/291) RCT 52 wks 200840 Insulin detemir 1.7 (5/291) Insulin glargine, usual and active titration 3 (228/7607) 0.09 events per Insulin glargine, usual titration Kennedy, 200637 RCT 24 wks patient-year Insulin glargine, active titration 0.14 events per patient-year Insulin glargine, morning administration + 1.3 (4/299) Glimepiride (G) 2-4 mg Standl, 2006180 RCT 24 wks Insulin glargine, bedtime administration + 0.7 (2/281) G 2-4 mg Insulin glargine algorithm 1 (investigator 0.9 (21/2315) led) Davies, 200538 RCT 24 wks Insulin glargine algorithm 2 (performed by 1.1 (25/2273) study subjects) Adjunct Insulin glargine (long-acting) added to oral therapy (metformin and 1.5 (4/267) Heine, 200542 RCT 26 wks sulfonylurea Adjunct Exenatide added to oral therapy 1.4 (4/282) (metformin and sulfonylurea) Bedtime Insulin glargine + G 1.8 (4/227) Fritsche, 200344 RCT 24 wks Morning Insulin glargine + G 2.1 (5/236) NPH insulin (intermediate acting) +G 2.6 (6/232) Insulin glargine (long-acting) 2.5 (9/367) Riddle, 200341 RCT 24 wks NPH insulin (intermediate acting) 1.8 (7/389) Rosenstock, Insulin glargine (long-acting) 0.4 (1/259) RCT 28 wks 200139 NPH insulin (intermediate acting) 2.3 (6/259) H. Non-specific Insulin studies Treated with insulin for <2 years ~7.0* (6/89) UK Hypoglycemia Prospective cohort 9-12 mos Treated with insulin for >5 years ~25.0* (19/77) Group 2007190 Sulfonylurea 7.0 (8/108) Murata, 200519 Prospective cohort 41 wks Long-acting insulin 5.5 (19/344) All types (regular, quick-acting, NPH, mixed, etc.) Hypoglycemia requiring a medical contact occurred in Nichols, 201026 Retrospective cohort 49 mos 1.9% of patients in the first year of insulin use, but by the fifth year the rate had fallen to 0,4%. No cases of required hospitalization. Insulin with sulfonylurea 2.8 (3/106) Insulin with thiazolidinedione 4.3 (8/187) 395 days Asche, 200823 Retrospective cohort Sulfonylurea monotherapy 2.6 (55/2117) of followup Thiazolidinedione monotherapy 1.7 (12/702) Metformin 0/2326 7.3 (66/901) 11.8/100 patient Leese, 200325 Retrospective cohort NR Insulin yrs [95% CI 9.5 to 14.1] *extracted from graph 112 Predictors and Consequences of Severe Hypoglycemia in Adults with Diabetes – Systematic Review of the Evidence Evidence-based Synthesis Program Table 3c. Sulfonylurea Studies Study Intervention (daily dose) Hypoglycemia Study and year Study type duration Control Incidence % (n/N) Adjunct Glimepiride 1-6 mg added to Arechavaleta, 1.5 (8/519) RCT 30 wks metformin 201152 Adjunct Sitagliptin 100 mg added to metformin 0.2 (1/516) Glimepiride 8 mg 0/248 Garber, 201151 RCT 52 wks Liragultide 1.2 mg 0/251 Liragultide 1.8 mg 0/247 Adjunct Glimepiride 2-6 mg added to 1.8 (15/1546) Matthews, metformin RCT 2 yrs 201049 Adjunct Vildagliptin 100 mg added to 0/1553 metformin Non-med. Assist. 1.5 (9/584) Adjunct Glipizde 5 mg added to metformin Med. Assist. Seck, 2010;50 1.5 (9/584) RCT 2 yrs Nauck, 2007177 Non-med. Assist. 0.2 (1/588) Adjunct Sitagliptin 100 mg added to metformin Med. Assist. 0.2 (1/588) Glimepiride 2-4 mg + liragultide 0.6 mg 0/233 Glimepiride 2-4 mg + liragultide 1.2 mg 0/228 Marre, 2009175 RCT 52 wks Glimepiride 2-4 mg + liragultide 1.8 mg 1.7 (4/234) Glimepiride 2-4 mg 0/114 Rosiglitazone 8 mg + Glimepiride 2-4 mg 0/232 Glimepiride 4 mg plus Metformin 0/242 Liragultide 0.6 mg plus Metformin 0/242 Nauck, 200953 RCT 26 wks Liragultide 1.2 mg plus Metformin 0/241 LEAD-2 Liragultide 1.8 mg plus Metformin 0/242 Placebo plus Metformin 0/121 Insulin glargine (long-acting) added to 0/232 metformin and sulfonylurea) Russell-Jones, RCT 26 wks Liraglutide added to metformin and 200954 LEAD-5 2.2 (5/230) sulfonylurea) Placebo added to metformin and sulfonylurea) 0/114 Glimepiride (G) 1–4 mg 0/225 Rosiglitazone (R) 4-8 mg 0/232 Chou, 200855 RCT 28 wks R to 4 mg + G to 4 mg (Regimen A) 0.4 (1/225) R to 8 mg + G to 4 mg (Regimen B) 0.9 (2/219) Glimepiride 2-4 mg + Insulin glargine, morning .3 (4/299) administration + Standl, 2006180 RCT 24 wks Glimepiride 2-4 mg + Insulin glargine, bedtime 0.7 (2/281) administration Adjunct Exenatide 20 μg added to oral therapy
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