A systematic literature review on the efficacy–effectiveness gap: comparison of randomized controlled trials and observational studies of glucose-lowering drugs

Figures & data

Figure 1 Flow chart.

Notes: (A) Studies comparing glucagon-like peptide-1 with insulin. (B) Studies comparing dipeptidyl peptidase-4 inhibitors with sulfonylurea.
Abbreviation: RCTs, randomized controlled trials.

Table 1 Characteristics of RCTs and observational studies comparing glucagon-like peptide-1 with insulin

	Authors	Duration, weeks	N	Age, years	Men, %	Body mass index, kg/m^2	Time since diagnosis of type 2 diabetes mellitus, years	Baseline HbA1c, %	Mean effect (95% confidence interval)a
Randomized controlled trials	Barnett et al^Citation30	16	138	54.9 (9.1)	47.1	31.1 (4.7)	7.4 (5.9)	9.0 (1.1)	−0.01 (−0.17, 0.15)
	Bergenstal et al^Citation18	24	248	53.0 (10.3)	48.0	33.9 (7.3)	9.3 (5.8)	10.3 (1.7)	0.91 (0.59, 1.23)
	Nauck et al^Citation20	24	667	57.5 (9.0)	51.7	32.5 (5.3)	9.5 (6.0)	8.4 (0.9)	−0.14 (−0.28, −0.01)
	Davies et al^Citation32	26	234	56.5 (9.1)	68.4	34.1 (5.3)	8.7 (4.5)	8.6 (0.7)	0.01 (−0.24, 0.26)
	Davies et al^Citation19	26	216	58.5 (10.0)	66.4	33.7 (4.7)	7.5 (5.5)	8.4 (0.9)	−0.42 (−0.63, −0.21)
	Diamant et al^Citation27	26	456	58.0 (9.5)	53.5	32.3 (5.1)	7.9 (5.0)	8.3 (1.1)	−0.16 (−0.29, −0.03)
	Heine et al^Citation29	26	535	58.9 (9.1)	55.8	31.4 (4.5)	9.6 (5.9)	8.3 (1.0)	0.02 (−0.12, 0.16)
	Inagaki et al^Citation33	26	427	56.8 (10.8)	67.9	26.2 (3.9)	9.0 (6.0)	8.5 (0.8)	−0.43 (−0.59, −0.26)
	Russell-Jones et al^Citation35	26	466	57.6 (10.0)	58.5	30.4 (5.3)	9.5 (6.1)	8.3 (0.9)	−0.24 (−0.08, −0.39)
	Bunck et al^Citation31	52	69	58.4 (8.0)	65.2	30.5 (3.8)	4.9 (4.2)	7.5 (0.6)	−0.10 (−0.54, 0.34)
	Weissman et al^Citation34	52	725	55.5 (9.5)	56.1	33.1 (5.5)	8.8 (6.3)	8.1 (0.9)	0.11 (−0.04, 0.27)
	Diamant et al^Citation26	84	456	58.0 (9.5)	53.5	32.3 (5.1)	7.9 (5.0)	8.3 (1.1)	−0.18 (−0.33, −0.02)
	Diamant et al^Citation25	156	456	58.0 (9.5)	53.5	32.3 (5.1)	7.9 (5.0)	8.3 (1.1)	−0.20 (−0.39, −0.02)
Observational studies	Karagianni et al^Citation39	26	47	62.0 (8.6)	34.0	34.4 (5.6)	11.9 (7.1)	8.4 (1.6)	−0.80 (−1.84, 0.24)
	Horton et al^Citation36	36	38,678	60.4 (13.3)	46.9	34.4 (9.1)	–	8.6 (2.2)	0.50 (0.46, 0.54)
	Thayer et al^Citation28,b	36	861	53.0 (8.9)	55.7	–	–	9.0 (6.1)	0.53 (–)
	Thayer et al^Citation28,b	52	1709	55.8 (11.0)	54.7	–	–	8.7 (1.7)	1.13 (–)
	Pawaskar et al^Citation37	52	5366	58.0 (–)	46.3	36.7	–	8.1 (–)	−0.20 (–)
	Hall et al^Citation38	52	2965	60.7 (11.4)	61.9	33.7 (6.5)	8.8 (5.7)	9.6 (3.8)	0.13 (−0.11, 0.38)
	Bounthavong et al^Citation40	102	51,977	64.2 (10.4)	96.8	33.0 (6.7)	–	8.8 (2.0)	−0.32 (−0.47, −0.18)

Notes: Data shown as mean (standard deviation) unless specified otherwise. Diamant et al^25–27 are based on the same RCTs, but with different follow-ups.

a The difference in change in HbA1c between treatment groups.

b Two cohort studies described in the same publication. – indicates data not reported.

Abbreviations: HbA1c, glycated hemoglobin; RCTs, randomized controlled trials.

Table 2 Characteristics of RCTs and observational studies comparing dipeptidyl peptidase-4 inhibitors with sulfonylurea

	Authors	Duration, weeks	N	Age, years	Men, %	Body mass index, kg/m^2	Time since diagnosis of type 2 diabetes mellitus, years	Baseline HbA1c, %	Mean effect (95% confidence interval)a
Randomized controlled trials	Kim et al^Citation55	4	33	57.8 (6.7)	58.6	25.5 (2.8)	5.3 (4.7)	7.2 (0.5)	0.00 (–)
	Shimoda et al^Citation58	12	50	63.1 (12.4)	31.0	25.1 (3.9)	–	7.4 (0.6)	2.70 (−0.10, 5.50)
	Srivastava et al^Citation50	18	50	–	–	25.9 (3.3)	–	8.3 (0.5)	0.54 (0.02, 1.06)
	Derosa et al^Citation57	26	167	58.1 (9.4)	49.1	27.8 (1.5)	6.7 (4.1)	7.8 (0.8)	0.00 (–)
	Jeon and Oh^Citation49	32	101	54.5 (10.7)	64.7	22.9 (6.0)	5.9 (1.7)	8.1 (1.0)	0.06 (−0.42, 0.54)
	Derosa et al^Citation53	52	453	–	49.6	27.3 (2.1)	5.0 (2.0)	8.3 (1.2)	0.20 (−1.73, 2.13)
	Rosenstock et al^Citation54	52	441	70.0 (4.3)	44.9	29.8 (4.5)	6.1 (6.3)	7.5 (0.7)	−0.05 (−0.23, 0.13)
	Nauck et al^Citation41	52	1172	56.7 (9.6)	59.2	31.3 (5.1)	6.4 (5.8)	7.7 (0.9)	0.00 (–)
	Göke et al^Citation45	52	858	57.6 (10.3)	51.8	31.4 (5.9)	5.5 (4.6)	7.7 (0.9)	0.06 (−0.05, 0.16)
	Ferrannini et al^Citation43	52	3118	57.5 (9.13)	53.5	31.8 (5.3)	5.7 (5.1)	7.3 (0.7)	0.09 (0.03, 0.15)
	Filozof and Gautier^Citation48	52	1007	59.5 (10.0)	52.0	31.0 (5.0)	6.6 (5.2)	8.5 (1.0)	0.04 (−0.11, 0.20)
	Arjona et al^Citation52	54	426	64.5 (9.9)	57.0	26.8 (4.8)	10.4 (7.7)	7.8 (0.7)	−0.11 (−0.29, 0.06)
	Arjona et al^Citation51	54	129	59.5 (9.5)	59.7	26.8 (5.0)	17.5 (8.9)	7.9 (0.7)	0.15 (−0.18, 0.49)
	Ahrén et al^Citation56	104	609	54.4 (9.9)	48.8	32.5 (5.5)	5.9 (4.8)	8.1 (0.8)	0.08 (–)
	Del Prato et al^Citation21	104	1759	55.5 (9.7)	50.8	31.2 (5.3)	5.5 (4.8)	7.6 (0.6)	−0.13 (−0.24, −0.02)
	Foley and Sreenan^Citation47	104	1092	54.8 (10.5)	55.8	30.7 (5.3)	2.2 (3.7)	8.7 (1.1)	0.13 (−0.06, 0.33)
	Göke et al^Citation46	104	858	57.6 (10.3)	51.8	31.4 (5.9)	5.5 (4.6)	7.7 (0.9)	−0.05 (−0.17, 0.06)
	Matthews et al^Citation44	104	3118	57.5 (9.13)	53.5	31.8 (5.3)	5.7 (5.1)	7.3 (0.7)	0.00 (0.00, 0.1)
	Seck et al^Citation42	104	1172	56.7 (9.6)	59.2	31.3 (5.1)	6.4 (5.8)	7.7 (0.9)	−0.03 (–)
Observational studies	Lee et al^Citation60	24	69	52.3 (12.8)	58.0	26.9 (3.9)	0.5 (0.5)	8.1 (0.8)	0.07 (−0.24, 0.37)
	Gitt et al^Citation61	52	256	65.2 (11.1)	52.0	–	5.0 (4.2)	7.4 (0.7)	−0.10 (−0.24, 0.04)
	Göke et al^Citation62	52	7410	62.6 (11.1)	54.0	30.8 (5.5)	5.8 (4.9)	7.7 (1.2)	−0.20 (−0.22, −0.09)
	Morgan et al^Citation59	52	16,832	61.9 (11.4)	59.8	32.1 (5.5)	4.6 (3.8)	8.7 (1.4)	0.30 (–)

Notes: Data shown as mean (standard deviation) unless specified otherwise. Nauck et al⁴¹ and Seck et al;⁴² Göke et al⁴⁵ and Göke et al;⁴⁶ and Ferrannini et al⁴³ and Matthews et al⁴⁴ are based on the same RCTs, but with different follow-ups.

a The difference in change in HbA1c between treatment groups. – indicates data not reported.

Abbreviations: HbA1c, glycated hemoglobin; RCTs, randomized controlled trials.

Figure 2 Effect estimates of studies comparing glucagon-like peptide-1 with insulin.

Notes: Difference in mean change HbA1c ±95% confidence interval. The difference in change in HbA1c between treatment groups. Diamant et al^25–27 are based on the same RCTs, but with different follow-ups. ^aTwo different cohorts analyzed and reported in the same publication. Red circle: RCTs. Blue filled square: observational studies with confounding adjustment. Blue open square: observational studies unadjusted for confounding.
Abbreviations: HbA1c, glycated hemoglobin; RCTs, randomized controlled trials.

Figure 3 Effect estimates of studies comparing dipeptidyl peptidase-4 inhibitors with sulfonylurea.

Notes: Difference in mean change HbA1c ±95% confidence interval. The difference in change in HbA1c between treatment groups. Nauck et al⁴¹ and Seck et al;⁴² Göke et al⁴⁵ and Göke et al;⁴⁶ and Ferrannini et al⁴³ and Matthews et al⁴⁴ are based on the same RCTs, but with different follow-ups, Red circle: RCTs. Blue filled square: observational studies with confounding adjustment. Blue open square: observational studies unadjusted for confounding.
Abbreviations: HbA1c, glycated hemoglobin; RCTs, randomized controlled trials.

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