Blood pressure and complications in individuals with type 2 diabetes and no previous cardiovascular disease:
national population based cohort study

From BMJ


Nyhetsinfo

Kommentar nederst från BT-expert prof Peter M Nilsson, Malmö

www red DiabetologNytt

ABSTRACT

Samuel Adamsson Eryd,1,2,3 So a Gudbjörnsdottir,1,2 Karin Manhem,2 Annika Rosengren,2,3 Ann-Marie Svensson,1 Mervete Mi araj,1 Stefan Franzén,1 Sta an Björck1

OBJECTIVES

To compare the risk associated with systolic blood pressure that meets current recommendations (that is, below 140 mm Hg) with the risk associated with lower levels in patients who have type 2 diabetes and no previous cardiovascular disease.

DESIGN

Population based cohort study with nationwide clinical registries, 2006-12. The mean follow-up was 5.0 years.

SETTING

861 Swedish primary care units and hospital outpatient clinics.

PARTICIPANTS

187 106 patients registered in the Swedish national diabetes register who had had type 2 diabetes for at least a year, age 75 or younger, and with no previous cardiovascular or other major disease.

MAIN OUTCOME MEASURES

Clinical events were obtained from the hospital discharge and death registers with respect to acute myocardial infarction, stroke, a composite of acute myocardial infarction and stroke (cardiovascular disease), coronary heart disease, heart failure, and total mortality. Hazard ratios were estimated for di erent levels of baseline systolic blood pressure with clinical characteristics and drug prescription data as covariates.

RESULTS

The group with the lowest systolic blood pressure (110-119 mm Hg) had a signi cantly lower risk of

non-fatal acute myocardial infarction (adjusted hazard ratio 0.76, 95% con dence interval 0.64 to 0.91; P=0.003), total acute myocardial infarction (0.85, 0.72 to 0.99; P=0.04), non-fatal cardiovascular disease (0.82, 0.72 to 0.93; P=0.002), total cardiovascular disease (0.88, 0.79 to 0.99; P=0.04), and non-fatal coronary heart disease (0.88, 0.78 to 0.99; P=0.03) compared with the reference group (130-139 mm Hg). There was no indication of a J shaped relation between systolic blood pressure and the endpoints, with the exception of heart failure and total mortality.

CONCLUSIONS

Lower systolic blood pressure than currently recommended is associated with signi cantly lower risk of cardiovascular events in patients with type 2 diabetes. The association between low blood pressure and increased mortality could be due to concomitant disease rather than antihypertensive treatment. 

Introduction

Several major hypertension guidelines have recently changed their recommended goal for systolic blood pressure in patients with diabetes.1-3 Instead of aiming for below 130 mm Hg, the current guidelines recom- mend below 140 mm Hg. The consequences of the changed guidelines are unknown.

Over the past 16 years, during which the previous rec- ommendations were in e ect, the average systolic blood pressure among Swedish primary care patients with type 2 diabetes has decreased by 15 mm Hg. In 2015, the average blood pressure of 300000 patients was 135/76 mm Hg.4 The overall excess risk of death among individuals with type 2 diabetes has fallen to a historically low 15%.5

The reason for the new blood pressure target was the lack of randomised studies with conclusive results to support the goal of below 130 mm Hg, together with information based on post hoc analyses of clinical trials and register studies.1 These observational studies have usually shown a J shaped relation between blood pres- sure and cardiovascular events, with an increased risk at the highest and lowest levels.

The relevance of this J curve phenomenon has been called into question given that observational studies of clinical trial data could be awed by uncontrolled con- founding—that is, major disease is a possible cause of low blood pressure.6 If so, the problem is exacerbated by the tendency of clinical trials to focus on patients at advanced stages of disease and an increased risk of car- diovascular events as a means of ensuring su cient statistical power and reasonable study size.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Hypertension is one of the major risk factors for cardiovascular disease, and the management of hypertension is a high priority in the treatment of type 2 diabetes Recent hypertension guidelines have raised the target blood pressure for patients with diabetes from below 130 mm Hg to below 140 mm Hg because of a lack of conclusive randomised studies to support the lower goal, together with observational studies showing a J shaped relation between blood pressure and complications

WHAT THIS STUDY ADDS

Lower systolic blood pressure than currently recommended is associated with a signi cantly lower risk of cardiovascular events in patients with type 2 diabetes Adjustment for comorbidity, mainly by exclusion of patients with previous cardiovascular disease, eliminates the J curve relation between blood pressure and stroke, myocardial infarction, and coronary heart disease

The association between low blood pressure and increased mortality might be caused by concomitant disease rather than antihypertensive treatment

the bmj | BMJ 2016;354:i4070 | doi: 10.1136/bmj.i4070

Earlier studies based on the Swedish national diabetes register have also shown a tendency toward a J shaped relation between blood pressure and cardio- vascular disease in patients with type 2 diabetes. To ensure statistical signi cance, however, they included patients with previous cardiovascular disease. The reg- ister has grown substantially over the past decade, enabling appropriate selection of patients while still enabling su cient statistical power. To test our hypoth- esis that the J curve phenomenon is caused by concom- itant comorbidities, we examined the predictive value of systolic blood pressure at baseline for future cardio- vascular events among patients with type 2 diabetes after excluding those with a history of cardiovascular or other major disease. In addition, we used several methods to minimise uncontrolled confounding by other risk factors.

We aimed to compare the risk associated with a systolic blood pressure that meets current recommenda- tions with the risk of lower levels in patients who have type 2 diabetes and no previous cardiovascular disease.  

Discussion

This observational study of 187106 individuals with type 2 diabetes who did not have previous cardiovascu- lar disease shows that those with systolic blood pres- sure lower than 120 mm Hg have a signi cantly lower long term risk of myocardial infarction, cardiovascular disease, and coronary heart disease than those with a systolic blood pressure of 130-139 mm Hg, which would meet the currently recommended goal.

Furthermore, we found no J shaped relation between systolic blood pressure and stroke, myocardial infarc- tion, or coronary heart disease. We did, however, nd a J shaped relation for both all cause mortality and heart 

failure. A secondary analysis showed that systolic blood pressure also exhibited a more or less a J shaped rela- tion with all studied outcomes when we included patients with previous disease. Accordingly, the J curve relation observed in real world data depends on patient selection and the extent to which comorbidity can be adjusted for.

The new goal of below 140 mm Hg for systolic blood pressure in patients with diabetes is based on several mainly observational studies.1-3 The European guide- lines highlight four studies as providing “supportive evidence” against reducing systolic blood pressure to below 130 mm Hg. The most often cited study is the ran- domised Action to Control Cardiovascular Risk in Dia- betes blood pressure trial (ACCORD BP), which failed to show any signi cant bene t for the primary composite cardiovascular endpoint from intensive antihyperten- sive treatment.12 The trial did, however, show that the risk of stroke was reduced by 40% in the group assigned to systolic blood pressure below 120 mm Hg. The rate of cardiovascular events was only half of that which had been expected when the study size was planned. The next two studies were post hoc analyses of clinical trials showing a J shaped relation between blood pressure and prognosis. Post hoc analysis of data from the Ongo- ing Telmisartan alone and in combination with the Ramipril Global Endpoint Trial (ONTARGET) showed that neither myocardial infarction nor cardiovascular death was related to baseline systolic blood pressure.13 Based on a subgroup analysis of patients with low blood pressure who experienced a cardiovascular event, the authors concluded that a higher baseline risk, rather than excessive reduction of blood pressure, was a key determinant of the J curve phenomenon.

A post hoc analysis of data from the International Verapamil SR/Trandolapril Study (INVEST), a compari- son of a β blocker and calcium antagonist based antihy- pertensive treatment strategy, showed that patients with systolic blood pressure below 130 mm Hg did not experience any favourable e ect compared with those with blood pressure of 130-140 mm Hg. Thus, the authors proposed a treatment goal of 130-139 mm Hg.14 In this study, however, patients with systolic blood pressure below 130 mm Hg had the least antihyperten- sive treatment, measured both as the number and dose of drugs. The nding indicates that lower blood pres- sure was not a treatment e ect but might have been caused by other disease.

The fourth highlighted study, NDR-BP-II, was an observational study of 53 553 individuals with type 2 diabetes that found a J curved relation between blood pressure and several cardiovascular complications.15 The national diabetes register has, however, grown con- siderably in size over the past decade, enabling appro- priate selection of patients while still ensuring su cient statistical power, as shown in the present study. While previous studies based on the diabetes register have included patients with a history of cardiovascular dis- ease, we have shown here that excluding them elimi- nates the J curve phenomenon for several, but not all, endpoints. Simple adjustment for these comorbidities in the regression models, as in the NDR-BP-II study, was not su cient to eliminate the J curve. These ndings strengthen the hypothesis that the J curve phenomenon is caused by more patients with comorbidities in the lowest blood pressure groups.

The results of the Systolic Blood Pressure Interven- tion Trial (SPRINT) have reset the debate about optimal levels.16 The randomised design for two di erent blood pressure targets was similar to the ACCORD BP study, but more than twice as many patients were included. Patients with diabetes, however, were excluded. SPRINT showed that the treatment goal of below 120 mm Hg was associated with much better outcomes than below 140 mm Hg. As discussed in a recent edito- rial, these two studies exhibit many similarities and point to the same conclusion—that is, that more inten- sive antihypertensive treatment than the current recom- mendation provides additional protection from cardiovascular events.17

Several recent reviews and meta-analyses have sum- marised the literature but arrived at di erent conclu- sions regarding the benefits of antihypertensive treatment below 140 mm Hg.6 18-21 We analysed the risk related to systolic blood pressure at baseline, regardless of whether it was due to antihypertensive treatment or uncontrolled confounding (concomitant disease, etc). We tried to minimise uncontrolled confounding in sev- eral ways. Firstly, we included only patients who had had diabetes for a year or more, which ensured ade- quate monitoring and treatment before baseline. Like the ACCORD and NDR-BP-II studies, we had an upper age limit and excluded patients aged ≥76 to minimise the impact of concomitant disease. We also excluded those with previous coronary heart disease, stroke, atrial brillation, cancer, or BMI <18, as well as the few with systolic blood pressure below 110 mm Hg, which was outside of the scope of the study. In addition, we used drug prescription data as markers for comorbidity and treatment intensity. Finally, missing data were imputed to preserve study size and maximise statistical power.

By selecting patients without previous reports of car- diovascular disease, we eliminated the J curve relation between blood pressure and stroke, myocardial infarc- tion, and coronary heart disease. Of concern, however, is that our adjustments did not eliminate the J curve rela- tion with total mortality. Worth noting is that the group with the lowest blood pressure also received the least antihypertensive treatment. We cannot therefore draw any conclusions about harmful e ects of intensive anti- hypertensive treatment. Patients in the group with the lowest blood pressure who died also had indications of more serious conditions, including a high rate of smok- ing and treatment with loop diuretics, spironolactone, and drugs for heart disease. They also had the highest rates of mortality from infection; diseases of the ner- vous, respiratory, and digestive systems; and external causes. Thus, this group would seem to include patients with a favourable prognosis, as well as a subgroup with complications that led to a high mortality rate. As the ONTARGET study concluded, the high mortality is probably more associated with high baseline risk rather than excessive reduction in blood pressure.13

Controlled clinical trials have the advantage of well de ned endpoints that can be examined when they appear and assessed in accordance with strict criteria in a blinded fashion, while the endpoints in observational studies, such as ours, rely on endpoints with varying degrees of accuracy. Data on stroke and myocardial infarction from the hospital discharge register are highly reliable.11 These diagnoses are usually based on a clinical evaluation on acute admission to hospital, which is highly important for ensuing treatment. The situation for our other endpoints, including heart fail- ure and total mortality, is di erent. Completeness of reporting and the date of onset are uncertain for heart failure, angina pectoris, and certain other cardiovascu- lar diagnoses, given that primary care data are not included in the hospital discharge register. It is evident from the drug prescription data that some patients who do not have previous diagnoses of major diseases use drugs that are indicated for cardiovascular complica- tions (spironolactone, furosemide, etc, and possibly β blockers as well). For causes of death, cardiovascular endpoints often appear together with other potentially fatal diagnoses, such as cancer, infection, or psychiatric problems. The cause of death register includes all deaths, regardless of whether they occurred in hospital or elsewhere. Fewer than 20% of death certi cates are based on autopsy reports.22 Furthermore, considerable discrepancies have been reported between certi cates and hospital discharge records.22 We believe that this di erence in the accuracy of outcome measurements explains the fact that the almost linear relation between systolic blood pressure and risk for the most well de ned endpoints was attenuated when we added less accurate and fatal endpoints. The J shaped relation was pronounced when the outcome was based solely on mortality data.

 

KOMMENTAR 

prof Peter M. Nilsson, Malmö

Ny observationsstudie från NDR anger association mellan lägre systoliskt blodtryck och lägre kardiovaskulär risk - betydelse för guidelines?

I en ny stor och välgjord observationsstudie från NDR har en författargrupp undersökt samband mellan systoliskt blodtryck (SBT) och risk hos patienter med typ 2 diabetes utan tidigare känd kardiovaskulär komplikation [1].

Resultatet anger sammanfattningsvis att man kunnat se linjära förhållanden mellan SBT och risk så att lägre observerat SBT associeras med lägre kardiovaskulär risk över hela skalan ner till 110 mmHg på ett monotont sätt utan s.k. J-kurva.

Enda undantaget var en ökad mortalitet som sågs vid SBT <120 mmHg men här kan det finnas störfaktorer som ev. skulle kunna påverka sambandet.

Studien är mycket stor och baseras på uppföljning av baslinje-SBT värden hos 187.106 patienter fria från kända tidigare komplikationer. Detta är i hög grad förväntade resultat och konfirmerar fynd i en klassisk observationell UKPDS publikation, också i BMJ (men ej citerad), som i princip angav samma observationella fynd, dock utan överrisk för mortalitet i det lägre SBT intervallet [2].

Tolkningen blir sammantaget att patienter med lägre blodtryck löper lägre risker, och det är ju välkommet  - men ingen stor nyhet. Det som gjorts i den nya studien är att man justerat för en rad störfaktorer, inklusive data från Läkemedelsregistret. Problemet är dock att man i detta register inte kan identifiera på vilken indikation som kardiovaskulärt aktiva läkemedel har givits och detta vållar problem. Vad man skulle önska, och av betydelse för nya guidelines, är separata analyser för just behandlade hypertoniker med DM2, en uppgift som kan fås från NDR och som tidigare använts [3]. Man kan hoppas att författarna vill återkomma med en sådan mer fokuserad analys.


Man ser i Tabell 1 att antalet antihypertensiva läkemedel är lägre ju lägre blodtryck patienterna har. Inte förvånande, men det innebär att de patienter som befinner sig i de lägre blodtrycksgrupperna INTE har behandlats dit, utan istället har ett naturligt lägre tryck. Rimligen är det väl så att dessa patienter har ett friskare kärlsystem vilket leder till både lägre tryck och mindre risk för CVD. Analyserna baserat på enskilda läkemedelsgrupper anger en del överraskningar, t.ex. överrisker vid användande av CCB, vilket inte stöds av fynd i RCT. Här kan finnas störsamband, t.ex. att gamla rökare kan tänkas få lungneutrala CCB vilket därmed kan markera överrisker.

Vid EASD i Munchen kommer det att vara en debatt om resultaten i SPRINT-studien (utan diabetespatienter) och ifall man ev. skulle kunna extrapolera fynden i SPRINT till att även gälla patienter med typ 2 diabetes. Debatten äger rum fredag den 16/9 med start 12:15.


Peter M Nilsson
Malmö

Referenser:
1. Adamsson Eryd S, Gudbjörnsdottir S, Manhem K, Rosengren A, Svensson AM,Miftaraj M, Franzén S, Björck S. Blood pressure and complications in individualswith type 2 diabetes and no previous cardiovascular disease: national populationbased cohort study. BMJ. 2016 Aug 4;354:i4070.
2. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD,Turner RC, Holman RR. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospectiveobservational study. BMJ. 2000 Aug 12;321(7258):412-9.
3. Cederholm J, Gudbjörnsdottir S, Eliasson B, Zethelius B, Eeg-Olofsson K,Nilsson PM; NDR. Blood pressure and risk of cardiovascular diseases in type 2 diabetes: further findings from the Swedish National Diabetes Register (NDR-BP II). J Hypertens. 2012 Oct;30(10):2020-30.

 

Rekommenderat blodtrycksmål vid diabetes ifrågasätts

Socialstyrelsen höjde nyligen den rekommenderade blodtrycksgränsen för patienter med diabetes. Detta kan leda till att fler patienter drabbas av stroke eller hjärtinfarkt, visar en ny studie vid Sahlgrenska akademin. Den nya studien är världens hittills största i ämnet ochbaseras på data från Nationella Diabetesregistret.

I februari 2015 höjde Socialstyrelsen i sina riktlinjer för diabetesvård gränsen för systoliskt blodtryck (blodtrycket vid hjärtats sammandragning). Tidigare låg gränsen på 130 mm Hg och i de nya rekommendationerna höjdes den till 140 mm Hg. Den rekommenderade gränsen har betydelse för hur intensivt man behandlar patienter med blodtryckssänkande läkemedel.

Bakgrunden till den ändrade rekommendationen var forskning som tydde på att inte bara höga blodtrycksvärden, utan också värden under 130 mm Hg kunde leda till ökad sjuklighet i hjärtkärlsjukdomar.

Forskarna bakom den nya studien ifrågasätter nu detta. Deras studie visar ett linjärt samband mellan blodtryck och hjärtkärlsjukdom. Ju lägre blodtryck desto färre fall av stroke och hjärtinfarkt, alltså även på de lägsta nivåerna.

– Rekommendationerna att acceptera högre blodtryck hos patienter med diabetes tror vi är felaktiga. De kan leda till fler fall av stroke och hjärtinfarkt i patientgruppen, säger Staffan Björck, docent i njurmedicin vid Sahlgrenska akademin, Göteborgs universitet, och en av forskarna bakom studien.

Den nya studien bygger på data från Nationella Diabetesregistret, patientregistret och läkemedelsregistret. Den omfattar 187 000 patienter med diabetes typ 2, som i genomsnitt följts i fem år. Det finns en väsentlig skillnad i upplägget mellan den här studien och de studier som Socialstyrelsen baserar sina rekommendationer på. I den nya studien ingår inte patienter som redan drabbats av allvarliga sjukdomar.

– Det vi har sett i vår studie är att om vi tar bort individer med tidigare allvarlig sjuklighet då försvinner sambandet mellan lågt blodtryck och ökad risk för stroke och hjärtinfarkt, säger Samuel Adamsson Eryd, medicine doktor och försteförfattare till studien.

Till detta finns en naturlig förklaring.

– Lågt blodtryck kan bero på att man är allvarligt sjuk och har man med dessa patienter i en studie ser det ut som att lågt blodtryck ger mer hjärtkärlsjukdom, säger Staffan Björck.

I Sverige finns cirka 300 000 patienter med diabetes, men problemet med blodtrycksgränserna berör inte bara dem. Både europeiska och amerikanska expertorganisationer har höjt den rekommenderade gränsen till 140 mm Hg för systoliskt blodtryck. Eftersom den nya studien är mycket större än alla tidigare studier i ämnet har den betydelse för diskussionerna om blodtrycksgränser både i Sverige och utomlands.

Studien Blood pressure and complications in individuals with type 2 diabetes and no previous cardiovascular disease: national population based cohort study publicerades i BMJ den 4 augusti.

Länk till artikel:http://www.bmj.com/content/354/bmj.i4070.long


Staffan Björck, docent vid Sahlgrenska akademin, Göteborgs universitet


Samuel Adamsson Eryd, medicine doktor och forskare vid Sahlgrenska akademin, Göteborgs universitet

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