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Table 2 Summary of study findings

From: Efficacy and safety of metformin in the management of type 2 diabetes mellitus in older adults: a systematic review for the development of recommendations to reduce potentially inappropriate prescribing

Authors and publication year Outcomes Metformin cases/na (%) Comparator cases/na (%) Unadjusted Risk ratiob
(95% CI)
Reported Statistical comparisonc Result favours
Tier 1 outcomes (hypoglycaemia and adverse events): comparisons against other non-specific treatments
 Cryer 2005 [31]   Metformin Usual care    
 Subgroup ≥ 65 years Any SAE 371/2515 (14.8) 93/569 (16.3) 0.90 (0.73, 1.11) NR M
Tier 1 outcomes (hypoglycaemia and adverse events): comparisons against other specific treatments
 Janka 2007 [35]   Insulin glargine + OAD (glimepiride and metformin) Premixed insulin    
(n = 63 patients)
Confirmed + unconfirmed hypoglycaemia (n = 67 patients)     
5.6 events per p-yr. 11.4 events per p-yr 0.49 (0.41, 0.59) p = 0.01 M
Confirmed hypoglycaemia 3.7 events per p-yr 9.1 events per p-yr   p = 0.008 M
Confirmed symptomatic hypoglycaemia 2.2 events per p-yr 5.0 events per p-yr 0.40 (0.33, 0.50) p = 0.06 M
Confirmed nocturnal hypoglycaemia 0.4 events per p-yr 0.7 events per p-yr 0.44 (0.33, 0.59) p = 0.26 M
Severe hypoglycaemia 0.0 events per p-yr 0.1 events per p-yr   p = 0.21 M
One or more treatment-emergent AEs 32/67 (47.8) 27/63 (42.9) 0.55 (0.27, 1.12)   
0.14 (0.01, 2.61) NR C
1.11 (0.76, 1.63)
 Josephkutty et al. 1990 [36]   Metformin Tolbutamide   NR C
Side effects 32 side effects reported by 21 patients 15 side effects reported by 20 patients
 Schweizer et al. 2009 [43]   Metformin Vildagliptin    
AEs 83/165 (50.3) 74/167 (44.3) 1.14 (0.90, 1.43) NR C
SAEs 6/165 (3.6) 5/167 (3.0) 1.21 (0.38, 3.90) NR C
Gastrointestinal AEs 41/165 (24.8) 25/167 (15.0) 1.66 (1.06, 2.60) NR C
Hypoglycaemia 2/165 (1.2) 0/167 (0.0) 5.06 (0.24, 104.61) NR C
Tier 2 outcomes: comparisons against other non-specific treatments
 Cryer 2005 [31]   Metformin Usual care    
All-cause mortality 60/2515 (2.4) 12/569 (2.1) 1.13 (0.61, 2.09) p = 0.878 C
 Subgroup ≥ 65 years All-cause hospitalisations 334/2515 (13.3) 88/569 (15.5) 0.86 (0.69, 1.07) p = 0.178 M
 Inzucchi 2005 [34]   Metformin No insulin sensitizer    
1-year mortality 246/1273 (19.3) 2014/6641 (30.3) 0.64 (0.57, 0.72) HR = 0.92 (0.81, 1.06) M
1-year MI readmission 210/1273 (16.5) 1247/6641 (18.8) 0.88 (0.77, 1.00) HR = 1.02 (0.86, 1.20) C
1-year HF readmission 435/1273 (34.2) 2859/6641 (43.1) 0.79 (0.73, 0.86) HR = 1.06 (0.95, 1.18) C
1-year all-cause readmission 759/1273 (59.6) 4268/6641 (64.3) 0.93 (0.88, 0.97) HR = 1.04 (0.96, 1.13) C
 Masoudi 2005 [39]   Metformin No insulin sensitizer    
Mortality 460/1861 (24.7) 4345/12069 (36.0) 0.69 (0.63, 0.75) HR = 0.87 (0.78, 0.97) M
All-cause readmission 1265/1861 (68.0) 8702/12069 (72.1) 0.94 (0.91, 0.97) HR = 0.94 (0.89, 1.01) M
HF readmission 1091/1861 (58.6) 7821/12069 (64.8) 0.90 (0.87, 0.94) HR = 0.92 (0.86, 0.99) M
Readmission for metabolic acidosis 2.3% 2.6% P = 0.40   
 MacDonald 2010 [38]   Metformin No antidiabetic drugs    
Mortality 155/376 (41) 733/1306 (56) 0.73 (0.65, 0.84) OR = 0.65 (0.48, 0.87) M
 Moore et al. 2013 [40]   Metformin Not on metformin    
(n = 35 patients) (n = 91 patients)
Cognitive performance NR NR OR = 1.75 (0.81, 3.78) C
p = 0.158
 Roussel et al. 2010 [42] Mortality: Metformin No metformin    
Patients 65–80 years 191/3791 (5.0) 532/6768 (7.9) 0.64 (0.55, 0.75) HR = 0.77 (0.62, 0.95), p = 0.02 M
Patients >80 years 71/598 (11.9) 220/1492 (14.7) 0.81 (0.63, 1.03) HR = 0.92 (0.66, 1.28), p = 0.61 M
Tier 2 outcomes: comparisons against other specific treatments
 Evans 2010 [32]   Metformin monotherapy + combination (n = 205) SU monotherapy    
(n = 217)
1-year mortality NR NR OR = 0.60 (0.37, 0.97) M
Long-term mortality NR NR OR = 0.67 (0.51, 0.88) M
 Roumie 2012 [41]   Metformin SU    
(n = 64,009 patients) (n = 54,005 patients)
 Subgroup ≥ 65 years Hospitalization for acute MI, stroke or death 15.9 per 1,000p–yrs 24.6 per 1,000p–yrs   HR = 0.85 (0.78, 0.92) M
Hospitalization for acute MI or stroke 12.9 per 1,000p–yrs 18.5 per 1,000p–yrs   HR = 0.88 (0.81, 0.97) M
 Lapane 2015 [37] Hospitalisation for hypoglycaemia Metformin monotherapy SU monotherapy    
(n = 6151) (n = 5807)
All ages 132 in 6518 p-yrs 289 in 6307 p-yrs 0.43 (0.35, 0.53) HR = 0.42 (0.33, 0.53) M
Age 75–84 55 in 2524 p-yrs 104 in 2455 p-yrs 0.51 (0.37, 0.71) HR = 0.50 (0.34, 0.73) M
Age 85+ 39 in 2248 p-yrs 100 in 2167 p-yrs 0.38 (0.26, 0.54) HR = 0.38 (0.25, 0.58) M
Hospitalisation for fractures related to falls
All ages 180 in 6305 p-yrs 194 in 6174 p-yrs 0.94 (0.76, 1.15) HR = 0.88 (0.69, 1.12) M
Age 75–84 70 in 2478 p-yrs 86 in 2375 p-yrs 0.78 (0.57, 1.07) HR = 0.73 (0.50, 1.05) M
Age 85+ 74 in 2142 p-yrs 65 in 2114 p-yrs 1.12 (0.81, 1.57) HR = 1.05 (0.68, 1.59) C
Falls
All ages 1844 in 4546 p-yrs 1864 in 4560 p-yrs 0.99 (0.93, 1.06) HR = 1.02 (0.94, 1.11) C
Age 75–84 703 in 1785 p-yrs 756 in 1693 p-yrs 0.88 (0.80, 0.98) HR = 0.90 (0.79, 1.02) M
Age 85+ 697 in 1519 p-yrs 691 in 1547 p-yrs 1.03 (0.92, 1.14) HR = 0.98 (0.86, 1.12) M
 Hung 2013 [33]   Metformin (n = 109) Glyburide (n = 72)    
47 in 181 p-yrs
 Subgroup ≥ 71 years Non-fatal CVD 30 in 414 p-yrs Glimepiride (n = 50) 0.28 (0.18,0.44) HR = 0.30 (0.18, 0.48) M
Non-fatal CVD 30 in 414 p-yrs 18 in 167 p-yrs 0.67 (0.38, 1.21) NR M
 Inzucchi 2005 [34]   Metformin Thiazolidinedione    
Mortality 246/1273 (19.3) 237/819 (28.9) 0.67 (0.57, 0.78) NR M
MI readmission 210/1273 (16.5) 154/819 (18.8) 0.88 (0.73, 1.06) NR M
HF readmission 435/1273 (34.2) 402/819 (49.1) 0.70 (0.63, 0.77) NR M
All-cause readmission 759/1273 (59.6) 555/819 (67.8) 0.88 (0.82, 0.94) NR M
 Solomon 2009 [44]   Metformin Thiazolidinediones    
Fractures 110/4235 (2.6) 74/2347 (3.2)
SU
0.82 (0.62,1.10) RR = 0.76 (0.56, 1.02) M
Fractures 110/4235 (2.6) 480/13709 (3.5) 0.74 (0.60, 0.91) NR M
 Tzoulaki 2009 [45]   Metformin monotherapy 1st generation SU
monotherapy
   
>1.6mil intervals d
 Subgroup ≥ 65 years MI NR NR   HR = 0.79 (0.65, 0.96) M
CHF NR NR   HR = 0.76 (0.68, 0.85) M
All-cause mortality NR NR   HR = 0.72 (0.67, 0.79) M
   2nd generation SU
monotherapy
   
MI NR NR   HR = 0.82 (0.74, 0.91) M
CHF NR NR   HR = 0.85 (0.79, 0.91) M
All-cause mortality NR NR   HR = 0.74 (0.70, 0.78) M
   Rosiglitazone
monotherapy
   
MI NR NR   HR = 0.85 (0.54, 1.33) M
CHF NR NR   HR = 0.93 (0.65, 1.33) M
All-cause mortality NR NR   HR = 0.98 (0.76, 1.27) M
   Rosiglitazone
combination
   
MI NR NR   HR = 0.81 (0.63, 1.06) M
CHF NR NR   HR = 0.76 (0.61, 0.93) M
All-cause mortality NR NR   HR = 1.10 (0.94, 1.28) C
   Pioglitazone alone and combined    
MI NR NR   HR = 1.23 (0.74, 2.08) C
CHF NR NR   HR = 0.90 (0.64, 1.26) M
All-cause mortality NR NR   HR = 1.54 (1.15, 2.04) C
   Other drugs and combinations    
MI NR NR   HR = 0.87 (0.77, 0.98) M
CHF NR NR   HR = 0.93 (0.85, 1.01) M
All-cause mortality NR NR   HR = 0.74 (0.70, 0.78) M
  1. AEs adverse events; SAEs serious adverse events; MI Myocardial Infarction; CVD cardiovascular disease; CHF congestive heart failure; P-YRs patient-years; M Metformin; SU Sulfonylureas; C Comparator; CI confidence interval; HR hazard ratio; OR Odds ratio; RR risk ratio; NR Not Reported
  2. anumber of patients with the outcome/total patients unless stated otherwise, unreported counts/rates were derived from available data where possible
  3. bCalculated risk ratio unadjusted for covariates, zero cell adjustment applied where relevant
  4. cBased on reported comparison adjusted for covariates, or if not reported the unadjusted risk ratio
  5. dtotal treatment intervals across all treatments (metformin plus comparators) was >1.6 million, patients could have multiple intervals on different treatments