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Table 2 Summary of study findings

From: Effectiveness and safety of dipeptidyl peptidase 4 inhibitors in the management of type 2 diabetes in older adults: a systematic review and development of recommendations to reduce inappropriate prescribing

Authors and publication year Outcomes DPP-4 inhibitor cases/na (%) Comparator cases/na (%) Risk ratiob (95% CI) Reported Statistical comparison Result favoursc
Tier 1 outcomes (hypoglycaemia and adverse events), comparisons against placebo
 Barnett et al. 2013 [31]
 QAd = moderate
SAEs Linagliptin Placebo    
14/162 (8.6) 5/79 (6.3) 1.37 (0.51, 3.66) NR C
Severe AEs 9/162 (5.6) 3/79 (3.8) 1.46 (0.41, 5.25) NR C
Significant AEs 4/162 (2.5) 0/79 (0.0) 4.40 (0.24, 80.8) NR C
Hypoglycaemia 37/162 (22.8) 13/79 (16.5) 1.39 (0.78, 2.46) NR C
 Barzilai et al. 2011 [30]
 QAd = moderate
  Sitagliptin Placebo    
Clinical AEs 47/102 (46.1) 55/104 (52.9) 0.87 (0.59, 1.29) Diff in % = −6.8%, (−20.0, 6.7) D
Clinical SAEs 7/102 (6.9) 14/104 (13.5) 0.51 (0.21, 1.26) Diff in % = −6.6%, (−15.2, 1.9) D
Hypoglycaemia 0/102 (0.0) 0/102 (0.0) 1.0 (0.02, 49.9) NR Neither
 SAVOR-TIMI 53   Saxagliptin Placebo    
 Mosenzon et al. 2015 [43]
 Subgroup P > =75
 QAd = high
Bone fracture 57/1169 51/1161 1.11 (0.77, 1.61) HR = 1.13 (0.77, 1.65) C
 Schweizer et al. 2013 [53]
 QAd = low
  Vildagliptin Placebo    
AEs 29/50 (58.0) 40/55 (72.7) 0.80 (0.49, 1.29) NR D
SAEs 7/50 (14.0) 9/55 (16.4) 0.86 (0.32, 2.30) NR D
Hypoglycaemia 0.49 events per patient-year 0.96 events per patient-year 0.53 (0.26, 1.08) p = 0.970 D
 Shih et al. 2015 [36]
 QAd = low
Hospitalisation for sepsis: DPP-4 inhibitor use by casese DPP-4 inhibitor use by controlse    
Current DPP-4 users only 1148/43015 (2.7) 1152/43015 (2.7) 1.01 (0.93, 1.09) OR = 0.97 (0.89, 1.07) D
Used any time in past year 3523/43015 (8.2) 3276/43015 (7.6) 1.09 (1.03,1.14) OR = 1.01 (0.95, 1.06) C
 Strain et al. 2013 [52]   Vildagliptin Placebo    
 QAd = high AEs 66/139 (47.5) 63/139 (45.3) 1.05 (0.81, 1.35) NR C
SAEs 8/139 (5.8) 5/139 (3.6) 1.60 (0.54, 4.77) NR C
Hypoglycaemia 3/139 (2.2) 1/139 (0.7) 3.00 (0.32, 28.5) NR C
Tier 1 outcomes (hypoglycaemia and adverse events), comparisons against other active treatments
 Banerji et al. 2010 [29] Normal renal function Vildagliptin + metformin TZD + metformin    
 QAd = low AEs 54/144 (37.5) 29/84 (34.5) 1.09 (0.76, 1.56) NR C
 Subgroup P ≥ 65 SAEs 2/144 (1.4) 1/84 (1.2) 1.17 (0.11, 12.7) NR C
  Mildly impaired renal function
AEs 59/171 (34.5) 32/77 (41.6) 0.83 (0.59, 1.16) NR D
SAEs 5/171 (2.9) 4/77 (5.2) 0.56 (0.16, 2.04) NR D
 Ferrannini et al. 2009 [54]
 QAd = low
 Subgroup P ≥ 65
Hypoglycaemic events Vildagliptin Glimepiride    
6/351 (1.7) 59/361 (16.4) 0.1 (0.05, 0.24) NR D
 Hartley 2015 [37]
 QAd = low
  Sitagliptin Glimepiride    
AEs 118/241 (49.0) 115/236 (48.7) 1.00 (0.84, 1.21) NR Neither
SAEs 7/241 (2.9) 6/236 (2.5) 1.14 (0.39, 3.35) NR C
Asymptomatic hypoglycemia 16/241 (6.6) 35/236 (14.8) 0.45 (0.25, 0.79) NR D
Symptomatic hypoglycemia 2/241 (0.8) 11/236 (4.7) 0.18 (0.04, 0.79) p = 0.009 D
 Matthews et al. 2010 [55]
 QAd = low
 Subgroup P ≥ 65
  Vildagliptin Glimepiride    
Hypoglycaemia 8/392 (2.1) 69/397 (17.5) 0.12 (0.06, 0.24) p < 0.001 D
 Penfornis et al. 2012 [49]
 QAd = low
  DPP-4 inhibitors COAD    
Hypoglycaemia 60/931 (6.4) 52/257 (20.1) 0.32 (0.23, 0.45) p < 0.001 D
Severe hypoglycaemia 1/931 (0.1) 6/257 (2.4) 0.05 (0.01, 0.38) p = 0.001 D
 Rosenstock et al. 2013 [59]
 QAd = low
  Alogliptin Glipizide    
Hypoglycaemia 12/222 (5.4) 57/219 (26.0) 0.21 (0.11, 0.39) NR D
AEs 163/222 (73.4) 151/219 (68.9) 1.06 (0.85, 1.33) NR C
SAEs 16/222 (7.2) 13/219 (5.9) 1.21 (0.58, 2.52) NR C
 Schernthaner et al. 2015 [59]
 QAd = low
  Saxagliptin + metformin Glimepiride + metformin    
Hypoglycaemia 21/359 (5.8) 125/359 (34.8) 0.17 (0.11, 0.26) NR D
Severe hypoglycaemia 4/359 (1.1) 55/359 (15.3) 0.07 (0.03, 0.20) OR = 0.06 (0.02, 0.17) D
AEs (excluding hypoglycaemia) 213/359 (59.3) 213/359 (59.3) 1.00 (0.89, 1.13) NR Neither
SAEs 41/359 (11.4) 32/359 (8.9) 1.28 (0.83, 1.99) NR C
Deaths 1/359 (0.3) 1/359 (0.3) 1.00 (0.06, 15.93) NR Neither
 Schweizer et al. 2009 [40]
 QAd = low
  Vildagliptin Metformin    
AEs 74/167 (44.3) 83/165 (50.3) 0.88 (0.70, 1.11) NR D
SAEs 5/167 (3.0) 6/165 (3.6) 0.82 (0.26, 2.65) NR D
Gastrointestinal AEs 25/167 (15.0) 41/165 (24.8) 0.60 (0.38, 0.94) NR D
Hypoglycaemia 0/167 (0.0) 2/165 (1.2) 0.20 (0.01, 4.09) NR D
 Sicras-Mainar and Navarro-Artieda 2014 [50]
 QAd = very low
  Vildagliptin + metformin Sulfonylureas + metformin    
Hypoglycaemia 47/270 (17.4) 307/717 (42.8) 0.41 (0.31, 0.53) p < 0.001 D
 Viljoen et al. 2013 [46]
 QAd = very low
  DPP-4 inhibitors Never treated with DPP-4    
Hypoglycaemia 4/129 (3.1) 24/302 (7.9) 0.39 (0.14, 1.10) p = 0.062 D
 Driessen et al. 2014 [45]
 QAd = low
Fractures DPP-4 inhibitor Other non-insulin anti-diabetic drugs    
70–79 years NR NR   HR = 1.16 (0.95, 1.42) C
80 + years NR NR   HR = 1.0 (0.74,1.34) Neither
Tier 1 outcomes (hypoglycaemia and adverse events), DPP-4 inhibitors as an additional treatment
 Chien et al. 2011 [32]
 QAd = low
  Sitagliptin + OAD combinations OAD combinations    
AEs 5/49 (10.2) 3/49 (6.1) 1.67 (0.40, 6.97) NR C
Hypoglycaemia 1/49 (2.0) 0/49 (0.0) 3.0 (0.13, 71.9) NR C
 Kadowaki et al. 2014 [38]
 Subgroup P ≥ 65
 QAd = low
  Teneligliptin + glimepiride Placebo + glimepiride    
AEs (including hypoglycaemia) 0/27 (0.0) 1/34 (2.9) 0.42 (0.02, 9.87) NR D
ADRs (including hypoglycaemia) 0/27 (0.0) 1/34 (2.9) 0.42 (0.02, 9.87) NR D
Tier 2 outcomes (cardiovascular outcomes), comparisons against placebo
 Johansen et al. 2012 [58]
 QAd = low
 Subgroup P ≥ 65
  Linagliptin Comparatorsf    
Fatal or non-fatal MI or stroke, or hospitalisation for unstable angina pectoris 5/929 (0.5) 14/549 (2.6) 0.21 (0.08, 0.58) HR = 0.28, (0.1–0.79) D
 TECOS
 Green et al. 2015 [13]
 QAd = low
 Subgroup P ≥ 65
  Sitagliptin Placebo    
Composite CV outcome (first confirmed event of CV death, non-fatal MI, nonfatal stroke, or hospitalization for unstable angina) NR NR   HR = 1.01 (0.90, 1.15) C
 SAVOR-TIMI 53
 Scirica et al. 2013 [12]
 Scirica et al. 2014 [41]
 Subgroup P ≥ 75
 Leiter et al. 2015 [42]
 Subgroup P ≥ 65
 QAd = high
Subgroup P ≥ 75 Saxagliptin Placebo    
CV death, nonfatal MI, or nonfatal ischemic stroke 117/1169 (10.0) 129/1161 (11.3) 0.90 (0.71, 1.14) HR = 0.96 (0.75, 1.22) D
Hospitalisation for HF Subgroup P ≥ 65 79/1169 (6.8) 57/1161 (4.9) 1.38 (0.99, 1.92) HR = 1.47 (1.05, 2.08) C
CV death, nonfatal MI, or nonfatal ischemic stroke 334/4290 (7.8) 367/4271(8.6) 0.91 (0.79, 1.04) HR = 0.92 (0.79, 1.06) D
CV death, MI, stroke, hospitalization for unstable angina, HF, or coronary revascularization 570/4290 (13.3) 593/4271(13.9) 0.96 (0.86, 1.06) HR = 0.96 (0.85, 1.07) D
MI 141/4290 (3.3) 170/4271(4.0) 0.83 (0.66, 1.03) HR = 0.86 (0.69, 1.07) D
CV mortality 158/4290 (3.7) 166/4271(3.9) 0.95 (0.77, 1.17) HR = 0.92 (0.74, 1.13) D
Non-CV mortality 98/4290 (2.3) 76/4271(1.8) 1.28 (0.95, 1.73) HR = 1.22 (0.92, 1.63) C
All-cause mortality 253/4290 (5.9) 239/4271(5.6) 1.05 (0.89, 1.25) HR = 1.01 (0.86, 1.20) C
Nonfatal ischemic stroke 77/4290 (1.8) 68/4271(1.6) 1.13 (0.82, 1.56) HR = 1.17 (0.85, 1.61) C
Hospitalisation for/due to:
CR 210/4290 (4.9) 234/4271(5.5) 0.89 (0.75, 1.07) HR = 0.87 (0.73, 1.05) D
HF 180/4290 (4.2) 149/4271(3.5) 1.20 (0.97, 1.49) HR = 1.25 (1.01, 1.56) C
Hypoglycaemia 34/4290 (0.8) 25/4271(0.6) 1.35 (0.81, 2.27) HR = 1.29 (0.78, 2.14) C
Unstable angina 38/4290 (0.9) 38/4271(0.9) 1.00 (0.64, 1.56) HR = 0.89 (0.56, 1.39) D
 White et al. 2013 [44]
 QAd = low
  Alogliptin Placebo    
Death from CV causes, or nonfatal MI or stroke 141/934 (15.1) 149/973 (15.3) 0.99 (0.8, 1.22) HR = 0.98 (0.78, 1.24) D
Tier 2 outcomes (cardiovascular outcomes), comparisons against other active treatments
 Chang et al. 2015 [33]
 Subgroup P ≥ 65
 QAd = low
  DPP-4 inhibitors plus metformin Sulfonylureas plus metformin    
Any CV event NR NR   HR = 0.86 (0.72, 1.02) D
MI NR NR   HR = 0.86 (0.44, 1.70) D
HF NR NR   HR = 1.01 (0.72, 1.43) C
Ischaemic stroke NR NR   HR = 0.83 (0.68, 1.02) D
 Chen et al. 2015 [34]
 Subgroup P ≥ 75
 QAd = low
  Sitagliptin Non-sitagliptin    
Composite of ischemic stroke, MI, or CV death 59/486 (12.1) 104/949 (11.0) 1.11 (0.82, 1.50) p = 0.463 C
Ischemic stroke 42/486 (8.6) 77/949 (8.1) 1.07 (0.74, 1.53) p = 0.705 C
 Giorda et al. 2015 [48]
 QAd = low
  DPP-4 inhibitor use by casese DPP-4 inhibitor use by controlse    
Any admission for HF 256/14613 (1.8) 2881/146130 (2.0) 0.89 (0.78, 1.01) OR = 1.00 (0.94, 1.07) Neither
Incident HF 135/7212 (1.9) 1285/72120 (1.8) 1.05 (0.88, 1.25) OR = 1.01 (0.92, 1.11) C
Re-admission for HF 37/1727 (2.1) 338/17222 (2.0) 1.09 (0.78, 1.53) OR = 1.02 (0.84, 1.22) C
All-cause mortality 306/38248 (0.8) 6717/382313 (1.8) 0.46 (0.41, 0.51) OR = 0.94 (0.90, 0.98) D
 Ou et al. 2015 [35]
 Subgroup P 61–80
 Subgroup P ≥ 81
 QAd = low
  DPP-4 inhibitors + metformin Sulfonylureas + metformin    
All-cause mortality
61–80 NR NR   HR = 0.57 (0.46, 0.71) D
P ≥ 81 NR NR   HR = 0.61 (0.43, 0.87) D
MI
61–80 NR NR   HR = 0.47 (0.26, 0.83) D
P ≥ 81 NR NR   HR = 0.70 (0.25, 2.00) D
Ischemic stroke
61–80 NR NR   HR = 0.49 (0.24, 1.00) D
P ≥ 81 NR NR   HR = 0.63 (0.50, 0.80) D
Hospitalisation for HF
61–80 NR NR   HR = 0.78 (0.52, 1.16) D
P ≥ 81 NR NR   HR = 0.33 (0.13, 0.87) D
 Rosenstock et al. 2013 [59]
 QAd = low
  Alogliptin Glipizide    
Major adverse cardiac events 1/222 (0.5) 2/219 (0.9) 0.49 (0.04, 5.44) NR D
 Schweizer et al. 2009 [40]
 QAd = low
  Vildagliptin Metformin    
CV and cerebrovascular events 2/167 (1.2) 2/165 (1.2) 1.0 (0.14, 6.93) NR Neither
 Sicras-Mainar and Navarro-Artieda 2014 [50]
 QAd = very low
  Vildagliptin + metformin Sulfonylureas + metformin    
CV events 12/270 (4.4) 62/717 (8.6) 0.51 (0.28, 0.94) p = 0.025 D
Ischemic heart disease 2/270 (0.7) 15/717 (2.1) 0.35 (0.08, 1.54) p = 0.043 D
Cerebrovascular accident 6/270 (2.2) 31/717 (4.3) 0.51 (0.22, 1.22) p = 0.042 D
Renal failure 4/270 (1.5) 16/717 (2.2) 0.66 (0.22, 1.97) p = 0.138 D
 Tziomalos et al. 2015 [51]
 QAd = very low
  DPP-4 inhibitors Other antidiabetic drugs    
In-hospital mortality in people admitted with acute ischaemic stroke 0/27 (0.0) 11/73 (15.1) 0.12 (0.01, 1.91) p < 0.05 D
Modified Rankin Scale of disability [mean (SD)] 2.1 (1.9) 3.2 (2.1)   p < 0.05 D
 Yu et al. 2015 [47]
 QAd = low
  DPP-4 inhibitor use by casese DPP-4 inhibitor use by controlse    
Hospitalisation for HF 54/1118 (4.8) 808/17626 (4.6) 1.05 (0.81, 1.38) OR = 0.88 (0.63, 1.22) D
  1. AEs Adverse events, ADRs Adverse drug reactions, C Comparator, CI Confidence interval, COAD Conventional oral antidiabetic drugs, CV Cardiovascular, D DPP-4 inhibitor, Diff Difference, HF Heart failure, HR Hazard ratio, MI Myocardial Infarction, CR Coronary revascularization, NR Not Reported, OAD Oral anti-diabetic agents, P Participants, SAEs Serious adverse events, anumber of patients with the outcome/total patients, unless stated otherwise; bZero cell adjustment applied where relevant; cBased on reported comparison or if not reported, the computed risk ratio; d QA: quality appraisal based on study limitations suggested by Guyatt et al. (2008) [26]; e Case-control study: cases are patients with the outcome, controls are matched patients without, numerator is count of patients using DPP-4 inhibitors; fData pooled over 8 trials, 6 comparing against placebo only