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Multimorbidity of cardiometabolic diseases: prevalence and risk for mortality from one million Chinese adults in a longitudinal cohort study

Objectives The evolution of multimorbidity describes the continuum from a healthy status to the development of a single disease and further progression to multimorbidity with additional diseases. We investigated the evolution of cardiometabolic multimorbidity and risk for mortality in a Chinese population. Design Longitudinal cohort study using data from the CHinese Electronic health Records Research in Yinzhou (CHERRY) study, with 5.43 million person–years follow-up (median 5.16 years). Participants Data for 1 038 704 adults (total 22 750 deaths) were analysed. Exposure Cardiometabolic multimorbidity was defined as ever being diagnosed with two or more of three diseases: hypertension, diabetes and cardiovascular disease (CVD). Primary and secondary outcome measures Age-adjusted and sex-adjusted HRs were calculated for all-cause mortality. Results The cardiometabolic disease status of 105 209 (10.1%) individuals changed during the follow-up. The prevalence of cardiometabolic multimorbidity increased from 2.41% (95% CI: 2.38% to 2.44%) to 5.94% (95% CI: 5.90% to 5.99%). Baseline multimorbidity status showed the HR (95% CI) was 1.37 (1.33 to 1.42) in those with one disease, 1.71 (1.64 to 1.79) in those with two diseases and 2.22 (2.00 to 2.46) in those with three diseases. The highest HRs were observed for CVD only (3.31, 95% CI: 3.05 to 3.59) or diabetes and CVD (3.12, 95% CI: 2.37 to 4.11). Those with hypertension only had the lowest HR (1.26, 95% CI: 1.22 to 1.30). Longitudinal data showed the HRs (95% CI) in patients with one, two and three diseases were 1.36 (1.32 to 1.41), 2.03 (1.96 to 2.10) and 2.16 (2.05 to 2.29), respectively. Conclusions The prevalence of cardiometabolic multimorbidity in a general Chinese population increased more than doubled over 5 years, indicating rapid evolution of cardiometabolic multimorbidity. A history of CVD dominates the risk for mortality. A complementary strategy for primary and secondary prevention of cardiometabolic diseases is needed in China.


Reviewer 1
Overview: This paper aimed to estimate the prevalence of cardiometabolic comorbidities and investigate the progress of multimorbidity in a study from a developed region in east China through the linkage with all available health information systems for the local residents. The data quality for those health information systems may need to be more explained and clarified. Although large sample size with rich information included and detailed data presented, given only one developed area covered, the prevalence and trends of cardiometabolic multimorbidity presented from this study may not applicable to other places and certainly not be representable for Chinese population. This significantly reduced the scientific value of the paper and it would be more valuable if including analyses on the associations between various risk factors and the cardiometabolic multimorbidities. Response: We thank the Reviewer for this suggestion. Detailed information related to the data quality for the health information systems was described previously [BMJ Open 2018;8(2):e01969]. We addressed the relatively important information, especially regarding the exposure and the outcomes, in the Method Section. E.g. "Diagnosis of these cardiometabolic diseases (and date of diagnosis) were obtained from multiple sources: diseases management database (primary care), EMRs (hospital care), and disease surveillance database (disease registry). Date in disease surveillance was considered the gold standard for the date of diagnosis." (page 7, line 86-89). "Death was confirmed by the death certificate in the health information system, as previously described.[Scientific reports 2016;6:31609] Diseases and deaths were classified according to the International Classification of Diseases, Tenth Revision (ICD-10)." (page 7, line 98-100). As stated in the protocol [BMJ Open 2018; 8(2):e019698], data completeness varies in CHERRY. We have now provided number and percentages of participants having at least one measurement of the covariates in this study in the Result Section (page 9, line 146-149).
We agree that CHERRY study is based on regional population in the developed area of China and the prevalence of cardiometabolic multimorbidity may not nationally representative. We have stated this in the study limitation (page 15, line 325-326). However, as mentioned in the Comment & Response of a recent JAMA paper [JAMA. 2017;317(16):1689], even the most famous population-based cohort study with half a million Chinese participants -the China Kadoorie Biobank (CKB) -was not designed to be nationally representative due to the diversity of populations in China. Moreover, we believe that the rapid evolution of cardiometabolic multimorbidity, the association with mortality using longitudinal information of disease status, and therefore the need for a complementary strategy for primary and secondary prevention of cardiometabolic disease found in our study should be not only happened in this region but also happened in other places in China sooner or later in China. In this sense, our study may still have important implications.
As suggested, we now explore the extent to which conventional factors (BMI, smoking, education level and location) could explain the associations between cardiometabolic multimorbidity and mortality. HRs adjusted for these additional factors were calculated in people with full information on above factors. Results were shown in the new eTable 6. And we stated in the Results Section (page 11, line 214-217) "Broadly similar association were observed among the 788,703 participants with full information on additional risk factors (BMI, smoking, education level and location) after further adjustment for those factors (Supplementary eTable 6)."

Reviewer 2
Overview: Zhang et al analyzed big data from 1,038,704 Chinese individuals from the CHERRY database. There were 22,750 deaths after a follow-up of 5.16 years. They showed that during followup the prevalence of multimorbidity (hypertension, diabetes and CVD) more than doubled, with CVD contributing mostly to the risk of death. The study is of interest, the manuscript is well written, the analysis is sound and the conclusions are justified by the results. Comments: 1.The results are somehow anticipated. It is known from previous studies that the prevalence of CVD and CVD risk factors is increasing in the Chinese population and that history of CVD is associated with increased risk of CVD and total death. Response: We thank for the reviewer's comment. We agree that it is widely known that prevalence of individual disease in China is increasing. However, we believe that the key findings from our study using longitudinal information of the disease status, i.e. the rapid evolution of cardiometabolic multimorbidity and their associations with mortality, were still novel, especially in the Chinese population. History of CVD is associated with deaths. However, evidence on history of CVD with or without other accompanied cardiometabolic diseases was limited.
2.A lot of information is missing: type of CVD, risk factor control, medications, change of BMI, change of smoking status, etc. Response: We thank for the reviewer's comment. We also now stated in the Results Section (page 9, line 149-154) that "The mean±SD age at baseline was 42.5±14.8 years (51.4% women). The mean BMI was 22.5±2.5 kg/m2. According to Asian-specific BMI cutoffs, 24.1% were overweight (23-25 kg/m2) and 13.9% were obese (BMI ≥25 kg/m2). At the last visit during follow-up, the mean BMI was 22.5±2.6 kg/m2; 23.9% were overweight and 14.8% were obese. From baseline to the last visit, the proportion of former smokers changed from 2.2% to 2.4% and the proportion of current smokers changed from 18.9% to 20.0%." Regarding the history of CVD, we stated in page 10, line 170-173 "50,458 (94.4%) of all 53,473 patients have information on type of CVD. Within these patients, 26,282 had CHD, 23,538 had cerebrovascular diseases and 638 had both CHD and cerebrovascular diseases respectively. " Moreover, we now explore the extent to which conventional factors (BMI, smoking, education level and location) could explain the associations between cardiometabolic multimorbidity and mortality. HRs adjusted for these additional factors were calculated in people with full information on above factors. Results were shown in the new eTable 6. And we stated in the Results Section (page 11, line 214-217) Broadly similar association were observed among the 788,703 participants with full information on additional risk factors (BMI, smoking, education level and location) after further adjustment for those factors (Supplementary eTable 6)."

Reviewer 3
Overview: Cardiometabolic comorbidity data are critical developing appropriate interventions. The study described prevalence and hazard ratios of a population in an urban area using data from medical records. It gives insights on the evolution of cardiometabolic conditions.

Comments:
Page 2: Abstract: Results: Lines 37-40 and 46 -50 describe the same results? Response: Both lines 37-40 and 46 -50 in Results described the HRs of cardiometabolic comorbidity for mortality. However, lines 37-40 reported HRs for mortality using baseline status of multimorbidity. Line 46-50 reported HRs using longitudinal status of multimorbidity (i.e. with repeat information on multimorbidity).
Page 3: Abstract: Last sentence: A complementary strategy of what is needed in the Chinese population?
Page 10: Re-write the sentence, Lines 165-166. Not advisable to start a sentence with a number. Response: We have re-phrased the sentence as "Among 927,946 participants without any diagnosed cardiometabolic disease at baseline, 73,302 (7.9%) developed one or more cardiometabolic diseases, of which 47,903 (5.2%) developed hypertension only." (page 10, line 179-181) Page 11: Line 217 rather than investigated write described…… Response: Revised as suggested.

Discussion
Page 12: Line 224-226. How do these results compare with other studies? Response: We thank the Reviewer for this suggestion. We compared these results in the discussion section (page 13, Line 252-272). We stated that "limited publications are available on the epidemiology of multimorbidity in a general Chinese population. A systematic review of nine published studies in China reported the prevalence of multimorbidity among those aged ≥60 years ranged from 6.4% (95% CI: 5.1-8.0) to 76.5% (95% CI: 73.6-79.2). [Geriatr Gerontol Int. 2015;15(1):1-10] However, most of the included studies considered morbidities in addition to cardiometabolic diseases and only reported prevalence based on number of diseases, which prevented us making direct comparisons. … Compared with developed countries, about 0.52% of participants aged ≥40 years (mean age 53.6±11.6 years) in our cohort had multimorbidity of diabetes and CVD (regardless of hypertension, 0.47%+0.05%=0.52%, eTable 1), which was similar as 0.7% reported in the UK Biobank (mean age 56.7±8.1 years). [JAMA 2015;314(1):52-60] About 1.3% of participants aged ≥60 years in our cohort had multimorbidity of diabetes and CVD, compared with 5% from a recent US survey involving people aged ≥65 years. [JAMA. 2007;298:1160-2] Previous studies in China and other countries have also shown that the prevalence of multimorbidity increased significantly with age. [BMC Med. 2014;12:188;Lancet. 2012;380:37-43] Older adults should therefore be a major population targeted for cardiometabolic multimorbidity prevention, considering population aging." Page 13: Lines 249 -260. How do these results compare with other studies? Response: We thank the Reviewer for this suggestion. Regarding the association of multimorbidity with mortality, we compared results with other studies in page 14 line 306-317. Though our results may suggest that associations between mortality and hypertension, diabetes, and cardiovascular disease were additive in this population, we found significant heterogeneities within each disease combination. In contrast, The results from the ERFC involving 91 cohort studies (mainly Western populations) estimated the HR for mortality was about 2 in participants with one cardiometabolic multimorbidity condition (type 2 diabetes, coronary heart disease, or stroke) and the association was multiplicative. However, they did not include hypertension and only used baseline disease status. We observed a broadly similar HR for patients with diabetes. Detailed discussion was shown in page 14 line 306-317.
Page 14: Line 290-293: Is the conclusion from this study which is in an urban setting or from another study. A reference is needed to compare with studies in rural settings. Response: This conclusion is from this study. Although Yinzhou District is a developed area in China, it has towns/villages located in the urban and rural areas respectively, which allowed us to investigate this heterogeneity. The conclusion were made according to the finding in the Results Section (page 11, line 199-201), where we illustrated that "HRs for cardiometabolic comorbidity were … higher in those living in urban areas (Supplementary eTable 4)." eTable 3: Correct lase in the sentence: "Number of disorders at lase visit" Response: Revised as suggested