Obesity is an established risk factor for stroke,1 but the association of increased body mass index (BMI) with survival after stroke remains contentious. Contrary to evidence in the general population,2 in patients with established cardiovascular disease, increased BMI has been shown to be independently associated with better outcome.3–6 Many studies have shown that increased BMI has a protective effect on survival after stroke,7,8 while other studies have not confirmed an obesity paradox in patients with stroke.9 The association between BMI and composite major adverse cardiovascular event (MACE) and its individual constituent outcomes have, however, not been studied using a population-based cohort in patients with any subtype of incident stroke.
Using a large population-based cohort in the United Kingdom, this study aimed to examine the relationship between BMI and MACE outcomes during long-term follow-up in patients with any subtype of incident stroke.
Methods Data sourceThis prospective population-based cohort study used the UK Clinical Practice Research Datalink (CPRD) GOLD database of anonymized longitudinal primary care electronic health records,10 linked to secondary care hospitalization data [Hospital Episode Statistics (HES)],11 national mortality data [Office for National Statistics (ONS)],12 and social deprivation data [Index of Multiple Deprivation (IMD) 2015].13 Individuals included in CPRD GOLD database, from a network of general practices across the UK, are representative of the UK general population in terms of sex, age, and ethnicity,10 thereby validating CPRD GOLD for epidemiological research. This study was approved by the Independent Scientific Advisory Committee of the Medicines and Healthcare products Regulatory Agency (Protocol number 19_023R). Requests to access CPRD data are made through the Independent Scientific Advisory Committee (
We identified a cohort of individuals with incident non-fatal stroke in either primary care (CPRD GOLD) or secondary care (HES) between 1 January 1998 and 31 December 2017. Details about this cohort were previously reported.14 Individuals with a record of major adverse cardiovascular event [including coronary heart disease (CHD), peripheral vascular disease (PVD), or heart failure] before incident stroke were excluded. Individuals were followed from date of incident stroke diagnosis until they developed a major adverse outcome, died, ceased contributing data, or end of data collection. The study flow diagram is shown in Supporting information, Figure S1.
Cohort demographics and baseline characteristicsAge was defined at the time of incident stroke. Ethnicity was categorized into six groups: Asian, Black, Mixed, Other, White, and unknown.15 To describe socioeconomic status, the English Index of Multiple Deprivation 201513 linked to the individual's residential postcode was used. IMD is a weighted mean across the seven domains, hence offers a single score to describe the concept of deprivation; categorized into quintiles [Quintile 1 (least deprived group) to Quintile 5 (most deprived group)]. Medication prescriptions (issue of prescription) at baseline were defined as a prescription within 12 months before incident stroke. For cholesterol (low-density lipoprotein, high-density lipoprotein, and total), BMI, blood pressure measures (diastolic and systolic), and glomerular filtration rate (GFR), the most recent values/measures within 24 months before incident stroke were used. All other comorbidities were defined based on the latest record before incident stroke.
Body mass indexBMI was categorized according to the WHO criteria as underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5–24.9 kg/m2), overweight (BMI 25.0–29.9 kg/m2), obesity Class I (BMI 30.0–34.9 kg/m2), obesity Class II (BMI 35.0–39.9 kg/m2), obesity Class III (BMI ≥ 40 kg/m2).16 Accordingly, and in line with accumulating epidemiologic evidence, we used as reference group (normal weight) patients with a BMI of 18.5–24.9 kg/m2.17
Outcome measuresFirst subsequent MACE after incident stroke was the primary outcome. MACE was defined as a composite of new onset coronary heart disease, recurrent stroke, PVD, heart failure, or cardiovascular-related mortality, based on record from across the linked data sources (CPRD, HES, or ONS registry). All-cause mortality was considered as a secondary outcome.
The study cohort and outcomes were identified from CPRD using Read codes, from HES using International Classification of Diseases, tenth revision (ICD-10) codes and Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures (OPCS) revision 4.6 for procedure codes. All code lists used are available for download online (
The Shapiro–Wilk test was used to assess normality of distribution for continuous variables.19 Kruskal–Wallis test for continuous data and χ2 test for categorical data were used to compare baseline characteristics between BMI categories. The level of missing values ranged between 3.1% for blood pressure measures to 57.4% for GFR. Details on the proportion of missingness is provided in Table S1. To estimate missing values for BMI, systolic and diastolic blood pressures, GFR, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol levels, multiple imputation by chained equations was used to generate 10 imputed datasets using all the other available patient variables.20 The imputed datasets were pooled into a single dataset using Rubin's rules.21 Differences in baseline characteristics between those with and without a BMI record within 24 months of incident stroke is provided in the Table S2. Event rates between BMI categories were analysed by multivariable Cox regression models using the category of normal BMI as reference. Time to event curves for BMI categories were made for MACE outcomes. Hazard ratios (HRs) and 95% confidence intervals (95% CI) for the outcomes according to BMI category were calculated in Cox regression models adjusted for: (a) age and sex; (b) age, sex, socioeconomic status, current smoking, history of alcohol problem, atrial fibrillation, chronic kidney disease, diabetes mellitus, dyslipidaemia, hypertension, transient ischaemic attack, prescription of angiotensin-converting enzyme (ACE) inhibitor, anti-hypertensive, anti-diabetic, anti-platelet, beta-blocker, calcium channel blocker, non-steroidal anti-inflammatory drugs, statin potency, diastolic and systolic blood pressure, GFR, total cholesterol (full adjustment model). Restricted cubic spline with 3–5 knots (lowest Akaike information criterion) was used for non-linear relationship between BMI and outcomes. All statistical analyses were performed using Stata SE version 16.1 (StataCorp LP). An alpha level of 0.05 was used for all analysis to define statistical significance.
ResultsA total of 30 702 individuals with baseline BMI record (53% women) were included in this study. The median age for the study cohort was 75 years (IQR: 65–82). The distribution of BMI within the study cohort is present in Figure S2. Most of the individuals were within the overweight and obesity categories (60.9%) and 35.1% had normal BMI. Clinical characteristics and medications prescribed at baseline across the BMI categories are presented in Table 1 and by sex in Table S3. Individuals in the obese classes (I–III) were younger and had higher prevalence of hypertension and diabetes mellitus at baseline.
Table 1 Characteristics of study population at time of incident stroke according to body mass index categories
| Characteristics |
<18.5 1217 (4.0%) |
18.5–24.9 10 783 (35.1%) |
25.0–29.9 10 979 (35.8%) |
30.0–34.9 5206 (17.0%) |
35.0–39.9 1749 (5.7%) |
≥ 40 kg/m2 n (%) 768 (2.5%) |
|
| Follow-up, median (IQR) | 10.2 (5.7–15.4) | 12.1 (7.2–16.6) | 13.4 (8.5–17.5) | 13.8 (8.8–17.8) | 13.3 (8.7–17.5) | 13.8 (8.2–17.7) | 0.0001 |
| Females | 935 (76.8) | 6144 (57.0) | 5164 (47.0) | 2620 (50.3) | 1025 (58.6) | 511 (66.5) | <0.001 |
| Age (years) median (IQR) | 81 (72–87) | 78 (69–85) | 74 (65–81) | 71 (62–79) | 68 (58–75) | 63.5 (53–72) | 0.0001 |
| Incident stroke subtype | <0.001 | ||||||
| Haemorrhagic stroke | 146 (12.0) | 1037 (9.6) | 869 (7.9) | 383 (7.4) | 139 (8.0) | 54 (7.0) | |
| Ischaemic stroke | 437 (35.9) | 3996 (37.1) | 4204 (38.3) | 2071 (39.8) | 703 (40.2) | 323 (42.1) | |
| Stroke (not specified) | 634 (52.1) | 5750 (53.3) | 5906 (53.8) | 2752 (52.9) | 907 (51.9) | 391 (50.9) | |
| Ethnicity | <0.001 | ||||||
| Asian | 18 (1.5) | 191 (1.8) | 197 (1.8) | 84 (1.6) | 23 (1.3) | 4 (0.7) | |
| Black | 9 (0.7) | 89 (0.8) | 105 (1.0) | 86 (1.7) | 39 (2.2) | 20 (2.6) | |
| Mixed | 0 | 12 (0.1) | 13 (0.1) | 11 (0.2) | 3 (0.2) | 3 (0.4) | |
| Other | 6 (0.5) | 75 (0.7) | 80 (0.7) | 38 (0.7) | 13 (0.7) | 4 (0.5) | |
| White | 1116 (91.7) | 9758 (90.5) | 10 031 (91.4) | 4748 (91.2) | 1598 (91.4) | 704 (91.7) | |
| Unknown | 68 (5.6) | 658 (6.1) | 553 (5.0) | 239 (4.6) | 73 (4.2) | 32 (4.2) | |
| Socioeconomic status | <0.001 | ||||||
| 1 (least deprived) | 233 (19.2) | 2369 (22.0) | 2386 (21.7) | 926 (17.8) | 249 (14.2) | 94 (12.2) | |
| 2 | 257 (21.1) | 2368 (22.0) | 2443 (22.3) | 1124 (21.6) | 368 (21.0) | 143 (18.6) | |
| 3 | 243 (20.0) | 2288 (21.2) | 2275 (20.7) | 1077 (20.7) | 372 (21.3) | 177 (23.1) | |
| 4 | 272 (22.4) | 1987 (18.4) | 2124 (19.4) | 1062 (20.4) | 374 (21.4) | 165 (21.5) | |
| 5 (most deprived) | 210 (17.3) | 1763 (16.4) | 1737 (15.8) | 1012 (19.4) | 384 (22.0) | 189 (24.6) | |
| Unknown | 2 (0.2) | 8 (0.1) | 14 (0.1) | 5 (0.1) | 2 (0.1) | 0 | |
| Current smokers | 349 (28.7) | 2177 (20.2) | 1841 (16.8) | 874 (16.8) | 306 (17.5) | 142 (18.5) | <0.001 |
| DBP (mmHg) | 78 (70–82) | 79 (70–83) | 80 (71–85) | 80 (73–86) | 80 (74–86) | 80 (75–88) | <0.001 |
| SBP (mmHg) | 138 (122–149) | 139 (128–148) | 140 (130–150) | 140 (130–150) | 140 (130–150) | 140 (130–150) | <0.001 |
| HDL cholesterol (mmol/L) | 1.8 (1.5–2.0) | 1.6 (1.3–1.8) | 1.4 (1.2–1.6) | 1.3 (1.1–1.5) | 1.2 (1.1–1.4) | 1.1 (1.0–1.3) | 0.0001 |
| LDL cholesterol (mmol/L) | 2.8 (2.5–3.2) | 2.9 (2.5–3.3) | 2.9 (2.4–3.4) | 2.9 (2.3–3.4) | 2.9 (2.3–3.4) | 2.9 (2.4–3.5) | 0.0001 |
| Total cholesterol (mmol/L) | 5.2 (4.6–5.6) | 5.1 (4.5–5.5) | 5.0 (4.4–5.6) | 5.0 (4.3–5.6) | 5.0 (4.3–5.6) | 5.0 (4.4–5.5) | 0.0001 |
| GFR | 67.5 (60.3–74.7) | 67.0 (60.3–73.0) | 67.4 (60.9–73.1) | 68.0 (61.0–73.9) | 68.7 (61.6–75.3) | 69.2 (63.0–76.0) | 0.0001 |
| Comorbidities at baseline | |||||||
| Alcohol problem | 61 (5.0) | 366 (3.4) | 300 (2.7) | 164 (3.2) | 48 (2.7) | 28 (3.7) | <0.001 |
| Atrial fibrillation | 154 (12.7) | 1273 (11.8) | 1159 (10.6) | 483 (9.3) | 166 (9.5) | 74 (9.6) | <0.001 |
| Cancer | 256 (21.0) | 2273 (21.1) | 1956 (17.8) | 818 (15.7) | 227 (13.0) | 97 (12.6) | <0.001 |
| Chronic kidney disease | 163 (13.4) | 1491 (13.8) | 1601 (14.6) | 824 (15.8) | 281 (16.1) | 102 (13.3) | 0.005 |
| Diabetes mellitus | 121 (9.9) | 1672 (15.5) | 2515 (22.9) | 1589 (30.5) | 660 (37.7) | 295 (38.4) | <0.001 |
| Type-1 diabetes | 11 (0.9) | 142 (1.3) | 174 (1.6) | 105 (2.0) | 40 (1.3) | 23 (3.0) | <0.001 |
| Type-2 diabetes | 95 (7.8) | 1331 (12.3) | 2112 (19.2) | 1408 (27.1) | 594 (34.0) | 265 (34.5) | <0.001 |
| Dyslipidaemia | 76 (6.2) | 1215 (11.3) | 1569 (14.3) | 846 (16.3) | 291 (16.6) | 124 (16.2) | <0.001 |
| Hypertension | 528 (43.4) | 5555 (51.5) | 6402 (58.3) | 3359 (64.5) | 1164 (66.6) | 503 (65.5) | <0.001 |
| Transient ischaemic attack | 263 (21.6) | 2472 (22.9) | 2629 (24.0) | 1167 (22.4) | 336 (19.2) | 131 (17.1) | <0.001 |
| Prescribed medications at baseline | |||||||
| ACE inhibitor | 287 (23.6) | 3518 (32.6) | 4455 (40.6) | 2637 (50.7) | 958 (54.8) | 429 (55.9) | <0.001 |
| Anti-diabetic | 73 (6.0) | 1272 (11.8) | 2025 (18.4) | 1326 (25.5) | 556 (31.8) | 254 (33.1) | <0.001 |
| Anti-hypertensive | 550 (45.2) | 5732 (53.2) | 6759 (61.6) | 3587 (68.9) | 1260 (72.0) | 545 (71.0) | <0.001 |
| Antiplatelets | 495 (40.7) | 4605 (42.7) | 4806 (43.8) | 2286 (43.9) | 745 (42.6) | 310 (40.4) | 0.090 |
| Beta-blockers | 265 (21.8) | 2604 (24.2) | 2996 (27.3) | 1480 (28.4) | 560 (32.0) | 246 (32.0) | <0.001 |
| Calcium channel blocker | 280 (23.0) | 2873 (26.6) | 3469 (31.6) | 1789 (34.4) | 657 (37.6) | 264 (34.4) | <0.001 |
| NSAIDS | 234 (19.2) | 2508 (23.3) | 3030 (27.6) | 1675 (32.2) | 598 (34.2) | 284 (37.0) | <0.001 |
| Statin | <0.001 | ||||||
| Low intensity | 39 (3.2) | 477 (4.4) | 596 (5.4) | 281 (5.4) | 107 (6.1) | 36 (4.7) | |
| Moderate intensity | 210 (17.3) | 2370 (22.0) | 3115 (28.4) | 1627 (31.3) | 567 (32.4) | 240 (31.3) | |
| High intensity | 32 (2.6) | 524 (4.9) | 755 (6.9) | 488 (9.4) | 188 (10.8) | 87 (11.3) | |
ACE, angiotensin converting enzyme; DBP, diastolic blood pressure; GFR, glomerular filtration rate; HDL, high-density lipoprotein; IQR, interquartile range; LDL, low-density lipoprotein; n, frequency/numbers; NSAIDS, non-steroidal anti-inflammatory drug; SBP, systolic blood pressure; %, percentage.
Nutritional status for the body mass index categories (kg/m2): underweight (<18.5); normal weight (18.5–24.9); pre-obese (25.0–29.9); obesity Class I (30.0–34.9); obesity Class II (35.0–39.9); obesity Class III (≥40).
During a median follow-up of 12.9 years (IQR: 7.9–17.2 years), 20 881 (68.0%) individuals had a subsequent MACE recorded. The proportion of subsequent MACE outcomes was similar across the BMI categories. Table 2 details the number and proportion for all the MACE and all the individual constituent outcomes.
Table 2 Number and proportion of first subsequent outcomes within the body mass index categories
| Outcomes |
<18.5 |
18.5–24.9 |
25.0–29.9 |
30.0–34.9 |
35.0–39.9 |
≥40 kg/m2 |
|
| Composite MACE | |||||||
| Follow-up time | 0.14 (0.03–1.10) | 0.21 (0.03–1.46) | 0.27 (0.04–1.77) | 0.23 (0.03–1.66) | 0.19 (0.03–1.67) | 0.16 (0.03–1.28) | 0.0001 |
| Number of events (percent) | 806 (66.2) | 7326 (67.9) | 7497 (68.3) | 3545 (68.1) | 1217 (69.6) | 490 (63.8) | 0.064 |
| CHD | |||||||
| Follow-up time | 0.83 (0.28–2.20) | 1.49 (0.31–3.42) | 1.91 (0.60–4.59) | 1.76 (0.52–3.86) | 2.89 (1.03–4.62) | 1.62 (0.90–3.79) | 0.0001 |
| Number of events (percent) | 24 (2.0) | 378 (3.5) | 459 (4.2) | 252 (4.8) | 86 (4.9) | 27 (3.5) | <0.001 |
| Recurrent stroke | |||||||
| Follow-up time | 0.15 (0.04–1.03) | 0.18 (0.03–1.24) | 0.19 (0.03–1.29) | 0.15 (0.02–1.15) | 0.11 (0.03–1.02) | 0.10 (0.02–1.05) | 0.0001 |
| Number of events (percent) | 490 (40.3) | 5119 (47.5) | 5580 (50.8) | 2636 (50.6) | 908 (51.9) | 379 (49.4) | <0.001 |
| PVD | |||||||
| Follow-up time | 1.83 (1.07–2.76) | 1.22 (0.50–2.89) | 1.58 (0.77–4.63) | 2.13 (0.73–4.67) | 2.26 (1.22–3.74) | 4.93 (1.23–8.63) | 0.2636 |
| Number of events (percent) | 17 (1.4) | 114 (1.1) | 97 (0.9) | 61 (1.2) | 19 (1.1) | 2 (0.3) | 0.087 |
| Heart failure | |||||||
| Follow-up time | 1.56 (0.64–3.35) | 1.23 (0.32–3.47) | 2.33 (0.74–4.64) | 2.12 (0.54–5.62) | 2.14 (0.59–4.70) | 2.68 (1.30–5.84) | 0.004 |
| Number of events (percent) | 20 (1.6) | 209 (1.9) | 241 (2.2) | 136 (2.6) | 62 (3.5) | 20 (2.6) | <0.001 |
| Cardiovascular mortality | |||||||
| Follow-up time | 0.07 (0.02–0.83) | 0.09 (0.02–1.37) | 0.10 (0.02–1.95) | 0.12 (0.02–2.15) | 0.16 (0.02–2.64) | 0.09 (0.01–0.90) | 0.0797 |
| Number of events (percent) | 255 (21.0) | 1506 (14.0) | 1120 (10.2) | 460 (8.8) | 142 (8.1) | 62 (8.1) | <0.001 |
| All-cause mortality | |||||||
| Follow-up time | 0.35 (0.4–2.29) | 0.68 (0.06–3.25) | 0.84 (0.06–4.17) | 1.05 (0.06–4.14) | 0.69 (0.06–4.18) | 0.43 (0.04–2.38) | 0.0001 |
| Number of events (percent) | 573 (47.1) | 3421 (31.7) | 2557 (23.3) | 1053 (20.2) | 314 (18.0) | 140 (18.2) | <0.001 |
CHD, coronary heart disease; MACE, major adverse cardiovascular event; PVD, peripheral vascular disease.
Follow-up time: Time from incident stroke event to first subsequent event reported as median with interquartile range in years
In multivariable analysis, higher BMI were associated with lower risk of subsequent MACE [overweight: HR 0.96 (95% CI 0.93–0.99)]; PVD [overweight: HR 0.65 (95% CI 0.49–0.85); obesity Class III: HR 0.19 (95% CI 0.50–0.77)]; cardiovascular-related death [overweight: HR 0.80 (95% 0.74–0.86); obesity Class I: HR 0.79 (95% CI 0.71–0.88); obesity Class II: HR 0.80 (95% CI 0.67–0.96)]; and all-cause mortality [overweight: HR 0.75 (95% CI 0.71–0.79); obesity Class I: HR 0.75 (95% CI 0.70–0.81); obesity Class II: HR 0.77 (95% CI 0.68–0.86)] when compared with those with normal BMI—Table 3. Tables S4, S5, and S6 present the results disaggregated by sex, diabetes mellitus, and smoking status at time of incident stroke, respectively. Tables 4 and S7 presents similar results after excluding 5627 (18.3%) individuals with a cancer diagnosis at baseline and excluding 8735 (28.5%) individuals with first subsequent outcomes within 30 days of incident stroke, respectively. The Kaplan–Meier curves for MACE and all-cause mortality across the BMI categories over a 10-year follow-up period is presented in Figure 1.
Table 3 Outcomes in body mass index subgroups
| Outcomes |
<18.5 HR (95% CI) |
25.0–29.9 HR (95% CI) |
30.0–34.9 HR (95% CI) |
35.0–39.9 i = 1749 (5.7%) HR (95% CI) |
≥ 40 kg/m2 n = 768 (2.5%) HR (95% CI) |
| Composite MACE | |||||
| Age and sex adjusted | 1.14 (1.06–1.23) | 0.96 (0.93–0.99) | 0.98 (0.95–1.03) | 1.10 (1.04–1.17) | 1.07 (0.97–1.17) |
| Full adjustment | 1.12 (1.05–1.21) | 0.96 (0.93–0.99) | 0.98 (0.94–1.02) | 1.08 (1.01–1.15) | 1.04 (0.95–1.14) |
| CHD | |||||
| Age and sex adjusted | 0.81 (0.53–1.22) | 1.00 (0.87–1.15) | 1.20 (1.02–1.41) | 1.29 (1.01–1.63) | 1.01 (0.68–1.51) |
| Full adjustment | 0.85 (0.56–1.29) | 0.94 (0.82–1.09) | 1.05 (0.89–1.24) | 1.06 (0.83–1.35) | 0.82 (0.55–1.23) |
| Recurrent stroke | |||||
| Age and sex adjusted | 1.01 (0.92–1.10) | 1.00 (0.97–1.04) | 1.00 (0.96–1.05) | 1.07 (1.00–1.15) | 1.05 (0.94–1.16) |
| Full adjustment | 1.00 (0.91–1.09) | 1.01 (0.98–1.05) | 1.02 (0.97–1.07) | 1.09 (1.02–1.18) | 1.06 (0.95–1.18) |
| PVD | |||||
| Age and sex adjusted | 1.96 (1.17–3.26) | 0.71 (0.54–0.93) | 1.00 (0.73–1.37) | 1.02 (0.62–1.66) | 0.28 (0.07–1.14) |
| Full adjustment | 1.91 (1.14–3.19) | 0.65 (0.49–0.85) | 0.79 (0.57–1.09) | 0.70 (0.42–1.17) | 0.19 (0.05–0.77) |
| Heart failure | |||||
| Age and sex adjusted | 1.09 (0.69–1.74) | 1.12 (0.93–1.35) | 1.60 (1.28–1.99) | 2.62 (1.96–3.50) | 2.60 (1.63–4.15) |
| Full adjustment | 1.13 (0.71–1.80) | 1.05 (0.87–1.26) | 1.41 (1.12–1.76) | 2.10 (1.56–2.83) | 1.97 (1.23–3.17) |
| Cardiovascular mortality | |||||
| Age and sex adjusted | 1.57 (1.38–1.80) | 0.80 (0.74–0.87) | 0.82 (0.74–0.91) | 0.89 (0.75–1.06) | 1.16 (0.90–1.50) |
| Full adjustment | 1.53 (1.34–1.75) | 0.80 (0.74–0.86) | 0.79 (0.71–0.88) | 0.80 (0.67–0.96) | 1.02 (0.79–1.32) |
| All-cause mortality | |||||
| Age and sex adjusted | 1.73 (1.58–1.89) | 0.75 (0.71–0.79) | 0.76 (0.70–0.81) | 0.80 (0.71–0.90) | 1.06 (0.89–1.26) |
| Full adjustment | 1.64 (1.50–1.80) | 0.75 (0.71–0.79) | 0.75 (0.70–0.81) | 0.77 (0.68–0.86) | 0.99 (0.84–1.18) |
CHD, coronary heart disease; HR, hazards ratio; MACE, major adverse cardiovascular event; PVD, peripheral vascular disease.
Full adjustment for age, sex, socioeconomic status, current smoking, history of alcohol problem, atrial fibrillation, chronic kidney disease, diabetes mellitus, dyslipidaemia, hypertension, transient ischaemic attack, prescription of ACE inhibitor, anti-hypertensive, anti-diabetic, anti-platelet, beta-blocker, calcium channel blocker, non-steroidal anti-inflammatory drug, statin potency, diastolic and systolic blood pressure, glomerular filtration rate, total cholesterol.
Reference category: Normal weight patients with a BMI of 18.5–24.9 kg/m2
Table 4 Outcomes in body mass index subgroups excluding patients with cancer at time of incident stroke (
| Outcomes |
<18.5 HR (95% CI) |
25.0–29.9 HR (95% CI) |
30.0–34.9 HR (95% CI) |
35.0–39.9 HR (95% CI) |
≥40 kg/m2 HR (95% CI) |
| Composite MACE | |||||
| Full adjustment | 1.13 (1.04–1.22) | 0.97 (0.93–1.00) | 0.97 (0.93–1.02) | 1.07 (1.00–1.15) | 1.06 (0.96–1.17) |
| CHD | |||||
| Full adjustment | 0.99 (0.65–1.52) | 0.95 (0.82–1.11) | 1.05 (0.87–1.25) | 1.06 (0.82–1.37) | 0.84 (0.55–1.27) |
| Recurrent stroke | |||||
| Full adjustment | 1.00 (0.90–1.11) | 1.02 (0.98–1.07) | 1.02 (0.97–1.08) | 1.10 (0.12–1.19) | 1.08 (0.97–1.21) |
| PVD | |||||
| Full adjustment | 1.92 (1.09–3.40) | 0.69 (0.51–0.92) | 0.73 (0.51–1.05) | 0.72 (0.43–1.22) | 0.21 (0.05–0.85) |
| Heart failure | |||||
| Full adjustment | 0.89 (0.49–1.60) | 1.05 (0.85–1.30) | 1.46 (1.14–1.87) | 2.12 (1.53–2.94) | 2.11 (1.27–3.50) |
| Cardiovascular mortality | |||||
| Full adjustment | 1.48 (1.27–1.72) | 0.78 (0.71–0.85) | 0.77 (0.68–0.86) | 0.77 (0.64–0.94) | 1.10 (0.84–1.45) |
| All-cause mortality | |||||
| Full adjustment | 1.68 (1.52–1.86) | 0.74 (0.70–0.79) | 0.73 (0.67–0.80) | 0.75 (0.66–0.86) | 1.03 (0.85–1.25) |
CHD, coronary heart disease; HR, hazards ratio; MACE, major adverse cardiovascular event; PVD, peripheral vascular disease.
Full adjustment for age, sex, socioeconomic status, current smoking, history of alcohol problem, atrial fibrillation, chronic kidney disease, diabetes mellitus, dyslipidaemia, hypertension, transient ischaemic attack, prescription of ACE inhibitor, anti-hypertensive, anti-diabetic, anti-platelet, beta-blocker, calcium channel blocker, non-steroidal anti-inflammatory drug, statin potency, diastolic and systolic blood pressure, glomerular filtration rate, total cholesterol.
Reference category: Normal weight patients with a BMI of 18.5–24.9 kg/m2
When compared with normal BMI, underweight was associated with a higher risk of MACE [HR 1.12 (95% CI 1.05–1.21)], PVD [HR 1.91 (95% CI 1.14–3.19)], cardiovascular-related death [HR 1.53 (95% CI 1.34–1.75)], and all-cause mortality [HR 1.64 (95% CI 1.50–1.80)].
Individuals who were obese had a higher risk of subsequent heart failure [obesity Class I: HR 1.41 (95% CI 1.12–1.76); obesity Class II: HR 2.10 (95% CI 1.56–2.83); obesity class III: HR 1.97 (95% CI 1.23–3.17)] when compared with those with a normal BMI.
The association between BMI and MACE as well as all-cause mortality was non-linear as shown by the restricted cubic splines, Figure 2. The risk for both subsequent MACE and all-cause mortality outcomes were significantly higher at lower BMI and lower from BMI greater than 25 kg/m2.
Enlarge this image.Figure 2. (A,B) Restricted cubic splines for the association between body mass index (continuous variable) and outcomes. MACE, major adverse cardiovascular event.
In this prospective population-base cohort study of 30 702 patients with incident stroke followed for a median duration of 12.9 years, overweight or obesity was associated with a more favourable prognosis for subsequent MACE, PVD, cardiovascular mortality, and all-cause mortality, irrespective of sex, diabetes mellitus, smoking, or cancer at time of incident stroke.
After the first reports of the stroke–obesity paradox,22 several confirmatory reports were subsequently published.23 The stroke–obesity paradox comes in contrast to the well-established association between obesity and risk of cardiovascular disease in the general population.24 Different explanations were proposed to explain this paradoxical conclusion. It was suggested that this may simply represent an erroneous finding associated with methodology pitfalls like reverse causation, that is, low body weight may be an index for the presence of chronic diseases like cancer, malnutrition, infectious disease, smoking duration, and intensity, which in turn increase mortality.25 For example, in a NHANES analysis, the obesity paradox was present among persons with dysglycaemia, but was absent in the subgroup of never-smokers.26 To identify potential reverse causation in our analysis, we performed subgroup analyses in patients with and without diabetes mellitus, current smoking, and patients without cancer diagnosis at the time of incident stroke. In our cohort, diabetes mellitus was less prevalent while current smoking and cancer were more prevalent in underweight patients. The stroke–obesity paradox was present irrespective of diabetes mellitus, smoking, or cancer at time of incident stroke. Although these findings do not support the explanation of reverse causation, still it may be possible that this might have occurred by other chronic illnesses that we did not consider in our analysis.
Another suggested explanation for the stroke–obesity paradox was residual confounding.25 In our analysis, the results were adjusted for many prospectively registered patient characteristics like age, sex, socioeconomic status, comorbidities, and concurrent medication. We cannot exclude the possibility that additional unmeasured confounding bias might have been introduced, for example, comorbidities that are associated with cardiovascular outcomes, might have not been equally distributed among BMI strata. However, key comorbidities of cardiovascular risk are featured within the metabolic syndrome comprising hypertension, diabetes, hyperlipidaemia all well associated with excessive body weight. Those factors were well included in the multivariate adjusted assessments and—in accordance with common knowledge—a higher, not lower, prevalence of such comorbidities with higher body weight was observed in our study. Hence a higher risk profile of relevant cardiovascular risk factors may be concluded for patients with higher BMI.
Main strengths of this analysis can be seen in the large size of this prospective population-base cohort, the long duration of follow-up exceeding a decade, and the large number of outcome events. Moreover, to minimize the risk of bias due to residual confounding, the results were adjusted for a wide range of comorbidities and clinical covariates. Also, to identify potential reverse causal pathways, we performed subgroup analyses according to sex, diabetes, current smoking habit, and cancer (excluding those with a diagnosis) at the time of incident stroke. A limitation of the study was that BMI was the only marker of obesity that we analysed, as there were no available data about other anthropometric markers of obesity like waist-hip-ratio or waist circumference. Given that BMI is an imperfect marker of obesity, it would be interesting to see in other cohorts whether the obesity-paradox remains present when other markers of obesity are analysed. Moreover, combined models showed that within BMI groups, waist circumference can further stratify cardiovascular risk.27,28 Finally, our analysis was not designed to assess the effect of weight management in stroke survivors as there were no available data on change of weight during follow-up. Recently, an analysis in the ORIGIN dataset identified weight loss an independent risk factor for higher mortality compared to no weight loss.29
From the restricted cubic spline plots, 23 and 25 kg/m2 maybe better BMI cut-off points for increased or decreased risk of subsequent MACE and all-cause mortality outcomes respectively for this population-based study. These cut-offs will need to, however, be explored in other populations. It is important to note that the conclusions of this analysis as well as previous reports of the stroke–obesity paradox, should only be viewed as a putative association and should not be perceived as proof of causality. Therefore, no recommendations about weight management after stroke should be based on these conclusions. Ongoing randomized controlled trials might provide further evidence to guide weight management recommendations in stroke survivors. Semaglutide was recently associated with sustained, clinically relevant reduction in body weight30 and is currently assessed for the reduction of cardiovascular events in patients with overweight or obesity and prior cardiovascular disease including stroke.31
ConclusionsIn this prospective population-base cohort study of 30 702 patients with incident stroke followed for a median duration of 12.9 years, overweight or obesity was associated with a more favourable prognosis for subsequent MACE, PVD, and mortality, irrespective of sex, diabetes mellitus, smoking, or cancer at time of incident stroke.
Author ContributionsR. K. A. and G. N. were involved in the study conception. Analysis was performed by R. K. A. The manuscript was drafted by R. K. A. with support from G. N.
All authors reviewed and approved the final manuscript. RKA is the guarantor.
AcknowledgementsWe thank the practices that contributed to the CPRD GOLD. The authors of this manuscript certify that they comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle.32
Conflict of interestR. K. A. currently holds an NIHR-SPCR funded studentship (2018-2021). S. W. is currently an employee of Janssen R&D.
FundingR. K. A. is funded by a National Institute for Health Research School for Primary Care Research (NIHR SPCR) PhD studentship award. The views expressed are those of the authors and not necessarily those of the NIHR, the NHS, or the Department of Health and Social Care.
© 2021. This work is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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; Doehner, Wolfram 2 ; Iyen, Barbara 1 ; Weng, Stephen F 1 ; Qureshi, Nadeem 1 ; Ntaios, George 3 1 Primary Care Stratified Medicine, School of Medicine, University of Nottingham, Nottingham, UK
2 Berlin Institute of Health, Charité—Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany; Department of Internal Medicine and Cardiology (Virchow Klinikum), Charité Universitätsmedizin Berlin, and German Centre for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany; Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Berlin, Germany
3 Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece