Network meta-analysis

Pancreatic cancer

Type 2 diabetes (adults)

longest follow-upRecorded harmsDoses of a drug pooledHazard ratio (from event counts)

Randomized trials

Treatments

24,546

Participants

Events

In plain language

Across 14 trials with 24,546 participants, 0 of 13 treatments had a clearly better result than placebo on pancreatic cancer, and for 13 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide injection: hazard ratio (from event counts) 0.29 (95% credible interval 0.02 to 3.06).

Lower values favor the treatment. "Clearly" means the 95% credible interval excludes no difference. These are averages across trials; they do not say how any one person will respond. Not medical advice.

Network of trials

Each circle is a treatment; each line joins treatments that were randomized against each other in at least one trial.

Node area shows participants; line width shows trials comparing two treatments directly. Blue: GLP-1 receptor agonist containing treatments; grey: comparators. Hover over or tab to a node or line for details.

Effects compared with Placebo

Hazard ratio (from event counts). Lower values favor the treatment.

Versus Placebo, log scale. Blue: Bayesian random effects posterior median with 95% credible interval (thick) and 95% prediction interval (dashed). Amber diamond: frequentist estimate with 95% confidence interval. Hover over or tab to a row for its values.

Effects of each treatment versus Placebo
Treatment	Bayesian HR (95% CrI)	95% prediction interval	Verdict
Semaglutide injection SEMA_SC	0.29 (0.02 to 3.06)	0.02 to 3.97	Unclear
Semaglutide tablet SEMA_PO	0.52 (0.04 to 5.96)	0.03 to 7.26	Unclear
Exenatide extended release injection EXENER_SC	0.59 (0.04 to 7.55)	0.03 to 10.10	Unclear
Exenatide injection EXEN_SC	0.60 (0.04 to 8.59)	0.03 to 10.62	Unclear
Tirzepatide injection TIRZ_SC	0.69 (0.04 to 11.12)	0.03 to 14.31	Unclear
Insulin lispro (prandial) INS_LISPRO	0.69 (0.04 to 10.24)	0.04 to 12.33	Unclear
Insulin glargine INS_GLARGINE	0.78 (0.05 to 11.14)	0.04 to 13.46	Unclear
Mazdutide injection MAZD_SC	0.79 (0.05 to 12.30)	0.04 to 15.09	Unclear
Standard care or no added treatment STANDARD_CARE	0.80 (0.05 to 12.43)	0.04 to 15.74	Unclear
Albiglutide injection ALBI_SC	1.02 (0.25 to 4.00)	0.16 to 5.79	Unclear
Sitagliptin SITAGLIPTIN	1.20 (0.11 to 13.36)	0.08 to 16.90	Unclear
Dulaglutide injection DULA_SC	1.36 (0.40 to 3.78)	0.25 to 5.64	Unclear
Liraglutide injection LIRA_SC	1.70 (0.23 to 13.08)	0.18 to 16.78	Unclear

Ranking

How likely each treatment is to be among the best. Rankings ignore the size of differences and their certainty, so read them with the effects above.

League table

Every treatment against every other: hazard ratio (from event counts) of the row treatment versus the column treatment, posterior median and 95% credible interval. Green: row clearly better; red: row clearly worse.

Every treatment in a row compared with every treatment in a column
Row versus column	PLACEBO	SEMA_SC	SEMA_PO	EXENER_SC	EXEN_SC	TIRZ_SC	INS_LISPRO	INS_GLARGINE	MAZD_SC	STANDARD_CARE	ALBI_SC	SITAGLIPTIN	DULA_SC	LIRA_SC
PLACEBO	PLACEBO	3.44 0.33 to 40.16	1.92 0.17 to 24.18	1.68 0.13 to 25.67	1.68 0.12 to 26.80	1.45 0.09 to 25.46	1.45 0.10 to 22.45	1.28 0.09 to 19.71	1.27 0.08 to 19.73	1.25 0.08 to 21.68	0.98 0.25 to 3.95	0.83 0.07 to 9.48	0.74 0.26 to 2.50	0.59 0.08 to 4.39
SEMA_SC	0.29 0.02 to 3.06	SEMA_SC	0.55 0.02 to 18.77	0.48 0.01 to 17.47	0.48 0.01 to 18.75	0.42 0.01 to 16.73	0.41 0.01 to 15.12	0.37 0.01 to 14.41	0.37 0.01 to 13.34	0.36 0.01 to 13.19	0.29 0.02 to 4.33	0.24 0.01 to 4.61	0.21 0.02 to 2.98	0.17 0.01 to 3.62
SEMA_PO	0.52 0.04 to 5.96	1.81 0.05 to 54.61	SEMA_PO	0.89 0.02 to 31.73	0.86 0.02 to 33.90	0.75 0.02 to 34.62	0.74 0.02 to 29.07	0.65 0.02 to 28.08	0.67 0.02 to 26.94	0.66 0.02 to 27.54	0.52 0.03 to 8.82	0.43 0.01 to 13.31	0.38 0.02 to 5.57	0.31 0.01 to 5.69
EXENER_SC	0.59 0.04 to 7.55	2.06 0.06 to 73.37	1.13 0.03 to 43.20	EXENER_SC	0.99 0.02 to 44.95	0.87 0.02 to 37.60	0.81 0.02 to 37.50	0.74 0.02 to 33.56	0.78 0.02 to 32.54	0.73 0.02 to 34.43	0.59 0.03 to 10.04	0.49 0.01 to 14.54	0.43 0.03 to 6.84	0.34 0.01 to 7.78
EXEN_SC	0.60 0.04 to 8.59	2.09 0.05 to 83.50	1.16 0.03 to 46.26	1.02 0.02 to 44.53	EXEN_SC	0.88 0.02 to 39.57	0.86 0.02 to 40.41	0.76 0.02 to 33.03	0.77 0.02 to 36.77	0.73 0.02 to 34.68	0.59 0.03 to 11.78	0.50 0.01 to 17.96	0.44 0.02 to 8.19	0.35 0.01 to 9.83
TIRZ_SC	0.69 0.04 to 11.12	2.35 0.06 to 95.52	1.34 0.03 to 60.22	1.14 0.03 to 54.52	1.14 0.03 to 56.98	TIRZ_SC	0.93 0.02 to 49.35	0.87 0.02 to 42.11	0.88 0.02 to 42.74	0.85 0.02 to 43.55	0.66 0.03 to 15.96	0.57 0.01 to 23.29	0.51 0.02 to 10.65	0.40 0.01 to 12.19
INS_LISPRO	0.69 0.04 to 10.24	2.42 0.07 to 88.03	1.35 0.03 to 57.65	1.23 0.03 to 50.98	1.17 0.02 to 54.03	1.07 0.02 to 48.57	INS_LISPRO	0.90 0.02 to 43.01	0.90 0.02 to 42.50	0.90 0.02 to 47.72	0.69 0.04 to 13.58	0.59 0.01 to 22.22	0.52 0.03 to 9.80	0.41 0.02 to 11.32
INS_GLARGINE	0.78 0.05 to 11.14	2.70 0.07 to 113	1.54 0.04 to 61.01	1.34 0.03 to 59.20	1.31 0.03 to 59.05	1.15 0.02 to 53.34	1.12 0.02 to 50.37	INS_GLARGINE	1.01 0.02 to 45.18	0.98 0.02 to 47.94	0.78 0.04 to 16.08	0.65 0.02 to 24.63	0.59 0.03 to 10.62	0.46 0.02 to 13.05
MAZD_SC	0.79 0.05 to 12.30	2.68 0.07 to 97.76	1.50 0.04 to 66.56	1.28 0.03 to 64.50	1.30 0.03 to 62.16	1.14 0.02 to 57.92	1.12 0.02 to 50.90	0.99 0.02 to 47.67	MAZD_SC	0.97 0.02 to 49.59	0.79 0.04 to 16.82	0.66 0.02 to 24.18	0.57 0.03 to 11.46	0.45 0.02 to 14.12
STANDARD_CARE	0.80 0.05 to 12.43	2.75 0.08 to 114	1.52 0.04 to 63.73	1.36 0.03 to 63.84	1.37 0.03 to 57.60	1.17 0.02 to 55.22	1.11 0.02 to 57.22	1.02 0.02 to 48.23	1.04 0.02 to 52.56	STANDARD_CARE	0.78 0.03 to 17.29	0.66 0.02 to 27.64	0.59 0.03 to 11.49	0.47 0.01 to 14.67
ALBI_SC	1.02 0.25 to 4.00	3.51 0.23 to 58.34	1.94 0.11 to 36.01	1.70 0.10 to 34.55	1.71 0.08 to 35.44	1.51 0.06 to 35.13	1.45 0.07 to 28.17	1.28 0.06 to 27.67	1.27 0.06 to 28.25	1.29 0.06 to 29.67	ALBI_SC	0.83 0.05 to 13.14	0.75 0.14 to 4.62	0.60 0.05 to 6.45
SITAGLIPTIN	1.20 0.11 to 13.36	4.11 0.22 to 94.18	2.35 0.08 to 76.36	2.03 0.07 to 72.42	1.98 0.06 to 74.94	1.75 0.04 to 76.39	1.70 0.04 to 67.35	1.55 0.04 to 63.23	1.52 0.04 to 58.91	1.52 0.04 to 65.10	1.20 0.08 to 18.27	SITAGLIPTIN	0.88 0.06 to 13.10	0.69 0.03 to 16.91
DULA_SC	1.36 0.40 to 3.78	4.66 0.34 to 66.66	2.61 0.18 to 40.35	2.31 0.15 to 39.75	2.25 0.12 to 44.25	1.98 0.09 to 40.86	1.93 0.10 to 35.07	1.70 0.09 to 34.21	1.74 0.09 to 33.25	1.69 0.09 to 35.11	1.33 0.22 to 7.17	1.14 0.08 to 15.63	DULA_SC	0.78 0.08 to 7.54
LIRA_SC	1.70 0.23 to 13.08	5.85 0.28 to 136	3.22 0.18 to 70.30	2.95 0.13 to 73.09	2.85 0.10 to 86.30	2.52 0.08 to 82.66	2.45 0.09 to 65.55	2.17 0.08 to 65.15	2.21 0.07 to 62.05	2.13 0.07 to 68.22	1.68 0.16 to 19.75	1.46 0.06 to 30.70	1.28 0.13 to 13.12	LIRA_SC

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.351 (95% CrI 0.088 to 1.243), log scale
Residual deviance: 15.5 for 31 data points
DIC: 22.4 (pD 6.9)
Largest R-hat: 1.001
Smallest ESS: bulk 6,429, tail 4,504
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR06 N(0, 1.5^2); PR09 log normal(-1.87, 1.52^2) on tau^2 (Adverse events, pharm vs placebo control)

Inconsistency

Do trials comparing two treatments directly agree with the indirect evidence through other treatments?

No comparison here has both direct and indirect evidence, so inconsistency cannot be checked by node splitting.

Small study effects

A comparison adjusted funnel plot: each point is one trial comparison, centered on its own network estimate. Asymmetry can signal that small trials with unfavorable results are missing.

Fewer than ten trial comparisons, too few to judge funnel plot asymmetry.

Comparability of the trials

Checked across designs (the set of treatments each trial compares) for eligibility, outcome definition and assessment, and the baseline factors above. Flags point to possible intransitivity; notes describe variation that is not tied to design.

NoteOutcome assessment, time point: selected time points span 5 to 365.26 weeks
NoteOutcome assessment, analysis set: mixed: full_analysis 1, modified_itt 2, randomized 1, safety 10
NoteOutcome assessment, definition: mixed: hypoglycemia requiring medical assistance 1, minor (symptomatic, glucose below 54 mg/dL) or major hypoglycemia 1, not stated 7, primary MACE: serious cardiovascular death, myocardial infarction or stroke, defined retrospectively 1, severe hypoglycemia by ADA classification 1, Severe hypoglycemia needing another person to give carbohydrate, glucagon or other measures (protocol) 1, severe hypoglycemia, subject unable to treat self 1, severe hypoglycemic events, adverse event of special interest 1
NoteOutcome assessment, adjudicated: mixed: no 2, not stated 9, yes 3
NoteOutcome assessment, proportion method: mixed: not stated 13, observed 1
NoteOutcome assessment, intercurrent events (discontinuation): mixed: not stated 13, treatment_policy 1
NoteRisk of bias, blinding: mixed: double_blind 8, open_label 6
NoteRisk of bias, funding: mixed: industry 13, non_industry 1
NoteData handling, input conversions: arms_combined 5, printed_denominator 2

Comparability items per trial
Trial	time weeks	analysis set	definition	instrument	adjudicated	proportion method	intercurrent events (discontinuation)	intercurrent events (rescue)	blinding	funding	start year	Eligibility
PIONEER 4	57	safety	not stated	not stated	yes	not stated	not stated	not stated	double_blind	industry	2016	Age 18 or older; T2D on metformin with or without SGLT2i; HbA1c 7.0 to 9.5 percent; eGFR 60 or more
REWIND	365.26	randomized	Severe hypoglycemia needing another person to give carbohydrate, glucagon or other measures (protocol)	not stated	not stated	not stated	treatment_policy	not stated	double_blind	industry	2011	age 50 or older with T2D; HbA1c 9.5 percent or less; BMI 23 or more; CV disease or risk factors
NCT00765817	30	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2008	adults 18 or older; insulin glargine 20 U/d or more alone or with metformin or pioglitazone; HbA1c 7.1 to 10.5 percent; BMI 45 or less
NCT01029886	26	modified_itt	primary MACE: serious cardiovascular death, myocardial infarction or stroke, defined retrospectively	not stated	no	observed	not stated	not stated	open_label	industry	2010	adults 18 or older with type 2 diabetes on oral agents, HbA1c 7.1 to 11.0 percent, BMI 45 or less
NCT01617434	27	safety	severe hypoglycemia, subject unable to treat self	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2012	age 18 to 80; HbA1c 7.0 to 10.0 percent; BMI 20 to 45; basal insulin analogue 20 U or more with or without metformin
NCT02465515	140.89	safety	severe hypoglycemic events, adverse event of special interest	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2015	type 2 diabetes with established cardiovascular disease
DURATION-NEO-2	28	safety	minor (symptomatic, glucose below 54 mg/dL) or major hypoglycemia	not stated	not stated	not stated	not stated	not stated	open_label	industry	2013	age 18 or older; HbA1c 7.1 to 11.0 percent; BMI 45 or lower; metformin 1500 mg or more
AWARD-CHN2	52	safety	not stated	not stated	yes	not stated	not stated	not stated	open_label	industry	2012	age 18 or older; BMI 19 to 35 kg/m2; HbA1c 7.0 to 11.0 percent on metformin and/or sulfonylurea
SUSTAIN™ 5	35	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2014	age 18 or older (20 in Japan); HbA1c 7.0 to 10.0 percent; stable basal insulin with or without metformin; eGFR 30 or more
NCT02229227	26	safety	not stated	not stated	not stated	not stated	not stated	not stated	open_label	industry	2014	age 18 to 75; HbA1c 7.0 to 9.5 percent at screening; BMI 40 or less; basal plus prandial insulin
SUSTAIN™	35	safety	severe hypoglycemia by ADA classification	not stated	not stated	not stated	not stated	not stated	open_label	industry	2014	Japanese; age 20 or older; HbA1c 6.5 to 9.5 percent on one OAD or 7.0 to 10.5 percent on diet and exercise
NCT03311724	16	modified_itt	not stated	not stated	yes	not stated	not stated	not stated	double_blind	industry	2017	age 18 to 75; T2D at least 6 months; HbA1c 7.0 to 10.5%; BMI 23 to 45; diet or stable metformin
NCT04466904	20	safety	not stated	not stated	no	not stated	not stated	not stated	double_blind	industry	2020	age 18 to 75; T2D on diet and exercise or stable metformin; HbA1c 7.5 to 11.0 percent; BMI 20 to 35
S003079	5	safety	hypoglycemia requiring medical assistance	not stated	not stated	not stated	not stated	not stated	open_label	non_industry	2010	age 18 to 80, HbA1c 7.5 to 12 percent, BMI 21 to 35, T2D at least 6 months

Trial data

What each trial contributes. Arm rows give the arm value with its standard error, or events over participants; contrast rows give the hazard ratio (from event counts) on the analysis scale (log) against the trial's first row. Flags mark converted, combined or approximated inputs.

Trial data entering this analysis
Trial	Arm	Treatment	Week	Data	Events / N	Flags	Source
PIONEER 4	A1	SEMA_PO	57	arm, events	0 / 285		R0015836:Supplement Table S8
PIONEER 4	A2	LIRA_SC	57	arm, events	1 / 284		R0015836:Supplement Table S8
PIONEER 4	A3	PLACEBO	57	arm, events	0 / 142		R0015836:Supplement Table S8
REWIND	A1	PLACEBO	365.26	arm, events	12 / 4,952		R0018537:Table 3
REWIND	A2	DULA_SC	365.26	arm, events	19 / 4,949		R0018537:Table 3
NCT00765817	A1	EXEN_SC	30	arm, events	0 / 138		R0027069:Results
NCT00765817	A2	PLACEBO	30	arm, events	0 / 123		R0027069:Results
NCT01029886	A1	EXENER_SC	26	arm, events	0 / 461		R0011287:Results
NCT01029886	A2	LIRA_SC	26	arm, events	0 / 451		R0011287:Results
NCT01617434	A1	LIRA_SC	27	arm, events	1 / 226		R0026247:Results
NCT01617434	A2	PLACEBO	27	arm, events	0 / 225		R0026247:Results
NCT02465515	A1	PLACEBO	140.89	arm, events	5 / 4,732		registry:outcomes
NCT02465515	A2	ALBI_SC	140.89	arm, events	6 / 4,731		registry:outcomes
DURATION-NEO-2	A1	EXENER_SC	28	arm, events	0 / 182		R0010641:Table 3
DURATION-NEO-2	A2	SITAGLIPTIN	28	arm, events	0 / 122		R0010641:Table 3
DURATION-NEO-2	A3	PLACEBO	28	arm, events	0 / 61		R0010641:Table 3
AWARD-CHN2	A1+A2	DULA_SC	52	arm, events	0 / 515	arms_combined	R0023722:Results
AWARD-CHN2	A3	INS_GLARGINE	52	arm, events	0 / 259		R0023722:Results
SUSTAIN™ 5	A1+A2	SEMA_SC	35	arm, events	0 / 264	arms_combined	R0012671:Table 2
SUSTAIN™ 5	A3	PLACEBO	35	arm, events	0 / 133		R0012671:Table 2
NCT02229227	A1	ALBI_SC	26	arm, events	0 / 402		registry:outcomes
NCT02229227	A2	INS_LISPRO	26	arm, events	0 / 412		registry:outcomes
SUSTAIN™	A1+A2	SEMA_SC	35	arm, events	0 / 205	arms_combined	R0014736:Results
SUSTAIN™	A3	SITAGLIPTIN	35	arm, events	1 / 103		R0014736:Results
NCT03311724	A1	PLACEBO	16	arm, events	0 / 26		R0010282:Results
NCT03311724	A2+A3+A4	TIRZ_SC	16	arm, events	0 / 85	arms_combined	R0010282:Results
NCT04466904	A1+A2+A3	MAZD_SC	20	arm, events	0 / 24	arms_combined	R0009340:Results
NCT04466904	A4	DULA_SC	20	arm, events	0 / 6	printed_denominator	R0009340:Results
NCT04466904	A5	PLACEBO	20	arm, events	0 / 12	printed_denominator	R0009340:Results
S003079	A1	EXEN_SC	5	arm, events	0 / 18		R0025923:Results
S003079	A2	STANDARD_CARE	5	arm, events	0 / 18		R0025923:Results

Rerun this analysis yourself

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