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) | Â | Â | |
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) | HRÂ =Â 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) | HRÂ =Â 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) | HRÂ =Â 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) | HRÂ =Â 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) | HRÂ =Â 0.87 (0.78, 0.97) | M | |
All-cause readmission | 1265/1861 (68.0) | 8702/12069 (72.1) | 0.94 (0.91, 0.97) | HRÂ =Â 0.94 (0.89, 1.01) | M | |
HF readmission | 1091/1861 (58.6) | 7821/12069 (64.8) | 0.90 (0.87, 0.94) | HRÂ =Â 0.92 (0.86, 0.99) | M | |
Readmission for metabolic acidosis | 2.3% | 2.6% | PÂ =Â 0.40 | Â | Â | |
 MacDonald 2010 [38] |  | Metformin | No antidiabetic drugs |  |  |  |
Mortality | 155/376 (41) | 733/1306 (56) | 0.73 (0.65, 0.84) | ORÂ =Â 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 | ORÂ =Â 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 | ORÂ =Â 0.60 (0.37, 0.97) | M | ||
Long-term mortality | NR | NR | ORÂ =Â 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) | HRÂ =Â 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) | HRÂ =Â 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) | HRÂ =Â 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) | HRÂ =Â 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) | HRÂ =Â 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) | HRÂ =Â 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) | RRÂ =Â 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 | Â | HRÂ =Â 0.76 (0.68, 0.85) | M | |
All-cause mortality | NR | NR | Â | HRÂ =Â 0.72 (0.67, 0.79) | M | |
 |  | 2nd generation SU monotherapy |  |  |  | |
MI | NR | NR | Â | HRÂ =Â 0.82 (0.74, 0.91) | M | |
CHF | NR | NR | Â | HRÂ =Â 0.85 (0.79, 0.91) | M | |
All-cause mortality | NR | NR | Â | HRÂ =Â 0.74 (0.70, 0.78) | M | |
 |  | Rosiglitazone monotherapy |  |  |  | |
MI | NR | NR | Â | HRÂ =Â 0.85 (0.54, 1.33) | M | |
CHF | NR | NR | Â | HRÂ =Â 0.93 (0.65, 1.33) | M | |
All-cause mortality | NR | NR | Â | HRÂ =Â 0.98 (0.76, 1.27) | M | |
 |  | Rosiglitazone combination |  |  |  | |
MI | NR | NR | Â | HRÂ =Â 0.81 (0.63, 1.06) | M | |
CHF | NR | NR | Â | HRÂ =Â 0.76 (0.61, 0.93) | M | |
All-cause mortality | NR | NR | Â | HRÂ =Â 1.10 (0.94, 1.28) | C | |
 |  | Pioglitazone alone and combined |  |  |  | |
MI | NR | NR | Â | HRÂ =Â 1.23 (0.74, 2.08) | C | |
CHF | NR | NR | Â | HRÂ =Â 0.90 (0.64, 1.26) | M | |
All-cause mortality | NR | NR | Â | HRÂ =Â 1.54 (1.15, 2.04) | C | |
 |  | Other drugs and combinations |  |  |  | |
MI | NR | NR | Â | HRÂ =Â 0.87 (0.77, 0.98) | M | |
CHF | NR | NR | Â | HRÂ =Â 0.93 (0.85, 1.01) | M | |
All-cause mortality | NR | NR | Â | HRÂ =Â 0.74 (0.70, 0.78) | M |