Time dictates: emerging clinical analyses of the impact of circadian rhythms on diagnosis, prognosis and treatment of disease

Abstract

Since the advent of modern molecular tools, researchers have extensively proven that essential cellular machineries show robust circadian (~24 hour) variations in their pace. This molecular rhythmicity translates in most organ systems directly into time of day dependent variation in physiology, which in turn provides the mechanistic rationale for why timing on a daily basis should matter in many aspects of human health. However, these basic science findings have been slow to move from bench to bedside since clinical studies are still lacking to demonstrate the importance of timing. Therefore, it has not been clear how physicians might incorporate knowledge of our natural 24 hour rhythms into their routine practise. This review is a brief summary of results from recently completed clinical studies on hypertension, myocardial infarction, diabetes mellitus, and adrenal dysfunction to highlight new evidence on the emerging importance of circadian rhythms in diagnosis, prognosis and treatment of disease.

Introduction

Twenty-four hour biological clocks (“circadian” clocks) within living organisms are fascinating achievements of nature. They allow temporal separation of otherwise conflicting biochemical events by partitioning the physiology of cells to different stages of the day¹. Virtually all aspects of cellular and tissue biology oscillate every day, with huge changes in gene and protein expression affecting second messenger availability, membrane excitability, metabolic parameters, redox balance and antioxidant capacity¹. Interestingly, upon development of leading morbidities (e.g. cardiovascular and metabolic diseases), many of these fundamental cellular properties are dysregulated. The potential of restoring circadian rhythms in order to treat such conditions has been demonstrated in animal models². However, large clinical trials have only recently been conducted to present clear evidence for physicians that timing matters at the bedside for common conditions. Nonetheless, the concept of delivering certain drugs at particular times of day to maximise their potency, and minimise side effects, has seen promise in patients. This is exemplified by the long-standing use of statins at night time³, when their effects are maximal, and treatment of cancer patients with specialised rhythmic dosing regimes that take into account their endogenous 24 hour rhythms⁴. Here we present some recent exemplars of cardiovascular, metabolic and endocrine pathophysiology that can be modulated with knowledge of the circadian clockwork.

Hypertension

Systolic blood pressure (SBP) and diastolic blood pressure (DBP) of healthy normotensive individuals rapidly rises on waking and declines relative to daytime levels by >10% during sleep⁵. This pattern originates from daily rhythms in the renin-angiotensin-aldosterone system, autonomic activity, and from rest/activity-related differences in mental and physical stress^5,6. Diseases may alter sleep, autonomic and neuroendocrine function, with consequential modification of the 24 hour BP profile. Such subtle alterations in the daily BP are associated with an increased risk of left ventricular remodelling, renal pathology, cardio- and cerebrovascular events (CVE) and total mortality⁷.

A systematic review of nine hypertensive cohorts from Europe, Brazil, and Japan (The ABC-H study⁸, n=13 844) recently showed that elevated night time systolic BP (NSBP) independently predicted higher CVEs in most cohorts, and, overall, NSBP independently predicted CVEs. In view of these results and in accordance with recent European guidelines for ambulatory BP monitoring⁹ there is no evidence-based rationale for omitting the routine use of NSBP in patients diagnosed with hypertension, since NSBP plays a key role in hypertension-related morbidity and mortality. This is in concert with previous observations in acute stroke patients, in who preserved NSBP decline in the first 24 hours of onset was associated for each 10-mmHg difference with a twofold increase in likelihood of complete functional recovery (fourfold increase if considering diastolic values)^10,11.

Although daytime hypertension should not be ignored, night time BP may be the most important target of antihypertensive therapy in general^8,12. This conclusion of the ABC-H study is consistent with an open-label, single-centre, randomized trial reporting a greater reduction in CVEs and CV mortality when antihypertensives were dosed in the evening compared to morning dosing¹³. Further randomized trials are urgently needed to provide a firm evidence base to treat this prevalent condition.

Myocardial Infarction

Daily rhythms in the physiological regulation of BP and of blood clotting underlie the well-known increased incidence of acute ST-Elevation Myocardial Infarction (STEMI) in the morning^5,6. However, whether the myocardium’s ability to cope ischaemia is subject to a significant circadian pattern, or if onset time is a prognostic factor for outcomes, has not been clearly defined earlier. The largest clinical study to rigorously investigate this question enrolled approx. 24,000 patients with acute STEMI from a Swiss prospective multicentre registry¹⁴. As a measure of ischaemic burden, circadian variation of peak creatine kinase (CK) and in-hospital mortality was assessed in a well-defined population of patients (n=6223) who were treated with primary percutaneous coronary intervention (PCI) less than 6 hours after symptom onset. Using harmonic regression methods, a 24-hour pattern in ischemic burden was consistently identified in various subgroups of individuals. STEMI patients undergoing PCI with symptom onset at night presented with the highest peak CK values, while the lowest peak values were seen in patients with symptom starting in the morning. Moreover, the probability of in-hospital death was highest for patients with symptom onset around midnight. The rhythmic pattern in ischaemic burden was even more pronounced in patients with prior low risk of mortality. Thus, there is compelling evidence that the rhythmic nature of the myocardium’s vulnerability to ischaemia defines worse prognosis of STEMI at night. Importantly, this pattern was independent of ischaemia duration, raising the notion that symptom onset time might be a better factor for prognostic prediction compared to duration of ischaemia in STEMI patients undergoing primary PCI.

Diabetes Mellitus

Measurements of overnight blood glucose (BG) in non-diabetic subjects indicates that both it and plasma insulin concentrations remain almost constant¹⁵. Conversely, in diabetic patients, a significant morning elevation of BG before breakfast (fasting hyperglycaemia) is a frequent event, known as the dawn phenomenon¹⁵. In type 1 diabetes (T1DM) the most likely explanation is that the effects of nocturnal secretion of growth hormone on BG are not counterbalanced due to the absence of insulin. Therapy of T1DM is restricted to insulin replacement, which requires consideration of the circadian rhythm in insulin sensitivity, which shows a peak after midnight until 3 am. While targeting fasting normoglycaemia at dawn, the risk of nocturnal hypoglycaemia could be effectively reduced with a more physiological replacement of basal insulin using Continuous Subcutaneous Insulin Infusion (CS-II) or Long Acting Insulin Analogues [LA-IA], which do not result in peaks and troughs over the day¹⁵.

In type 2 diabetes (T2DM), the dawn phenomenon has been attributed recently to a transient increase in hepatic glucose production (gluconeogenesis) at dawn in the absence of compensatory insulin secretion¹⁵. Recently, it has become possible to precisely quantify the magnitude of the dawn phenomenon and its impact on overall BG control in a study of 248 subjects with T2DM by measuring overnight interstitial glucose (IG) concentration using continuous ambulatory monitoring¹⁶. An increase in IG (13–20 mg/dL) from the nocturnal nadir to pre-breakfast values was observed in all treatment groups, which took only oral therapies or were diet-controlled (Fig.1). Importantly, the dawn phenomenon had an impact on mean daily IG and HbA1c levels, which was again independent of treatment. The impact of the dawn phenomenon on the diabetic control in the overall population, which resulted in an elevation of 12 mg/dL in mean glucose concentration and 4 mmol/mol [0.4%] in HbA1c, was in agreement with the A1C-Derived Average Glucose study (an increment of 29 mg/dL in glucose corresponds to a 1% increment in HbA1c)¹⁷. Furthermore, the pre-breakfast increase in IG extended to the post-breakfast period with the highest values of the day seen then (mean values 191– 208 mg/dL)¹⁶.

Fig. 1.

Mean 24-h continuous glucose profiles of T2DM patients on diet alone treatment with the absence (solid curve) or with the presence of a dawn phenomenon (dashed curve), and of patients taking oral medication in the presence of a dawn phenomenon (dotted curve). Arrows show meal times. Figure adapted from reference #16.

Since it is thought that these early morning hyperglycaemic episodes progressively impair pancreatic beta-cell function on the background of insulin resistance, primarily at dawn, and independently of age, the primary target of treatment in T2DM is to re-establish near-normoglycaemia before and after breakfast (i.e. to treat the dawn phenomenon, Fig.1)^15,18. Furthermore, data from participants treated with diet alone showed that the dawn phenomenon is already present in those who are not on pharmacological treatment¹⁶. This suggests that treatment of the dawn phenomenon should be initiated before HbA1c has increased well beyond 7.0% rather than after, which is current practise¹⁵. Evening replacement of basal insulin in T2DM which abolishes the dawn phenomenon effectively by restraining hepatic glucose production and lipolysis is an optimal treatment (effective, easy, safe, and “natural”) that mimics the physiology of glucose homeostasis of healthy non-diabetic subjects¹⁵.

Adrenal Insufficiency

Serum cortisol levels of healthy individuals show a robust peak before waking and fall to a nadir during night-time sleep¹⁹. Hormone replacement therapy in adrenal insufficiency provides a life saving treatment, where the total daily dose of hydrocortisone is divided and administered 2-3 times a day (Fig.2). However, the achieved serum cortisol profile does not closely resemble the physiological circadian pattern since sharp peaks, followed by rapid declines in cortisol levels result in overexposure followed by underexposure around the clock¹⁹. Furthermore, the timing of the dose is likely to be different on a day-to-day basis resulting in different temporal exposure profiles. Importantly, over-replacement of cortisol (particularly during night-time sleep) may lead to impaired glucose tolerance, obesity, osteoporosis, and sleep disturbance¹⁹. Conversely, under-replacement during the daytime can be life threatening if the patient develops an intercurrent illness¹⁹. In line with these assumptions, patients taking chronic adrenal hormone replacement live significantly shorter and report reduced quality of life when compared to healthy controls^20,21. An international survey of 1245 patients with adrenal insufficiency showed recently that 38% of patients report difficulties with multiple dosing, greater fatigue, and greater impact on their quality of life²¹. In small, uncontrolled studies in patients with adrenal insufficiency, infusion of hydrocortisone by a programmable pump has restored a normal cortisol circadian rhythm (Fig.2) and improved quality of life in most patients, though outcomes have not been systematically reported^22,23. Therefore, it is highly likely that the non-physiological daily profile during standard replacement therapy is a major contributor to worse outcomes in adrenal insufficiency patients, although the level of evidence for this is still poor due a lack of randomised, placebo-controlled studies. Interestingly, time-released oral formulations of corticosteroids have recently been introduced successfully for the treatment of rheumatoid arthritis²⁴. Similar approaches to create a more physiological daily profile of steroid in the circulation could be beneficial for treating related conditions (e.g. adrenal insufficiency).

Fig. 2.

Mean 24-h cortisol profiles of healthy subjects (solid curve), of patients with adrenal insufficiency treated with either conventional therapy (dotted curve) or with programmed infusion therapy (dashed curve). Dark bars represent periods of darkness. Figure adapted from reference #23.

Summary

These recent clinical studies have demonstrated that the impact of the circadian clock on human physiology represents true potential for physicians and clinical researchers to capitalise on natural daily physiological variation to develop novel approaches in healthcare with more promising outcomes compared to conventional strategies. Moreover, existing drugs and therapies, whose side effect profiles are known well, can be utilised or re-purposed in a more efficient manner, which therefore reduces development costs and alleviates potential safety concerns, which are major hurdles during development of completely new drugs.

Key points.

• Night-time blood pressure may be the most important target of antihypertensive therapy.

• The daily rhythm in the myocardium’s vulnerability to ischaemia defines worse prognosis if ischaemia onset time is at night.

• The primary target of treatment in type 2 diabetes mellitus should be to re-establish near-normoglycaemia before and after breakfast.

• Conventional glucocorticoid replacement strategies achieve serum cortisol profiles with little resemblance to the physiological 24-hour pattern, which is believed to be the major explanation for worse outcomes in those with adrenal insufficiency and poor quality of life in rheumatoid arthritis.