Chronotherapy: Underutilized or Underwhelming in Diabetes and Hypertension?

The standard treatment of hypertension in patients with diabetes focuses on attaining blood pressure less than 140/90 or 130/80 mmHg in young patients with ASCVD risk factors. The renal/cardio protective effects of ACEI/ARBs in patients with diabetes also makes this class heavily utilized. While ACEI/ARB benefits are well documented, the best administration time for these agents is unclear. In fact, the 2016 ADA Guidelines reads “Consider the administration of antihypertensives at bedtime,” which is not exactly clear guidance or a glowing endorsement of bedtime dosing.

Chronotherapy involves the purposeful administration of antihypertensive pharmacotherapy at specific times to target the circadian rhythm of blood pressure. A patient with a normal 24-hour circadian blood pressure pattern has the lowest pressures during sleep-time (dipping) and the highest during the awakening period. This rise in blood pressure in the morning is commonly referred to as the “morning surge” and is the most common time period for cardiovascular events.

Several cohort studies now suggest that nighttime blood pressure may be the best predictor of cardiovascular disease compared to clinic, 24-hour, and daytime pressure using ambulatory blood pressure devices. Patients in these trials who did not exhibit a 10% decrease in blood pressure at night were classified “non-dippers” and were at increased risk for cardiovascular morbidity and mortality. Therefore, in management of hypertension, chronotherapy typically is characterized by nighttime dosing of anithypertensives to convert non-dippers to dippers.

Abundant evidence clearly indicates that bedtime dosing of ACEIs and ARBs is more effective in decreasing nighttime blood pressure compared to morning administration. Additionally, nighttime dosing of ACEI/ARBs may also help with daytime control. On the other hand, evidence for calcium channel blockers varies and diuretics are generally avoided because awakenings secondary to nocturia would prevent patients from dipping. ACEIs and ARBs improve the circadian patterns by lowering nighttime blood pressure, but the question remains on whether this intervention improves clinical outcomes.

  1. To date, only one trial large trial has investigated chronotherapy’s effects on cardiovascular outcomes. The MAPEC trial (Monitorización Ambulatoria para Prediccion de Eventos Cardiovasculares [i.e., Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events] randomized patients to take at least one blood pressure medication at bedtime or all medications upon awakening. After a median follow up of 5.6 years, the group randomized to bedtime administration of at least one antihypertensive medication had a 61% (HR 0.39; p<0.001) lower risk of total events compared to the group administering antihypertensives upon awakening. Furthermore, approximately 20% of MAPEC’s population included patients with diabetes whose results were equally impressive. (Hermida R, et al. Diabetes Care. 2011;34:1270).
  1. The evidence for chronotherapy on clinical outcomes is moderate in nature. However, safety must be considered before implementing this strategy. The HOPE trial investigated the effects of Ramipril taken at night compared to placebo in high risk patients. While this trial cannot answer questions regarding efficacy, it did illustrate an adequate safety profile in a patient population required to have one of the following: coronary artery disease, peripheral vascular disease, stroke, or diabetes plus one ASCVD risk factor(Yusuf S, New Engl J Med. 2000;342:145).
  1. Another safety consideration in chronotherapy is adherence. The adherence rate in chronic diseases is currently poor, roughly 50-60%. One prescribing trait contributes to the overall non-adherence rate is “timing adherence.” Timing adherence compares once daily to twice daily dosing regimens with the latter illustrating a nearly 28% decrease in adherence (Coleman C, et al. J Manag Care Pharm.2012;18:527). This is clearly an alarming statistic and applies to patients taking medications at different times in the day, including those instructed to take an ACEI or ARB at night.

More studies are needed to document outcomes with bedtime dosing of ACEI or ARBs, and whether once daily dosing at bedtime is associated with better adherence.  Also, the question of “quasi-adherence” [taking the medication “some” or “most” nights] and its effect on outcomes would be important. The evidence does seem to indicate that patients would benefit from chronotherapy, especially patients with diabetes, but careful monitoring of adherence must be done to prevent worsening control. My advice is to select patients carefully using a patient-centered approach and to use chronotherapy in patients with diabetes and uncontrolled hypertension.

Are you using chronotherapy in your practice? Are you monitoring adherence…and how?