htn in diabetes: more intensive control helps

 A study was published after its presentation at the recent Am Heart Assn meeting finding that a lower BP goal was better for individuals with diabetes (see htn dm intensive BP control NEJM2024 in dropbox, or DOI: 10.1056/NEJMoa2412006)

 

Details:

-- 12,821 patients who were 50 years of age or older with type 2 diabetes, elevated systolic blood pressure (defined as SBP between 130-180 mmHg if on BP meds, or at least 140mmHg if not), and an increased risk of cardiovascular disease (defined as clinical cardiovascular disease at least 3 months before  study entry, subcliical cardiovasc disease within 3 yrs of enrollment, 2 or more cardiovascular risk factors, and CKD with eGFR of 30-60), at 145 clinical sites across China from 2019-2022

-- patients were randomly assigned to receive intensive treatment that targeted a systolic blood pressure of less than 120 mmHg or standard treatment that targeted a systolic blood pressure of less than 140 mmHg

-- patients were randomized by their site of care; patients and physicians were aware of group assignments, though outcome assessors were not

-- BP was adjusted to achieve the targeted blood pressure, with patients being seen monthly for the the first 3 months and every 3 months thereafter if systolic blood-pressure targets were achieved or no more drug adjustment was planned. Otherwise, monthly visits would continue.

-- physicians followed treatment algorithms, not specified in the article other than to "titrate or add therapy not already in use" when BP above goal

-- lipids and glucose levels were managed according to guidelines (?use insulin, ?other meds for glucose control)

-- mean age 64 (55% were <65yo), 45% women

-- mean baseline BP140/76 mmHg

-- diabetes duration 10 yrs, history of clinical cardiovasc dz 23%/subclinical cardiovasc dz 34%; current smoker 25%, BMI 27 (normal for Chinese individuals is 18.5-23.9), waist circumference 95cm (normal for Chinese individuals being <85cm for men and <80cm for women)

-- A1c 7.6%, LDL 84 mg/dL, HDL 40 mg/dL, TG 130 mg/dL; eGFR 87 with eGFR<60 in 8%; microalb 20

-- BP meds in 99%: ACE inhibitor 14%, ARB 44%, calcium channel blocker 59%, diuretic 7%, a-blocker 1%, b-blocker 15%

-- diabetes meds in 99%: insulin 48%, metformin 67%, TZDs 3%, sulfonylureas 15%, alpha-glucosidase inhibitors (eg acarbose) 33%,  GLP-1 in 4%, DPP-4 in 10%, SGLT-2 in 10%

-- statin 65%, aspirin 50%

 

-- primary outcome: a composite of nonfatal stroke, nonfatal myocardial infarction, treatment or hospitalization for heart failure, or death from cardiovascular causes

-- secondary outcomes: fatal or nonfatal stroke, fatal or nonfatal myocardial infarction, treatment or hospitalization for heart failure, death from cardiovascular causes, death from any cause, and an expanded composite of the primary outcome or death from any cause. CKD  outcomes included progression of CKD (a composite of end-stage renal disease, an eGFR of <15, or a >50% decrease in eGFR from baseline) in patients with CKD at baseline, development of CKD (an eGFR of <60  and a >30% decrease from baseline) in patients without CKD at baseline, and incident albuminuria (a doubling of the urinary albumin-to-creatinine ratio from a value of <10 to a value of ≥10s) in all patients with or without CKD.  

-- serious adverse events were compiled

-- median follow-up of 4.2 years

 

Results:

-- 152 patients  (1.2%) discontinued the trial intervention, 605 (4.7%) were lost to followup, and 423 (3.3%) withdrew their consent

 

-- at one year, mean systolic blood pressure:

    -- intensive-treatment group: 121.6 mm Hg  (median 118.3 mmHg)

    -- standard-treatment group: 133.2 mm Hg (median 135.0 mmHg)

-- after appox 1 year, about 60% of patients in the intensive treatment group met the target SBP

 

graph of achieved systolic blood pressure over time, notable that there was reasonable stabilization in both groups after around 9 months, and those in the intensive group took between 0.5 to 0.8 more meds; diastolic trends were similar to these systolic ones

 

 

-- at 4.2 years, primary outcome events:

    -- intensive-treatment group: 393 patients, 1.65 events per 100 person-years

    -- standard-treatment group: 492 patients, 2.09 events per100 person-years

        --  21% lower in the intensive group, HR 0.79 (0.69 to 0.90), P<0.001

 

 

this graph shows that there is a separation of primary outcome events after about 1 year of treatment, with the apparent finding of increasing separation over time

 

 

-- the secondary outcomes comprising the individual outcomes in the primary composite along with the CKD outcomes were not adjusted for multiplicity and could not be evaluated statistically in a rigorous manner

   -- although fatal or nonfatal strokes (the most common individual outcome) in the unadjusted model were decreased by 21%, fatal or not fatal MI, treatment or hospitalization for heart failure, and death from cardiovascular causes were similar in each group

-- the renal effects were also similar in each group

-- use of hypoglycemic drugs, A1c, BMI, waist circumference, and lipid levels were similar during followup

-- serious adverse events: 

    -- overall similar in the treatment groups (35.5% in the intensive group and 36.3% in the standard treatment group), except for symptomatic hypotension [8 of 6414 people (0.1%) vs 1 of 6407 (<0.1%)] and hyperkalemia (2.8% vs 2.0%) which were more frequent in the intensive-treatment group]

 

Commentary

-- hypertension is a very modifiable cardiovascular risk factors in patients with diabetes and is a prime target for cardiovascular protection

-- the hypertension treatment goal in patients with diabetes is unclear:

    -- this article confirms the importance of lower hypertension goals and augments the SPRINT trial finding a 27% decrease in cardiovasc events, similar to the findings of this study: https://gmodestmedblogs.blogspot.com/2020/03/bp-tight-control-increases-life.html). but SPRINT excluded people with diabetes, a very large group indeed...

    -- there have been a few studies finding that on subgroup analyses of patients with diabetes, there was benefit from lower blood pressure readings: 

        -- the 2021 STEP study had similar outcomes in the 4359 people in the subgroup with diabetes vs no diabetes (https://gmodestmedblogs.blogspot.com/2021/09/hypertension-lower-target-blood.html )

        -- a recent open-label study (htn lower goal of 119mmHg better Lancet2024 in dropbox, or doi.org/10.1016/S0140-6736(24)01028-6), achieved an SBP of 119 in the intensive group vs 135 mmHg in the standard treatment group, associated with a 12% decrease in adverse cardiovascular outcomes in the intensive treatment group after 3.4 years (both this study and the current one were in Chinese individuals).

        -- there was also post-hoc analysis of the ACCORD trial, which i thought was pretty deeply flawed: https://gmodestmedblogs.blogspot.com/2014/12/intensive-glucose-control-and-heart.html (this was one of my first blogs, back in 2014!!)

        -- however, there was a negative Japanese study in patients who had a history of a stroke

             -- so, the issue of hypertension goal in those with diabetes remains unclear since evaluation of the subgroup with diabetes did not benefit consistently. And subgroup analyses do not have the statistical rigor of trials specifically addressing the issue of blood pressure treatment intensity in those with diabetes

 

-- so, this current study with a primary goal of people with hypertension plus diabetes does help clarify the issue, finding a very significant 21% lower likelihood of the composite cardiovascular events beginning after just 1 year of intensive treatment with an achieved SBP reduction from an average of 140mmHg down to 120 mmHg

    -- the graph above, with apparently splaying curves at the 5-year mark, suggests that treatment longer than the 5 years reported above may well continue to decrease cardiovascular risk further. 

    -- and this benefit was true for all of the subgroup analyses: age <65 vs older, age <80 vs older (though very few people >80yo), sex, prior cardiovasc disease, prior chronic kidney dz:

        --though their cutpoint eGFR was  >60 vs lower, and the average was 89 and only 8% with eGFR<60, so a pretty renally-healthy group), level of baseline SBP, hemoglobin A1c level, duration of diabetes, or duration of hypertension

-- this trial also found that intensive blood pressure control was likely the reason for the benefit, since the A1c was relatively low at 7.7% and did not significantly change during the study (7.5%) [though no comment on changes in lipids or smoking]

-- the current study also found that the combo of fatal and nonfatal stroke was by far the most common cardiovascular event (and is the most common cardiovasc complication of hypertension in the Chinese population), and they found that the crude rates were lowest with intensive BP therapy, 1.19 (1.06-1.23) events per 100 person-yrs vs 1.50 (1.35-1.66) per 100 person-yrs

 

Limitation:

-- this was not a double-blind study, which would tend to amplify any placebo effect

-- there were a few pertinent issues regarding which meds the participants were on:

    -- 65% were on statins (the recommendation being 100% in the US); lots of people were on insulin (48%) and sulfonylureas (15%), both of which have been found to increase adverse cardiovascular events in several studies; 33% were on acarbose (which has only mild glucose effect of about a 0.5 percentage point decrease in A1c and has been shown to have no cardioprotective effect) and very few were on GLP-1s (4%) or SGLT-2s (10%) which have been clearly shown to be cardioprotective (and renal protective as well). And there was no comment on whether there were changes in meds and which ones were used during the course of the study

    -- the meds used for hypertension were a bit different from what we tend to use based on studies from decades ago (a-blocker 1%, b-blocker 15%). And we are unaware of what combinations of meds or doses were during the study

-- this study was of a homogeneous and pretty healthy and young Chinese population (mean age 64)

    -- notably few people with CKD (with only 8% having an eGFR <60) given the duration of diabetes and hypertension, and 57% with heart disease

    -- also a pretty low A1c level of 7.6%, a pretty low baseline hypertension of 140/76

        -- all of these relatively mid medical problems would limit generalizability to those from different backgrounds, different cultures affecting diet/exercise/stress levels, different baseline medications used, poorer diabetes control and higher hypertension at baseline,  etc

  -- there was no information about relevant changes in other cardiovasc risk factors (eg lipids, smoking, eating habits, drinking, social stressors, depression,.........  And baseline/follow-up data were not available for several of them)

 

so,

-- this was another trial finding that lower systolic blood pressure is better, but in a different and likely very homogeneous population of Chinese participants who had relatively mild comorbidities and were on suboptimal meds for diabetes and unclear specific doses and combinations of antihypertensive meds

-- but, it is notable and important that this trial, as opposed to some of the older intensive BP control trials, had a large difference in achieved SBPs, 120 vs 133 mmHg, and found benefit by 1 year of intensive treatment

-- and, this trial replicated the results of the SPRINT trial (which did not have participants with diabetes), with a similar achieved SBP level of 121 mmHg vs 136mmHg and a similar 27% decrease in cardiovascular events

-- the current US recommendations:

    -- per the Am Diabetes Assn in their 2024 guidelines: hypertension is SBP>130 or DBP >80 mmHg (https://professional.diabetes.org/standards-of-care )

    -- per the AHA/ACC in their 2017 guidelines: hypertension is SBP>130 or DBP >80 mmHg (https://gmodestmedblogs.blogspot.com/2017/11/new-aha-hypertension-guidelines.html), with their 2019 scientific statement preferentially supporting the use of ambulatory or home-based blood pressure recordings (https://gmodestmedblogs.blogspot.com/2019/03/new-aha-blood-pressure-measurement.html)

    -- per the KDIGO (Kidney Disease: Improving Global Outcomes) target blood pressure in 2021 guidelines: goal of SBP 120mmHg

    -- per the National Kidney Foundation journal American Journal of Kidney Diseases (AJKD) in 2019:  SBP goal of <130mmHg

    -- by the way, the observational Framingham Study found that hypertension was associated with cardiovascular outcomes, with increases starting in the 100-110 mmHg range (I could only find the graph for diastolic hypertension, since these old studies have not been digitized), and this study also found that systolic hypertension was more associated with adverse cardiovascular events than diastolic (though treating hypertension to that very low level does not necessarily mean that having that pressure without meds has the same benefit):

 

 

-- despite the limitations of this trial, its findings as well as what we have learned from other trials, make a strong case that the bottom line is a lower goal SBP, and the 120mmHg range is in general better (and, perhaps even lower, if tolerated??)

    -- and, of course, all trials have their limitations. our duty, i think, is to understand what these limitations are, and assess issues of biological plausibility as well as the aggregate data from the current and past trials to determine if the conclusions seem reasonable enough to apply them to the very different specific individuals we see regularly...

 

geoff

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