Blood Pressure and Complications in Individuals with Type 2 Diabetes and No Previous Cardiovascular Disease. ID BMJ

1 Blood Pressure and Complications in Individuals with Type 2 Diabetes and No Previous Cardiovascular Disease. ID BMJ 2016.033440 Dear Editor, Editorial Committee and Reviewers Thank you for your appreciation of our study, and for allowing us to send you a revised version of our article! Below we address the comments raised by the committee and the reviewers and outline the related changes made to the paper. Overall, we agree with the committee s concern on making claims about treatment guidelines. We should leave that to those who are responsible for that process. The main message of our study is, in fact, to question the use of observational studies as supportive evidence against reducing systolic blood pressure to below 130 mm Hg. The word evidence was used by the authors of the 2013 guidelines from the European Societies of Cardiology and Hypertension. But we believe that it is necessary to use all available information from real life observational studies as one of several sources for defining best practice. We have tried to be cautious about drawing conclusions about treatment, which has been noted by reviewer 2. We have followed your recommendation to further tone down causal inference in our conclusions and made changes in the manuscript that further emphasize association rather than causal effect, as described in our reply. We believe that the ongoing debate about blood pressure in diabetes would benefit from this new data. As this is by far the largest study on the topic, our results will greatly expand available data for discussions in future revisions of treatment guidelines. Apart from this specific value we believe that there is a broad interest in the results since decisions on how to treat blood pressure in patients with diabetes is an important part of daily work for physicians in primary care and internal medicine. We hope that we have answered all comments and made the required changes and that you will find our study suitable for your journal. We would like to inform you that an abstract on our study have been accepted for presentation at the 52nd European Association of the Study of Diabetes Annual Meeting in Münich, September 15. The following day, one of the main sessions is entitled Blood pressure in diabetes How low to go. It is not unlikely that our study will receive attention in this context. We therefore ask whether this presentation is in line with your peer review process? If not, we will of course adapt to any embargo policies that The British Medical Journal might have. Or would it perhaps be possible to coordinate a potential publishing of the article with this major international conference? Yours sincerely, Samuel Adamsson Eryd On behalf of the authors

2 Comments from the committee The committee was interested in the topic of your research. We thought this was a large and well conducted study of the impact of different blood pressure cut-offs on various cardiovascular outcomes. The following concerns were mentioned: The committee shared the reviewers concerns. The group with the lowest blood pressure had the highest total mortality so those who died of non-cvd causes (the majority of deaths) were not available to have a CVD event. Reply: Competing risks certainly affects the crude number of observed events as patients who die can t contribute with other events beyond that. In the analysis we have treated death as a censoring event which essentially means that the Kaplan-Meier estimates of survival curves for the other events represents the curves we would see in the absence of deaths. This relies on an assumption of censoring being non informative which may not be entirely fulfilled in some cases as patients who for example die from CV related causes (fatal MI, CHD and CVD) may have an elevated risk of nonfatal CV events compared to other patients had they not died. In the present study, only a relatively limited number of patients die from CV related causes and even if this would constitute an informative censoring this would have limited impact on the results. The assumption that censoring due to death from causes other than CV related is non-informative may have a better chance of holding, and this constitutes the majority of censorings due to death. While the impact of informative censoring could partly be explored using inverse probability of censoring weighting, this both adds considerable complexity to the already complex analysis and would need data on predictors of censoring to be available shortly prior to censoring for all patients and also that we could correctly model the censoring mechanism. We believe that this would not add any further value to the paper. The committee thought it was poorly described in places, and comparison of patients without and with pre-existing disease hard to follow, with the unselected group described only in the supplementary tables. Reply: The pre-defined objective was to study patients who were without previous cardiovascular disease. We realized, however, that readers might be interested in making comparisons between those with and without previous disease, and therefore added a supplemental table describing the baseline characteristics of a population including individuals with previous disease. The additional table was intentionally not placed in the main manuscript since we thought it might distract focus from the actual population being studied, namely those who were without previous diseases. To clarify the description of the study population we have changed the title of Table 1 from Baseline characteristics of subjects with various systolic blood pressure levels. Individuals with previous disease excluded and instead write Baseline characteristics of subjects with various systolic blood pressure levels. Inclusion criteria of the study population is well described in the text and figure 1. We have also changed the title of Table S1 from study population including individuals with previous disease to total population including those with previous disease. If the BMJ desires, we can easily insert this additional table in the main manuscript to facilitate comparison between the study population with and without those with previous disease.

3 The committee thought you might consider to tone down causal inference (conclusions in the abstract and the "what this adds") Reply: Thank you for your suggestion! We have modified our conclusions in an attempt to tone down causal inference. Previously we wrote: Lower systolic blood pressure than currently recommended can be beneficial for patients with type 2 diabetes. The association between low blood pressure and increased mortality is conceivably due to concomitant disease rather than antihypertensive treatment. Now we write: Lower systolic blood pressure than currently recommended is associated with significantly lower risk of cardiovascular events in patients with type 2 diabetes. The association between low blood pressure and increased mortality may be due to concomitant disease rather than antihypertensive treatment. Please word the objectives of the paper in the abstract more clearly. Reply: The objectives in the abstract have been modified to make it clearer: Objectives To compare the risk associated with a systolic blood pressure that meets current recommendations (i.e. below 140 mmhg) with the risk of lower levels in patients who have type 2 diabetes and no previous cardiovascular disease. The committee was slightly confused about the actual question being studied. You talk about the effect of BP treatment but in effect you are looking at the association of BP levels and outcomes. Reply: The main reason for conducting this study was a concern about recently changed treatment recommendations allowing a higher blood pressure. These changes are to a great extent based on findings from observational studies where conclusions have been drawn about treatment to low levels and associations have been referred to as evidence for a cause - effect relationship. The observational design of our study does not allow conclusions about blood pressure levels as an effect of antihypertensive treatment. We are only able to estimate the risk associated with having a certain systolic blood pressure, regardless of this being due to treatment or any other factor. As we have stated in the discussions section, page 17: We believe that caution should be exercised when using observational studies to draw conclusions about recommended treatment goals for blood pressure among high-risk patients. Uncertainty will always exist as to whether blood pressure is an effect of treatment or a disease that cannot be controlled for. As a consequence, we are cautious in our conclusions when we state that Lower systolic blood pressure than currently recommended is associated with significantly lower risk of cardiovascular events in patients with type 2 diabetes. We deliberately avoid to state whether these lower blood pressure levels should be achieved by antihypertensive treatment or other means. Since the recommended blood pressure targets were changed from below 130 mmhg to below 140 mmhg, we predefined the group with blood pressure between 130 and 140 mmhg as reference group when comparing the risk of having other blood pressure levels. In summary, our main objective was to compare the risk with a systolic blood pressure below 140 mmhg with the risk of lower levels. Our conclusion was that having lower levels is associated with significantly lower risk of cardiovascular events. We leave it to professional societies to decide whether the results will influence any revisions of current guidelines. We believe, however, that our study adds new and important information to the ongoing debate about the J- curve phenomenon and blood pressure targets.

4 You state that your hypothesis is that "the J-curve phenomenon (association of BP and bad outcomes in DM patients) is due to concomitant comorbidities, we examined the predictive value of systolic blood pressure at baseline on future cardiovascular events among patients with type 2 diabetes after excluding those with a history of cardiovascular or other major disease. In addition, we employed several methods to minimize uncontrolled confounding by other risk factors." To test the hypothesis you take a cohort without significant CV comorbidities at baseline, group them according to baseline BP levels and then see if overtime they develop bad outcomes. You conclude that the hypothesis is correct because you do not observe the J-curve phenomenon. In this group the association of BP and bad outcomes is linear. The aim was to compare the risk associated with a systolic blood pressure that meets current recommendations with the risk of lower levels in patients who have type 2 diabetes and no previous cardiovascular disease. In our opinion, it is more difficult to interpret the results when you make claims about treatment guidelines because we do not know to what extent the patients were being treated to meet a guideline goal. Did guidelines change during the time patients in the analysis were entered in the database (2006-2012)? Were patients being aggressively managed to meet the goal at baseline (i.e. entry into the database?) Did treatment intensity change over time for each patient? Reply: It is true that we are unable to know to what extent the patients were treated to meet the guideline goal and it is possible that some patients were aggressively managed to meet the goal at baseline. However, as we state in the discussion section: we included only patients with diabetes duration 1 year, which ensured adequate monitoring and treatment prior to baseline. Unfortunately, it is not possible to adjust for different intensity in antihypertensive treatment. The ideal situation would be to compare patients with low blood pressure due to intense treatment with patients with the same blood pressure but with low intensity treatment. This is, however, not possible due to confounding by indication for the drugs. We show in our study that treatment with several specific drugs is associated with a worse prognosis. Drugs such as β-blockers, loop-diuretics, spironolactone and thiazides are clearly used for other indications than hypertension. Hence, an important observation from our study is that prescription data can be used as a tool to adjust for comorbidity in observational studies. As discussed in our previous comment, we do not know for certain whether the observed blood pressure is due to treatment, concomitant disease or any other confounding factor. This is why we are only able to draw conclusions about the risk of having a certain blood pressure level, in contrast to being treated to a certain blood pressure level. In Sweden, the recommended blood pressure target in diabetes follow international guidelines and was unchanged between 1999 and 2014. It is possible that treatment intensity changed over time for each patient. These changes are often driven by risk factors and thus confounded by these. The only way to adjust for this would be marginal structural models, which would make the analysis very complex and difficult to interpret. This method also requires regular visits with complete data which is not the nature of our data. Our study design with long-term follow-up after careful baseline characterization of the patients is simple and straightforward. There are, however, certain limitations with this design which we have already declared in the discussion section, page 17: A decline in blood pressure during follow-up can be caused by comorbidity, changes in treatment or lifestyle, or a disease that is not easy to control for. Relying on a single measurement is likely to introduce a regression dilution effect due to the variability in blood pressure over time. This might lead to an attenuation of the relationship between blood pressure and outcome. We are not sure you can safely make claims about treatment guidelines. All we can safely observe is the effect of BP at one point in time. We cannot assume that a BP level at baseline is the

5 same as the goal BP level. We have concerns that you address the hypothesis but do not fulfil your aim. Reply: We agree that we cannot make claims about treatment guidelines, as discussed in our previous comments. But the current guidelines, both the European and from the American Diabetes Association (ADA), are derived from studies on non-diabetic patients, inconclusive trials, several observational studies and some, partly overlapping, meta-analyses of all these data. We therefore feel that there is an urgent need to provide new data to the ongoing discussion. We believe that our data are specifically relevant as it covers almost a whole nation and is obtained from day-to-day clinical practice. In the absence of large controlled trials in diabetes, all available information should be used to create a consensus about what to recommend. In the absence of new trials in diabetes, we have seen that the 2016 European guidelines (Piepoli et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice Eur Heart J May 23 2016) have changed slightly, recommending systolic blood pressure in type 2 diabetes to be less than 130 mm Hg in selected patients which might be quite confusing to the practicing physician when the blood pressure target was raised to <140 mm Hg just a few years ago. In the introduction section, pages 6-7 we state that our hypothesis is that the J-curve phenomenon is due to concomitant comorbidities We also state that The aim of the study was to compare the risk associated with a systolic blood pressure that meets current recommendations with the risk of lower levels in patients who have type 2 diabetes and no previous cardiovascular disease. In our opinion, we have gone farther than previous studies in adjusting for comorbidity by: Examining a large number of patients from a nationwide diabetes register including only patients with diabetes duration 1 year excluding the oldest patients excluding individuals with previous major disease using drug prescription data as markers for comorbidity adjusting for other potential confounding factors using validated nationwide registers as endpoint sources We hereby believe that we have been able to show that: Lower systolic blood pressure than currently recommended is associated with significantly lower risk of cardiovascular events in patients with type 2 diabetes with no previous cardiovascular disease. Adjustment for comorbidity, mainly by excluding patients with previous cardiovascular disease, eliminates the J-curve relationship between blood pressure and stroke, myocardial infarction and coronary heart disease. How many patients were in the NDR database but without available BP levels? Reply: In total, 431 892 individuals with type 2 diabetes were included in the NDR between 2006 and 2012. Of those, 12 394 individuals (2.9%) were missing information on systolic or diastolic blood pressure. Could baseline BP be treated as a continuous variable? Reply: Yes, it would be possible to treat baseline blood pressure as a continuous variable but it is also clear that a simple linear model with proportional hazards would not fit the data very well. This could be avoided by the use of spline functions but by doing that, it would become much harder to

6 communicate the results. Furthermore, the reported blood pressures are often rounded to the nearest 5 or 10 mmhg, so the data may not be truly continuous. The predefined objective of our study was to compare the risk between different levels of blood pressure, mainly focusing on the old and new guideline targets (<130 mmhg vs <140 mmhg). We agree that it would be interesting to also estimate the optimal blood pressure, but we think that this research question would require a large amount of additional analyses, and would therefore be suitable for a separate article. Page 12. The causes of death in the various BP groups appear in the Supplement need to add Table S3. Reply: This has been corrected. Next paragraph should refer to _nonfatal_ CVD. Reply: This has been corrected.

7 Comments from the external peer reviewers Reviewer: 1 This looks like a well balanced review. The authors have excluded people with previous heart conditions, so the relationship between blood pressure and death in Type 2 diabetics seems to be measured more accurately This paper gives useful information which can guide short-term treatment guidelines Reply: Thank you for your appreciation of our study!

8 Reviewer: 2 Comments: This is an excellent and clearly written paper. It is original and makes a significant and highly clinically relevant new contribution to the literature on lower blood pressure levels and CVD risk in diabetics. There remains significant controversy about the possibility of a J-shaped relationship between BP and CVD which has impacted on international guideline recommendations on blood pressure lowering treatment goals and this study is by far the largest investigation ever done on the topic. The study is observational rather than an RCT and the authors are appropriately cautious about drawing conclusions about treatment based on a non-randomised study. However the authors are able to undertake analyses with appropriate exclusions that no other study has been big enough to allow and the sensitivity analyses including and excluding people with prior CVD provides compelling, albeit indirect evidence that the apparent J-shaped association between BP and CVD risk is an artifact due to reverse causality. The study is hard to fault and from the text and the references it is clear that the authors have a lot of experience in analysing (and publishing) these large-scale linked national datasets. One issue, I would like the authors to comment on is the possibility of a competing risk, which I couldn't find any mention of in the Discussion. The group with the lowest blood pressure had the highest total mortality so those who died of non-cvd causes (the majority of deaths) were not available to have a CVD event. I am sure the authors have considered this issue and I may have missed it. If not, could the authors please discuss this. Reply: Our answer to this comment is given under the committees comments. I note that the authors chose not to exclude those on loop diuretics and other drugs commonly used in the management of CVD. I would probably have excluded them, but the authors have adjusted for these groups in the analyses. I am not suggesting they re-do the analyses, which would be a huge undertaking, and the authors comment on this issue in the Discussion section. My guess is that the J-shaped relationship with BP and CHF might disappear if they had been excluded. Reply: Excluding patients on loop diuretics from the analysis gives almost identical results as adjustment for loop diuretics statistically. However, we have shown that spironolactone and other more common antihypertensive drugs (β-blockers, thiazide-diuretics, calcium antagonists and cardiovascular drugs that cannot be classified as antihypertensive drugs) are also associated with an increased cardiovascular risk. An explanation for β-blockers for example, is that both heart failure and angina are potential indications for treatment apart from hypertension. Patients who are treated with all these common agents cannot be excluded. We have shown that, from a methodological point of view, medications should instead be used as covariates. We are not aware of previous studies that have used this important information for adjustment for comorbidity. One minor issue, the mean SBP in each of the BP categories are skewed to the lower end of the range. For example the 110-119mmHg mean is 113mmHg. This is because GPs round the BP measurement. We have published data showing GPs tend to round SBP levels to the nearest 10mmHg which would account for this finding. It would be worth mentioning this issue in the text

9 because I am sure the true mean SBP in each category is closer to the middle value than is reported. Reply: Thank you for your valuable comment! We agree that the explanation to the observed skewness is due to rounding to the nearest 10 mmhg. This digit preference have previously been described in other Swedish primary care cohorts. (Qvarnstrom M, Wettermark B, Ljungman C, Zarrinkoub R, Hasselstrom J, Manhem K, et al. Antihypertensive treatment and control in a large primary care population of 21 167 patients. J Hum Hypertens 2011; 25:484-491. Hasselstrom J, Zarrinkoub R, Holmquist C, Hjerpe P, Ljungman C, Qvarnstrom M, et al. The Swedish Primary Care Cardiovascular Database (SPCCD): 74 751 hypertensive primary care patients. Blood Press 2014; 23:116-125.) We have added comments on this in the result section, page 12, and in the discussion section, page 17.

10 Reviewer: 3 Comments: This very important paper describes the relationships between baseline BP and the subsequent risk of a range of important CV outcomes in people with diabetes. It is particularly important as this population has been the subject of substantial debate, with many people suggesting that BP lowering to below current targets may be harmful. These comments have been based on observational studies, including those from the registry used for this paper, which are prone to confounding and are therefore of uncertain reliability. The present analysis included a very large number of participants, allowing the authors to exclude those with previous CV disease, who are much more common at lower BP levels and are the likely source of residual confounding. When this was done, the relationship between BP and outcomes became linear for the vast majority of outcomes assessed, providing strong evidence in support of the likelihood of previous J-curve relationships being due to residual confounding, and the concept that BP levels below 120 are likely to be beneficial. There were only 2 outcomes for which a linear relationship was not clearly observed after excluding these individuals (heart failure and total mortality) but even these relationships were substantially attenuated after excluding existing CV disease, suggesting further unmeasured confounding is contributing. Furthermore, the apparently higher rates of death in the lowest BP group were due to factors that it is difficult to relate to BP lowering, and this population had the lowest doses of BP drugs. Taken together, these results strongly support BP lowering below current targets in diabetes, and are consistent with the existing but underpowered randomised trials. I think the description of previous studies in the discussion section could be shortened and the results summarised more succinctly. I also think it would be of interest to examine the relationship between BP levels and renal events if this is available. Reply: Thank you for your appreciation of our study and for your valuable comments! We believe that the detailed discussion on previous studies is of importance since we, point by point, try to explain why many of these studies, in our opinion, have been granted much weight when writing the guidelines. We agree that it would be interesting to examine the relationship between blood pressure levels and renal events. However, as this question was not included in our pre-defined objectives, we do not have access to the required data to perform these analyses for the moment. We estimate that it would take too much time to construct additional datasets to be able to add this question to the revised manuscript. We believe that this question instead may be suitable for a future follow-up study. Finally, studies showing an increased CV risk at lower BP levels have been published and promoted widely given their controversial nature. This higher quality and therefore more important study deserves the same airtime. Reply: Thank you for this comment!