Primary Care Corner with Geoffrey Modest MD: HTN Goal in Diabetics without CVD

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By Dr. Geoffrey Modest

A large Swedish population study found that in diabetics with no previous cardiovascular disease, there were progressively fewer cardiovascular events as the systolic blood pressure was lower (see doi.org/10.1136/bmj.i4070).

Details:

  • 187,106 patients in the Swedish national diabetes register for at least 1 year, <= 75 yo, and no known cardiovascular disease (CVD), from 2006-2012 with mean follow-up of 5.0 years. From 861 primary care units and hospital outpatient clinics
  • Most of the demographics got worse as the cohort in each 10-mm group of BP increased: median age was 55 in the lowest SBP group vs 64 in the highest; duration of diabetes 4.8 vs 6.8 years and the higher SBP group was more likely to be on more aggressive diabetes management;  LDL 2.8 vs 3.0 mmol/L but HDL 1.3 in all; more micro/macroalbuminuria in those with the highest SBP; and the mean number of BP meds was 0.7 in the SBP 110-19 cohort vs 1.1 in the 130-139 cohort vs 1.6 in the >160 mmHg cohort

Results:

  • ComparingSBP 110-119 mmHg vs those with SBP 130-199:
    • Non-fatal MI, RR 0.76 (0.64-0.91, p=0.003), 24% risk reduction
    • Total acute MI, RR 0.85 (0.72-0.99, p=0.04), 15% risk reduction
    • Non-fatal CVD, RR 0.82 (0.72-0.93, p=0.04), 18% risk reduction
    • Non-fatal coronary heart disease, , RR 0.88 (0.79-0.99, p=0.04),12% risk reduction
    • There was no suggestion of J-shaped relationship, except for heart failure and total mortality, and this was only significant for the lowest SBP group
  • Figure below shows that there was a consistent relationship between SBP and non-fatal CVD events over the course of the study. For all of the CVD endpoints, this relationship held, even after controlling for age, sex, duration of diabetes, type of diabetes treatment, HbA1c, smoking status, LDL, HDL, triglycerides, micro/macroalbuminura; as well as thiazide diuretics, loop diuretics, calcium antagonists, spironolactone, b-blockers, and drugs for heart disease. Of note, they did not control for those on vs not on antihypertensives, which may be important.

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Commentary:

  • So, why is it so difficult to zero-in on a goal blood pressure in diabetics? This study suggests that lower blood pressure is better. But the various guideline groups have been increasing the BP goal lately, though based on no new evidence: the ADA (Am Diabetes Assn) in 2016 set the overall BP guidelines at the higher level of <140/90 (see https://stg-blogs.bmj.com/bmjebmspotlight/2016/03/09/primary-care-corner-with-geoffrey-modest-md-new-diabetes-guidelines-from-ada/) and explicitly did not recommend it to be <130/70 in older adults, in conformity with JNC8 (which also has a higher goal than JNC7)
  • I think there could be various different explanations:
    • The current study focused on a less-sick population than most of the others: a younger cohort, who had no known baseline CVD, and some did not have treated hypertension
      • Is the diabetes itself different? (perhaps longer-standing diabetes creates end-organ changes which dictate different optimal BP goals)
      • Are we using diabetic medications which make things worse, and using more of them on patients with longer-standing and more treatment-resistant diabetes? Similarly with the antihypertensives?
        • In terms of diabetes control, a case in point here is the ACCORD trial, one of the major studies heralded as a reason to raise the target A1c. Those assigned to the “intensive control wing”, achieved an A1c of 6.4, but 91% were on a thiazolidinedione (TZD), vs an A1c of 7.5 in the less aggressively treated group but with 58% on a TZD. But the TZD of choice was rosiglitazone, which has the unfortunate tendency to increase cardiovascular outcomes (and is one of the reasons that I find it unfortunate that the FDA and most of us accept A1c as an acceptable clinical surrogate).
        • And, this brings up the issue of medication-flogging…. are those patients with easy-to-control diabetes or hypertension different? As in the first point, is there a fundamental difference in their pathophysiology or clinical outcome? A subgroup analysis of this ACCORD study actually found that those who achieved a lower A1c in fact did better, all the way down to an A1c of 6!!, but as the number of meds needed in the attempt to lower the A1c increased, they had worse outcomes (i.e., medication-flogging of patients to improve their A1c led to worse outcomes even at a much higher A1c). See Riddle MC. Diabetes Care; 33:983. An Italian observational study also found that the goal of A1c in terms of clinical outcomes was lower in those with fewer chronic medical conditions (see Greenfield S. Ann of Intern Med 2009; 151: 854).
        • This last point brings up the parallel issue: should the blood pressure goal be different in those with fewer chronic changes from long-standing hypertension (e.g. atherosclerosis, or changes in the local autoregulation of blood pressure at a microvascular level) vs those with perhaps newer onset hypertension with fewer of these changes? should we have different BP goals in those who easily achieve a blood pressure of 110-120 systolic if it can be achieved with 1-2 drugs, vs those with SBP of 140+ systolic, who would be struggling to achieve even close to the lower range with 4 drugs? It was certainly the case in the Swedish study that as the SBP of the cohort increased, there were more meds being used, distributed pretty evenly amongst the different types of meds.
        • The prior observational studies have often found a J-shaped relationship between blood pressure and CVD events in diabetics, though this has been questioned by the potential bias in observational studies that patients who had more bad outcomes at lower pressures did so because they were really sick at the start, and it was this increased morbidity that led to lower blood pressure. It is notable in the above Swedish study that the J-shaped curve did happen in those with lower blood pressure, but only for total mortality and heart failure, and not for the specific CVD outcomes, suggesting that there may have been issues that these patients with lower SBP were indeed sicker. In fact those who died in this Swedish study were likely to have had more comorbidities, since they had higher rates of smoking (32%), use of loop diuretics, spironolactone, and drugs for heart disease.
        • The ACCORD-BP study of diabetic patients (N Engl J Med 2010; 362: 1575), another wing of the above ACCORD study, found no overall benefit in 4733 patients in those achieving a systolic BP of 119 mm Hg vs 133.5 mm Hg, except for the prespecified secondary outcome of stroke, where there was a 41% decrease (p=0.01), but at the expense of an increase in serious adverse events (from 1.3% of the population to 3.3%). The absolute risk of stroke was 0.53%/yr vs 0.32%/yr, which translates roughly to 2.6% vs 1.6% over the 4.7 year study. The serious adverse events were largely hypotension/syncope/bradycardia or arrhythmia/hyperkalemia. The intensive group averaged 3.4 BP meds and the standard group 2.2. But, as opposed to many strokes, all of these serious adverse could be tracked and corrected, and there was no evidence of increased morbidity/mortality from these adverse events. Other trials, such as ONTARGET found a J-shaped curve, and the INVEST trial found no benefit if the SBP were lowered below 130, (though a subgroup analysis of ONTARGET found that it was those with a higher baseline risk who had CVD events, rather than the degree of reduction of the BP). These are the trials cited in JNC8 and the ADA guidelines as the reason to shoot for a higher SBP target.
      • So, my best guess is that lower SBP is better for those who don’t have lots of comorbidities and do have more easily treated hypertension, with the following caveats:

Also, https://stg-blogs.bmj.com/bmjebmspotlight/2015/03/06/primary-care-corner-with-geoffrey-modest-md-blood-pressure-goals-in-diabetics/, a recent meta-analysis found benefit of a goal SBP of around 130 to be better overall than 140.

 

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