J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

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Original Article

Volume 18, Number 9, September 2026, pages 599-611

Cytochrome P450 2D6 Metabolizer Phenotype Is Associated With Metoprolol Pharmacodynamics But Not With Metoprolol Discontinuation: A Retrospective Cohort Study in the All of Us Research Program

↓ Figure 1. CYP2D6 metabolizer phenotype and metoprolol discontinuation. Cause-specific hazard ratios (HRs) with 95% confidence intervals (CIs) for metoprolol discontinuation, with death treated as a competing event and the normal metabolizer as reference. Shown are the primary phenotype contrasts (poor, intermediate, and ultrarapid metabolizers vs normal metabolizers) under the terminal-gap discontinuation definition, the collapsed reduced-metabolizer contrast (poor plus intermediate vs normal), and the poor-metabolizer estimate under two alternative discontinuation definitions (90-day assumed supply and first gap of at least 30 days). The x-axis is on the log scale; the dashed line marks the null (HR = 1.0). All estimates include the null. IM: intermediate metabolizer; NM: normal metabolizer; PM: poor metabolizer; UM: ultrarapid metabolizer.

↓ Figure 2. Pharmacodynamic response by CYP2D6 phenotype. Adjusted associations between metabolizer phenotype and four pharmacodynamic outcomes, with the normal metabolizer as reference: (a) attained on-treatment heart rate (mean difference in beats/min), (b) bradycardia (odds ratio), (c) attained maximum daily dose (mean difference in mg), and (d) attainment of target dose (odds ratio). Estimates are shown for ultrarapid, intermediate, and poor metabolizers; the reference (normal metabolizer) is marked at the null (0 for mean differences, 1 for odds ratios). Teal indicates P < 0.05; gray indicates a non-significant estimate. Attained heart rate decreases monotonically with decreasing metabolizing capacity. CYP2D6: cytochrome P450 2D6; IM: intermediate metabolizer; NM: normal metabolizer; PM: poor metabolizer; UM: ultrarapid metabolizer.

↓ Figure 3. Reduced-metabolizer status and metoprolol discontinuation, by genetic ancestry. Within-stratum cause-specific HRs for the reduced-metabolizer contrast (poor plus intermediate vs normal metabolizers) across six genetic-ancestry groups, listed in the same order as Table 1, with 95% confidence intervals (CIs); marker area is proportional to random-effects weight. The South Asian stratum (amber) is the source of the significant between-stratum heterogeneity (I² = 64.7%; Cochran Q P = 0.01) and, given its small size (n = 215), is interpreted as hypothesis-generating. The diamond shows the DerSimonian–Laird random-effects pooled estimate (HR, 1.02; 95% CI, 0.95–1.08). The x-axis is on the log scale; the dashed line marks the null (HR = 1.0). HR: hazard ratios.

↓ **Table 1.** Ancestry-Stratified Reduced-Metabolizer Contrast (PM + IM vs NM)
Genetic ancestry	N	Events	HR (95% CI)
Between-stratum heterogeneity: I² = 64.7%; Cochran Q P = 0.01. Random-effects (DerSimonian–Laird) pooled HR, 1.02 (95% CI, 0.95–1.08). The significant heterogeneity was driven by the small South Asian stratum; a fixed-effect pooled estimate is not an appropriate summary (see Results). Because the strata are mutually exclusive groups within a single cohort, the Cochran Q test is the formal test of effect modification of the reduced-metabolizer contrast by genetic ancestry. Strata are listed alphabetically, and Figure 3 uses the same order. CI: confidence interval; HR: cause-specific hazard ratio; IM: intermediate metabolizer; NM: normal metabolizer; PM: poor metabolizer.
African	6,594	4,631	0.98 (0.93–1.04)
Admixed American	4,926	3,564	0.98 (0.92–1.05)
East Asian	543	362	0.97 (0.78–1.19)
European	30,892	20,379	1.02 (0.99–1.05)
Middle Eastern	110	83	1.24 (0.77–1.98)
South Asian	215	151	1.87 (1.31–2.68)

↓ Table 1. Ancestry-Stratified Reduced-Metabolizer Contrast (PM + IM vs NM)

Genetic ancestry

Events

HR (95% CI)

Between-stratum heterogeneity: I² = 64.7%; Cochran Q P = 0.01. Random-effects (DerSimonian–Laird) pooled HR, 1.02 (95% CI, 0.95–1.08). The significant heterogeneity was driven by the small South Asian stratum; a fixed-effect pooled estimate is not an appropriate summary (see Results). Because the strata are mutually exclusive groups within a single cohort, the Cochran Q test is the formal test of effect modification of the reduced-metabolizer contrast by genetic ancestry. Strata are listed alphabetically, and Figure 3 uses the same order. CI: confidence interval; HR: cause-specific hazard ratio; IM: intermediate metabolizer; NM: normal metabolizer; PM: poor metabolizer.

African

6,594

4,631

0.98 (0.93–1.04)

Admixed American

4,926

3,564

0.98 (0.92–1.05)

East Asian

543

362

0.97 (0.78–1.19)

European

30,892

20,379

1.02 (0.99–1.05)

Middle Eastern

110

1.24 (0.77–1.98)

South Asian

215

151

1.87 (1.31–2.68)

↓ **Table 2.** Baseline Characteristics of the Discontinuation-Eligible Cohort, by CYP2D6 Metabolizer Phenotype
Characteristic	PM (n = 2,470)	IM (n = 16,687)	NM (n = 24,123)	UM (n = 1,205)	Max SMD
^aGenetic-ancestry proportions differ across metabolizer groups by design, because CYP2D6 allele and phenotype frequencies vary by ancestral population; this structure motivated adjustment for genetic-ancestry principal components in all models and the ancestry-stratified analysis (Table 1), and it is not a balance failure. ^bBaseline heart rate was measured before metoprolol exposure and was used as a precision covariate only in the attained heart-rate model; it was not used as an adjustment covariate in the discontinuation or dose models (see Methods). The “Max SMD” column reports, for each categorical variable, the maximum absolute SMD across its categories versus normal metabolizers. The maximum SMD across the adjustment covariates (age, sex, indication, comorbidity, cotherapy, CYP2D6 inhibitor exposure, calendar year, and EHR density) was 0.089, indicating good balance across phenotype groups. Genetic ancestry is shown for cohort description and is excluded from this balance statement for the reason given above. Sex categories reflect the sex value recorded in the EHR; participants without a recorded value are shown as unknown or not reported. Rows reported as a single value followed by a percent sign indicate the percentage of participants within that phenotype column who have the characteristic; the denominators are the column Ns given in the header. Rows reported as n (%) give the count followed by the within-column percentage. AV: atrioventricular; bpm: beats per minute; COPD: chronic obstructive pulmonary disease; EHR: electronic health record; IM: intermediate metabolizer; NM: normal metabolizer; PM: poor metabolizer; SMD: standardized mean difference; UM: ultrarapid metabolizer; CYP2D6: cytochrome P450 2D6; SD: standard deviation; Max: maximum.
Age at index, mean (SD), years	60.3 (13.5)	59.7 (13.8)	59.1 (13.7)	58.9 (14.2)	0.086
Sex, n (%)					0.023
Female	1,287 (52.1)	8,747 (52.4)	12,476 (51.7)	627 (52.0)
Male	1,144 (46.3)	7,634 (45.7)	11,275 (46.7)	556 (46.1)
Unknown or not reported	39 (1.6)	306 (1.8)	372 (1.5)	22 (1.8)
Genetic ancestry, n (%)^a					0.444
European	2,121 (85.9)	12,477 (74.8)	16,294 (67.5)	705 (58.5)
African	172 (7.0)	2,409 (14.4)	4,013 (16.6)	270 (22.4)
Admixed American	170 (6.9)	1,484 (8.9)	3,272 (13.6)	207 (17.2)
East Asian	1 (0.0)	217 (1.3)	325 (1.3)	2 (0.2)
South Asian	4 (0.2)	62 (0.4)	149 (0.6)	8 (0.7)
Middle Eastern	2 (0.1)	38 (0.2)	70 (0.3)	13 (1.1)
Baseline heart rate, mean (SD), bpm^b	77.2 (13.1)	78.2 (13.7)	78.4 (13.5)	77.9 (13.0)	0.089
EHR density, mean (SD)	16.4 (22.0)	16.2 (21.9)	16.3 (21.7)	16.5 (22.7)	0.006
Follow-up, mean (SD), days	1,525.3 (1,736.0)	1,580.7 (1,807.7)	1,552.7 (1,793.5)	1,597.4 (1,830.8)	0.025
Calendar year of index, mean (SD)	2,017.2 (5.1)	2,017.1 (5.2)	2,017.2 (5.2)	2,016.8 (5.2)	0.077
Chronic kidney disease, %	38.6	39.4	40.5	42.9	0.049
COPD or asthma, %	38.7	39.9	40.1	40.9	0.029
Diabetes, %	40.0	41.6	44.1	45.8	0.083
Prior bradyarrhythmia, %	21.5	19.2	18.0	16.4	0.088
AV-nodal blocking cotherapy, %	12.5	12.0	12.7	13.5	0.026
Concomitant strong CYP2D6 inhibitor exposure, %	10.1	9.1	8.8	9.3	0.047
Concomitant moderate CYP2D6 inhibitor exposure, %	6.0	5.8	5.7	4.1	0.074
Metoprolol indication, n (%)					0.072
Heart failure	797 (32.3)	5,438 (32.6)	8,153 (33.8)	411 (34.1)
Hypertension	770 (31.2)	5,099 (30.6)	7,433 (30.8)	353 (29.3)
Atrial fibrillation	395 (16.0)	2,548 (15.3)	3,460 (14.3)	150 (12.4)
Acute myocardial infarction	139 (5.6)	1,106 (6.6)	1,544 (6.4)	90 (7.5)
Angina	142 (5.7)	942 (5.6)	1,388 (5.8)	91 (7.6)
Other or unknown	227 (9.2)	1,554 (9.3)	2,145 (8.9)	110 (9.1)

↓ Table 2. Baseline Characteristics of the Discontinuation-Eligible Cohort, by CYP2D6 Metabolizer Phenotype

Characteristic

PM (n = 2,470)

IM (n = 16,687)

NM (n = 24,123)

UM (n = 1,205)

Max SMD

^aGenetic-ancestry proportions differ across metabolizer groups by design, because CYP2D6 allele and phenotype frequencies vary by ancestral population; this structure motivated adjustment for genetic-ancestry principal components in all models and the ancestry-stratified analysis (Table 1), and it is not a balance failure. ^bBaseline heart rate was measured before metoprolol exposure and was used as a precision covariate only in the attained heart-rate model; it was not used as an adjustment covariate in the discontinuation or dose models (see Methods). The “Max SMD” column reports, for each categorical variable, the maximum absolute SMD across its categories versus normal metabolizers. The maximum SMD across the adjustment covariates (age, sex, indication, comorbidity, cotherapy, CYP2D6 inhibitor exposure, calendar year, and EHR density) was 0.089, indicating good balance across phenotype groups. Genetic ancestry is shown for cohort description and is excluded from this balance statement for the reason given above. Sex categories reflect the sex value recorded in the EHR; participants without a recorded value are shown as unknown or not reported. Rows reported as a single value followed by a percent sign indicate the percentage of participants within that phenotype column who have the characteristic; the denominators are the column Ns given in the header. Rows reported as n (%) give the count followed by the within-column percentage. AV: atrioventricular; bpm: beats per minute; COPD: chronic obstructive pulmonary disease; EHR: electronic health record; IM: intermediate metabolizer; NM: normal metabolizer; PM: poor metabolizer; SMD: standardized mean difference; UM: ultrarapid metabolizer; CYP2D6: cytochrome P450 2D6; SD: standard deviation; Max: maximum.

Age at index, mean (SD), years

60.3 (13.5)

59.7 (13.8)

59.1 (13.7)

58.9 (14.2)

0.086

Sex, n (%)

0.023

Female

1,287 (52.1)

8,747 (52.4)

12,476 (51.7)

627 (52.0)

Male

1,144 (46.3)

7,634 (45.7)

11,275 (46.7)

556 (46.1)

Unknown or not reported

39 (1.6)

306 (1.8)

372 (1.5)

22 (1.8)

Genetic ancestry, n (%)^a

0.444

European

2,121 (85.9)

12,477 (74.8)

16,294 (67.5)

705 (58.5)

African

172 (7.0)

2,409 (14.4)

4,013 (16.6)

270 (22.4)

Admixed American

170 (6.9)

1,484 (8.9)

3,272 (13.6)

207 (17.2)

East Asian

1 (0.0)

217 (1.3)

325 (1.3)

2 (0.2)

South Asian

4 (0.2)

62 (0.4)

149 (0.6)

8 (0.7)

Middle Eastern

2 (0.1)

38 (0.2)

70 (0.3)

13 (1.1)

Baseline heart rate, mean (SD), bpm^b

77.2 (13.1)

78.2 (13.7)

78.4 (13.5)

77.9 (13.0)

0.089

EHR density, mean (SD)

16.4 (22.0)

16.2 (21.9)

16.3 (21.7)

16.5 (22.7)

0.006

Follow-up, mean (SD), days

1,525.3 (1,736.0)

1,580.7 (1,807.7)

1,552.7 (1,793.5)

1,597.4 (1,830.8)

0.025

Calendar year of index, mean (SD)

2,017.2 (5.1)

2,017.1 (5.2)

2,017.2 (5.2)

2,016.8 (5.2)

0.077

Chronic kidney disease, %

38.6

39.4

40.5

42.9

0.049

COPD or asthma, %

38.7

39.9

40.1

40.9

0.029

Diabetes, %

40.0

41.6

44.1

45.8

0.083

Prior bradyarrhythmia, %

21.5

19.2

18.0

16.4

0.088

AV-nodal blocking cotherapy, %

12.5

12.0

12.7

13.5

0.026

Concomitant strong CYP2D6 inhibitor exposure, %

10.1

9.1

8.8

9.3

0.047

Concomitant moderate CYP2D6 inhibitor exposure, %

6.0

5.8

5.7

4.1

0.074

Metoprolol indication, n (%)

0.072

Heart failure

797 (32.3)

5,438 (32.6)

8,153 (33.8)

411 (34.1)

Hypertension

770 (31.2)

5,099 (30.6)

7,433 (30.8)

353 (29.3)

Atrial fibrillation

395 (16.0)

2,548 (15.3)

3,460 (14.3)

150 (12.4)

Acute myocardial infarction

139 (5.6)

1,106 (6.6)

1,544 (6.4)

90 (7.5)

Angina

142 (5.7)

942 (5.6)

1,388 (5.8)

91 (7.6)

Other or unknown

227 (9.2)

1,554 (9.3)

2,145 (8.9)

110 (9.1)

↓ **Table 3.** CYP2D6 Metabolizer Phenotype and Metoprolol Discontinuation: Primary and Sensitivity Analyses (Cause-Specific Cox Regression)
Analysis/definition	N	Events (rate)	Contrast	HR (95% CI)	P value
Death (629 events; 1.4%) was treated as a competing event and censored in the cause-specific models. Crude discontinuation under the primary definition was 67.4% (29,170 of 43,280) among poor, intermediate, and normal metabolizers combined and 68.8% (829 of 1,205) among ultrarapid metabolizers. The eligibility requirement for at least two dispensings defines the target population as patients who continued beyond a first fill (see Methods and Limitations). CI: confidence interval; HR: cause-specific hazard ratio; IM: intermediate metabolizer; NM: normal metabolizer; PM: poor metabolizer; UM: ultrarapid metabolizer; CYP2D6: cytochrome P450 2D6.
Primary (terminal-gap)	44,485	29,999 (67.4%)	PM vs NM	1.04 (0.99–1.09)	0.12
			IM vs NM	1.01 (0.99–1.03)	0.41
			UM vs NM	1.01 (0.94–1.08)	0.89
Reduced metabolizer	43,280	29,170 (67.4%)	PM + IM vs NM	1.01 (0.99–1.04)	0.24
Sensitivity: 90-day assumed supply	43,336	30,504 (70.4%)	PM vs NM	1.02 (0.97–1.07)	0.40
			IM vs NM	1.00 (0.98–1.03)	0.86
			UM vs NM	0.99 (0.92–1.06)	0.75
Sensitivity: first gap (≥ 30 days)	43,336	42,556 (98.2%)	PM vs NM	1.01 (0.97–1.05)	0.68
			IM vs NM	1.01 (0.99–1.03)	0.52
			UM vs NM	1.04 (0.98–1.11)	0.17

↓ Table 3. CYP2D6 Metabolizer Phenotype and Metoprolol Discontinuation: Primary and Sensitivity Analyses (Cause-Specific Cox Regression)

Analysis/definition

Events (rate)

Contrast

HR (95% CI)

P value

Death (629 events; 1.4%) was treated as a competing event and censored in the cause-specific models. Crude discontinuation under the primary definition was 67.4% (29,170 of 43,280) among poor, intermediate, and normal metabolizers combined and 68.8% (829 of 1,205) among ultrarapid metabolizers. The eligibility requirement for at least two dispensings defines the target population as patients who continued beyond a first fill (see Methods and Limitations). CI: confidence interval; HR: cause-specific hazard ratio; IM: intermediate metabolizer; NM: normal metabolizer; PM: poor metabolizer; UM: ultrarapid metabolizer; CYP2D6: cytochrome P450 2D6.

Primary (terminal-gap)

44,485

29,999 (67.4%)

PM vs NM

1.04 (0.99–1.09)

0.12

IM vs NM

1.01 (0.99–1.03)

0.41

UM vs NM

1.01 (0.94–1.08)

0.89

Reduced metabolizer

43,280

29,170 (67.4%)

PM + IM vs NM

1.01 (0.99–1.04)

0.24

Sensitivity: 90-day assumed supply

43,336

30,504 (70.4%)

PM vs NM

1.02 (0.97–1.07)

0.40

IM vs NM

1.00 (0.98–1.03)

0.86

UM vs NM

0.99 (0.92–1.06)

0.75

Sensitivity: first gap (≥ 30 days)

43,336

42,556 (98.2%)

PM vs NM

1.01 (0.97–1.05)

0.68

IM vs NM

1.01 (0.99–1.03)

0.52

UM vs NM

1.04 (0.98–1.11)

0.17

↓ **Table 4.** CYP2D6 Metabolizer Phenotype and Pharmacodynamic Secondary Outcomes
Outcome (model)	Contrast	Estimate (95% CI)	P value
^aThe attained heart-rate model additionally adjusted for baseline (pre-exposure) heart rate. No adjustment for multiple comparisons was applied; the contrasts that survive a Bonferroni correction across the 12 secondary comparisons are identified in the Results. CI: confidence interval; IM: intermediate metabolizer; NM: normal metabolizer; OR: odds ratio; PM: poor metabolizer; UM: ultrarapid metabolizer; CYP2D6: cytochrome P450 2D6.
Attained on-treatment heart rate, bpm (linear)^a	PM vs NM	−1.85 (−2.36 to −1.34)	< 0.001
	IM vs NM	−0.84 (−1.09 to −0.60)	< 0.001
	UM vs NM	+0.79 (0.07 to 1.51)	0.03
Bradycardia (logistic), OR	PM vs NM	1.19 (1.05–1.36)	0.009
	IM vs NM	1.16 (1.09–1.23)	< 0.001
	UM vs NM	0.95 (0.78–1.16)	0.62
Attained maximum daily dose, mg (linear)	PM vs NM	−5.28 (−12.67 to 2.11)	0.16
	IM vs NM	−6.68 (−10.26 to −3.09)	< 0.001
	UM vs NM	+13.33 (2.92 to 23.75)	0.01
Reached target dose (logistic), OR	PM vs NM	0.96 (0.83–1.10)	0.55
	IM vs NM	0.91 (0.85–0.97)	0.006
	UM vs NM	1.28 (1.07–1.54)	0.008

↓ Table 4. CYP2D6 Metabolizer Phenotype and Pharmacodynamic Secondary Outcomes

Outcome (model)

Contrast

Estimate (95% CI)

P value

^aThe attained heart-rate model additionally adjusted for baseline (pre-exposure) heart rate. No adjustment for multiple comparisons was applied; the contrasts that survive a Bonferroni correction across the 12 secondary comparisons are identified in the Results. CI: confidence interval; IM: intermediate metabolizer; NM: normal metabolizer; OR: odds ratio; PM: poor metabolizer; UM: ultrarapid metabolizer; CYP2D6: cytochrome P450 2D6.

Attained on-treatment heart rate, bpm (linear)^a

PM vs NM

−1.85 (−2.36 to −1.34)

< 0.001

IM vs NM

−0.84 (−1.09 to −0.60)

< 0.001

UM vs NM

+0.79 (0.07 to 1.51)

0.03

Bradycardia (logistic), OR

PM vs NM

1.19 (1.05–1.36)

0.009

IM vs NM

1.16 (1.09–1.23)

< 0.001

UM vs NM

0.95 (0.78–1.16)

0.62

Attained maximum daily dose, mg (linear)

PM vs NM

−5.28 (−12.67 to 2.11)

0.16

IM vs NM

−6.68 (−10.26 to −3.09)

< 0.001

UM vs NM

+13.33 (2.92 to 23.75)

0.01

Reached target dose (logistic), OR

PM vs NM

0.96 (0.83–1.10)

0.55

IM vs NM

0.91 (0.85–0.97)

0.006

UM vs NM

1.28 (1.07–1.54)

0.008