INTRODUCTION — Patients with insomnia have difficulty initiating sleep, difficulty maintaining sleep, or waking up early in the morning without the ability to return to sleep, and they also suffer from significant daytime symptoms such as fatigue, sleepiness, inattention, mood disturbance, or impaired performance .
Insomnia is one of the most common symptoms encountered in medical practice. In addition to immediate consequences reported by patients, insomnia also precedes or accompanies medical or psychiatric disorders and may occur as a response to physiologic or psychological stressors.
This topic provides a general overview of the epidemiology, risk factors, comorbidities, and consequences of insomnia. The evaluation, diagnosis and management of insomnia are discussed separately. (See "Evaluation and diagnosis of insomnia in adults" and "Overview of the treatment of insomnia in adults" and "Cognitive behavioral therapy for insomnia in adults" and "Pharmacotherapy for insomnia in adults".)
EPIDEMIOLOGY — Insomnia is a common medical complaint that generates over five million office visits per year in the United States alone .
Prevalence estimates vary according to the study design and definition of insomnia used. In cross-sectional surveys of ambulatory patients, one-third to two-thirds of adults endorse insomnia symptoms of any severity and approximately 10 to 15 percent endorse chronic insomnia with daytime consequences [3-6].
Insomnia is especially common in older adults and women. Prevalence is also increased among individuals who are unemployed, divorced, widowed, separated, or of lower socioeconomic status .
PATHOPHYSIOLOGY — Chronic insomnia is associated with physiological activation, even in the absence of a comorbid medical or psychiatric condition. A majority of studies have found increases in physiological activation, including cardiac, metabolic, hormone, and high frequency electroencephalographic (EEG) measures . Studies have shown increased activity during sleep in hypothalamic areas and occasional reduced hippocampal volume in patients with insomnia compared with controls [9,10].
In studies of healthy volunteers, experimentally-imposed physiological activation produces the poor sleep, daytime dysphoria (including fatigue without objective sleepiness), increased metabolic rate, and anxiety symptoms characteristic of chronic insomnia patients , while simple production of an insomnia sleep pattern results only in symptoms of mild sleep deprivation . These results imply that poor sleep in insomnia patients may reflect central nervous system activation rather than a primary sleep problem. An animal study of situational (stress) insomnia suggested that specific brain arousal sites are impacted by stress and associated with poor sleep . Modification of these brain arousal areas was associated with improved sleep after a similar stress. A series of studies have shown that more severe insomnia, as indicated by objective total sleep time of less than six hours, is associated with significant pathophysiology not seen in insomnia patients with longer objective sleep times .
RISK FACTORS AND COMORBIDITIES — Insomnia has a complex relationship with other medical and psychiatric disorders and is no longer considered "primary" or "secondary" depending on the presence or absence of an associated condition. In practice, the vast majority of patients have one or more risk factors or comorbidities that may be contributing to insomnia, and successful treatment requires attention to the insomnia itself as well as relevant comorbidities (table 1).
Intrinsic factors and genetics — Insomnia may be more common among people with a physiological or psychological vulnerability. Individual factors associated with an increased risk of insomnia include [15,16]:
●Female sex (especially peri- and postmenopausal)
●Previous episode of insomnia
●Family history of insomnia
●Predisposition toward being more easily aroused from sleep
●Trait sleep reactivity (ie, the propensity for exaggerated sleep disruption in response to stressful events)
A genetic basis for insomnia is not well characterized and is likely complex. Genome-wide association studies have identified a large number of potentially implicated loci, which overlap with risk profiles for depression, anxiety, neuroticism, type 2 diabetes, coronary artery disease, and low subjective well-being [17,18].
Psychiatric disorders — Chronic insomnia and psychiatric disorders frequently coexist . Approximately half of patients with chronic insomnia have a psychiatric disorder, and the majority of those with a psychiatric disorder have insomnia [3,20].
It can be challenging to identify psychiatric comorbidities in patients with insomnia, as patients may deny or minimize the role of the psychiatric disorder. As an example, a patient might say, "I would not be depressed if I could get a good night of sleep." Clinicians, on the other hand, may have a tendency to assume that insomnia is caused by the psychiatric disorder and focus more on the psychiatric condition, with the expectation that the insomnia will improve as the psychiatric condition improves. This may be a false assumption, as insomnia often persists independently.
Insomnia frequently precedes the development of psychiatric illness [21-23]. In prospective studies, individuals with insomnia are at significantly increased risk of developing a new psychiatric disorder (particularly major depression) within one year compared with individuals without insomnia.
Depression — Insomnia (or hypersomnia), when it exists along with depressed mood or loss of interest or pleasure, is one of nine diagnostic symptoms of unipolar major depression. Around 40 percent of people with insomnia have clinical depression, and up to 80 percent of patients with depression report insomnia symptoms, which frequently predate the development of depression [22-24]. (See "Unipolar depression in adults: Assessment and diagnosis".)
Early morning awakening is a hallmark symptom of depression, but adolescents and young adults with depression may report difficulty initiating sleep instead. Depressed patients may also complain that they have not slept at all for one or more nights, although sleep recordings of these nights show reduced (not absent) sleep. Depression is variably associated with a reduced latency to rapid eye movement (REM) sleep, including increased REM sleep in the first one-third of the night. (See "Stages and architecture of normal sleep".)
Treatment effects are also bidirectional but may be incomplete, and directed treatment of each disorder may be required. In a meta-analysis of 23 trials of nonpharmacologic or pharmacologic treatment for insomnia in patients with comorbid depression, insomnia therapy led to moderate to large improvements in depression outcomes as measured by the Hamilton or Beck depression scales . Simultaneous treatment of both disorders can increase the likelihood of an insomnia response and lead to more rapid control of depression at lower doses of antidepressant medication . (See "Overview of the treatment of insomnia in adults", section on 'Patients with comorbid psychiatric disorders'.)
Anxiety — Like depression, anxiety disorders share diagnostic overlap with insomnia. The majority of patients with anxiety report insomnia . Overall, anxiety disorders including generalized anxiety and posttraumatic stress are associated with increased subjective sleep disturbance, decreased total sleep time, and decreased sleep continuity . Treatment of both anxiety and sleep symptoms improves outcomes . Insomnia can develop before, at the same time, or after the onset of anxiety . (See "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Management of panic disorder with or without agoraphobia in adults".)
Substance use disorders — Insomnia is very common among patients with substance use disorders across a variety of substances and stages of illness. It predates alcohol dependency in the majority of patients with alcohol use disorder and is an important risk factor for relapse to drinking among those who have achieved abstinence [30-33]. (See "Insomnia in patients with a substance use disorder".)
Posttraumatic stress disorder — Patients with posttraumatic stress disorder (PTSD) frequently have insomnia. Specifically, one review estimated that 70 to 90 percent of patients with PTSD have difficulty falling or staying asleep . This is frequently associated with nightmares and fear of falling asleep or returning to sleep [33-36]. (See "Posttraumatic stress disorder in adults: Epidemiology, pathophysiology, clinical manifestations, course, assessment, and diagnosis" and "Nightmares and nightmare disorder in adults".)
Medical conditions — Insomnia that follows a chronic course can be comorbid with a medical illness or related to the medications required to treat the medical illness (table 1). Approximately 10 percent of patients with insomnia lasting greater than one month have a coexisting medical condition or take medication . Conversely, approximately 40 percent of patients with a medical problem have insomnia that follows a chronic course, compared with 8 percent in a control population .
Medical conditions that are often associated with chronic insomnia include pulmonary disease, hypertension, diabetes, cancer, chronic pain, and heart failure.
●Pulmonary disease – 25 to 50 percent of patients with pulmonary disease report insomnia . In addition, COPD symptoms and frequency of acute exacerbation are related to severity of insomnia . The high prevalence of insomnia in this patient population may be related to events that occur when the patient lies down and tries to fall asleep, such as increased work of breathing, pooling of secretions in the airways, and nocturnal bronchoconstriction. Insomnia may also be related to respiratory stimulant medications or glucocorticoids taken during the night.
●Hypertension – Hypertension and insomnia frequently co-occur . In addition, patients with chronic insomnia have been shown to have increased systolic and diastolic blood pressure during sleep (lack of nocturnal dip) . Insomnia with and without decreased total sleep time has been associated with an increased risk of hypertension and cardiovascular disease [40-42].
●Diabetes – Insomnia has been reported in up to half of patients with diabetes . This could be due in part to discomfort associated with diabetic neuropathy. In at least one large study, insomnia with reduced objective total sleep time has been identified as an independent risk factor for diabetes .
●Cancer – The prevalence of insomnia in patients with cancer is 30 to 50 percent . Contributing factors may include pain and other physical symptoms, side effects of treatment, emotional distress and psychiatric comorbidities, and the effects of hospitalization. (See "Insomnia in palliative care".)
●Chronic pain – Approximately 75 percent of patients with chronic pain have symptoms of insomnia . Predictors of insomnia in patients with chronic musculoskeletal pain include the presence of widespread pain, physical limitations, and reduced social participation . Even short-term treatment for insomnia can be associated with long-term improvement in sleep, chronic pain, and fatigue .
●Heart failure – Approximately 30 percent of patients with heart failure may have insomnia . The insomnia may be related to Cheyne-Stokes breathing or frequent awakenings due to nocturia caused by use of a diuretic. Insomnia and frequent awakenings have also been associated with an increased risk of atrial fibrillation [49,50]. (See "Sleep-disordered breathing in heart failure".)
●Others – Insomnia is observed with increased frequency in patients with rheumatologic disease (eg, arthritis, fibromyalgia), ischemic heart disease, urologic disease (eg, benign prostatic hyperplasia), endocrine disease (eg, menopause, hyperthyroidism), kidney disease, dermatologic disorders (eg, pruritus), and gastrointestinal disease (eg, gastroesophageal reflux).
Neurologic disorders — Insomnia is common in patients with neurologic disease. Among patients with Parkinson disease, over 80 percent report sleep disturbances . The deterioration of sleep may be exacerbated by the development of REM sleep behavior disorder . (See "Clinical manifestations of Parkinson disease".)
Patients with insomnia are at increased risk for development of dementia , and studies suggest that beta-amyloid and inflammation levels are also increased . Among patients with Alzheimer disease dementia, approximately 25 percent have insomnia . Continuing insomnia may be related to nocturnal agitation, delirium, and wandering, all of which may be related to increased stage 1 sleep and awakenings, which may produce further brain damage. (See "Sleep-wake disturbances and sleep disorders in patients with dementia".)
Medication and substances — A variety of medications can be associated with insomnia (table 1). Commonly implicated classes of medications and substances include:
●Central nervous system stimulants, such as caffeine, methylphenidate, amphetamine and modafinil.
●Respiratory stimulants, such as theophylline.
•Monoamine oxidase inhibitor antidepressants are associated with insomnia in nearly 70 percent of patients.
•Selective serotonin reuptake inhibitors, such as fluoxetine, are associated with insomnia in 5 to 35 percent of patients.
•Norepinephrine and dopamine reuptake inhibitors, such as bupropion, are associated with insomnia in 5 to 20 percent of patients.
•Serotonin and norepinephrine reuptake inhibitors, such as venlafaxine, are associated with insomnia in 4 to 18 percent of patients.
•Most tricyclic antidepressants are sedating, but some (eg, protriptyline) can produce insomnia.
●Beta blockers, such as propranolol, metoprolol, and pindolol, can produce sleep-onset insomnia, increased awakenings, and dreams.
●Glucocorticoids, such as prednisone and dexamethasone, are associated with increased wakefulness during the night . Insomnia may occur in 50 to 70 percent of patients who receive prednisone.
●Alcohol, caffeine, and tobacco.
●Over-the-counter medications, such as nasal decongestants and cold medicine.
Medications whose withdrawal can cause insomnia include sedatives, hypnotics, and glucocorticoids.
Other sleep disorders — Insomnia symptoms may co-occur with other sleep disorders, especially sleep apnea, restless legs syndrome (RLS), and circadian sleep-wake rhythm disorders.
Sleep apnea — Patients with sleep apnea have pauses in respiration during sleep that are frequently associated with brief arousals when they resume respiration. As a result, they often report frequent awakenings, poor sleep, or daytime deficits. Approximately 50 to 55 percent of patients being evaluated for sleep apnea report insomnia . Conversely, nearly 30 percent of patients with insomnia have sleep apnea . This proportion is even higher in patients with chronic, treatment-refractory insomnia referred to a sleep center; in such patients, the prevalence of sleep-disordered breathing has been reported to be as high as 90 percent .
In some cases, the insomnia does not improve despite successful treatment of the sleep apnea, indicating that the insomnia may be a comorbidity and not a consequence of sleep apnea. In these cases, additional therapy for insomnia may be indicated. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults" and "Central sleep apnea: Risk factors, clinical presentation, and diagnosis".)
Restless legs syndrome — RLS is characterized by an urge to move the legs, accompanied by sensations that are variably described as creeping, crawling, itching, or jitteriness in the legs. Symptoms emerge during periods of inactivity and are most prominent in the evening. As a result, an estimated 85 percent of patients with RLS have difficulty falling asleep . Patients are also likely to wake frequently during the night with discomfort in their legs. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults".)
Periodic limb movements of sleep — Periodic limb movements of sleep (PLMS) are repetitive and highly stereotyped limb movements during sleep. They usually involve the legs and occasionally involve the arms. PLMS may be accompanied by partial arousals, causing sleep fragmentation and difficulty maintaining sleep, although there is controversy among clinicians about whether PLMS alone contribute to insomnia in the absence of RLS. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults", section on 'Periodic limb movements of sleep'.)
Circadian rhythm sleep-wake disorders — Jet lag causes insomnia with an acute course. Night shift work is also commonly associated with insomnia, as individuals are attempting to sleep when their circadian rhythm is promoting wakefulness. (See "Jet lag" and "Sleep-wake disturbances in shift workers".)
Less common circadian disorders, such as delayed sleep-wake phase disorder and advanced sleep-wake phase disorder, also commonly manifest with insomnia symptoms due to misalignment of the circadian system with the desired sleep schedule. The key to suspecting an underlying circadian disorder is recognition of abnormal sleep-wake patterns, above and beyond the complaint of insomnia or daytime sleepiness. (See "Overview of circadian sleep-wake rhythm disorders", section on 'Clinical manifestations'.)
ADVERSE OUTCOMES — Chronic insomnia has an adverse impact on daytime function and quality of life, and insomnia with objective short sleep duration is associated with increased cardiovascular risk and mortality.
Quality of life — Patients with insomnia report increased fatigue, sleepiness, confusion, tension, anxiety, and depression compared with controls . Such dysphoria pervades other areas of life, causing patients with insomnia to report a decreased quality of life and degraded performance.
Patients with insomnia have decrements in both medical and emotional aspects of life, as determined by a standard measure of quality of life, the Medical Outcomes Study Short Form (SF-36) . The magnitude of the impairment was similar to that seen in patients with a chronic medical condition (eg, heart failure) or depression.
Quality of life can also be measured by looking at employment measures, such as promotions and sick time. Patients with insomnia are less likely to receive promotions and more likely to have errors or accidents, to be absent from work, and to have more health-related consequences [8,62]. The poor work performance, increased medical issues, and increased emotional burden associated with insomnia increase costs to society [63,64].
Cognitive function and performance — Patients with insomnia are almost universally concerned that their poor sleep has negative consequences on their performance of daily tasks and consistently report subjective performance deficits [65,66]. However, patients with insomnia tend to overestimate the magnitude of the performance deficit, just as they tend to overestimate the magnitude of their sleep deficits.
A meta-analysis of 24 studies found small differences in episodic memory, problem solving, and working memory in patients with insomnia compared with controls . No differences were found in general cognitive function, perceptual and psychomotor processes, procedural learning, verbal functions, attention (including alertness, reaction time, selective or sustained attention), and executive function (verbal fluency or cognitive flexibility). However, patients with more severe insomnia, including significant reduction in sleep duration, are at increased risk for cognitive impairment .
Self-medication — Patients who do not receive treatment for insomnia frequently seek over-the-counter remedies and have an increased risk of substance abuse . In untreated insomnia patients, approximately one-quarter have tried alcohol as a treatment . In an experimental study among volunteers with insomnia, alcohol increased total sleep time and slow wave sleep for a few nights, but these effects were lost by night six, and blinded subjects became more likely to self-administer alcohol compared with controls . (See "Risky drinking and alcohol use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis".)
Association with suicide — In longitudinal studies, insomnia has been associated with a small to moderate increase in the risk of suicidal thoughts and behaviors . Some studies have suggested that the association is primarily mediated by underlying depression, while in other studies, the association is present even after adjusting for psychiatric comorbidities . Other potential contributing factors and mediators include serotonergic dysfunction, dysfunctional beliefs and attitudes about sleep, cognitive dysfunction, and medications and substance misuse [72,73]. (See "Pharmacotherapy for insomnia in adults", section on 'Shared warnings and precautions'.)
Cardiovascular risk and mortality — Insomnia is associated with sympathetic nervous system activation, and a number of studies have shown an association between insomnia and elevated cardiovascular risk, including hypertension and myocardial infarction [40,74-81]. In particular, the combination of chronic insomnia and decreased objective total sleep time has been associated with increased risk for incident hypertension  and incident cardiovascular disease , and patients with insomnia have been observed to have a non-dipping blood pressure pattern at night  that can improve with insomnia treatment . Several prospective observational studies have shown an increased risk of cardiovascular disease and, in some cases, overall mortality in patients with insomnia that remains significant after adjusting for potential confounders [41,80,83,84].
Patients with insomnia and short nocturnal sleep time are at increased risk for diabetes , and treatment of insomnia in patients with diabetes has improved both sleep efficiency and glycemic control as measured by HbA1c in at least one study .
The physiological activation associated with chronic objective insomnia likely accounts for the association between insomnia and hypertension, cardiovascular disease, diabetes, and metabolic disorder [41,86,87].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Insomnia in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Insomnia (Beyond the Basics)" and "Patient education: Insomnia treatments (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●One-third to two-thirds of adults endorse insomnia symptoms of any severity and approximately 10 to 15 percent endorse chronic insomnia with daytime consequences. Insomnia is especially common in older adults and women. (See 'Epidemiology' above and 'Intrinsic factors and genetics' above.)
●Insomnia has a complex relationship with other medical and psychiatric disorders and is no longer considered "primary" or "secondary" depending on the presence or absence of an associated condition. Successful treatment requires attention to the insomnia itself as well as relevant comorbidities (table 1). (See 'Risk factors and comorbidities' above.)
•Approximately half of patients with chronic insomnia have a psychiatric disorder, and the majority of those with a psychiatric disorder have insomnia. Frequent comorbidities include mood disorders, substance use disorders, and posttraumatic stress disorder. (See 'Psychiatric disorders' above.)
•High-risk medical conditions for chronic insomnia include pulmonary disease, hypertension, diabetes, cancer, chronic pain, and heart failure. (See 'Medical conditions' above.)
•Neurodegenerative disorders including dementia and Parkinson disease are frequently accompanied by sleep disturbances and chronic insomnia. (See 'Neurologic disorders' above.)
•Medications and substances contribute to chronic insomnia in many patients. Commonly implicated classes include central nervous system stimulants, certain antidepressants, glucocorticoids, alcohol, tobacco, and caffeine.
•Insomnia symptoms commonly co-occur with other sleep disorders, especially sleep apnea, restless legs syndrome (RLS), and circadian sleep-wake rhythm disorders.
●Sequelae of insomnia include decreased quality of life, complaints of impaired daytime performance, and increased risk of medical and psychiatric comorbidities. (See 'Adverse outcomes' above.)
1 : American Academy of Sleep Medicine. International Classification of Sleep Disorders, 3rd ed, American Academy of Sleep Medicine, 2014.
2 : Trends in outpatient visits for insomnia, sleep apnea, and prescriptions for sleep medications among US adults: findings from the National Ambulatory Medical Care survey 1999-2010.
14 : Insomnia with objective short sleep duration is associated with cognitive impairment: a first look at cardiometabolic contributors to brain health.
15 : Stress and sleep reactivity: a prospective investigation of the stress-diathesis model of insomnia.
17 : Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways.
19 : A Systematic Review Assessing Bidirectionality between Sleep Disturbances, Anxiety, and Depression.
20 : National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005.
22 : Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention?
26 : Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder.
27 : Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults.
29 : Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder.
30 : Comprehensive assessment of insomnia in recovering alcoholics using daily sleep diaries and ambulatory monitoring.
32 : The sleep of abstinent pure primary alcoholic patients: natural course and relationship to relapse.
33 : Cognitive Behavioral Therapy for Insomnia Reduces Fear of Sleep in Individuals With Posttraumatic Stress Disorder.
34 : Sleep disturbances in patients with post-traumatic stress disorder: epidemiology, impact and approaches to management.
36 : Sleep disturbance in PTSD and other anxiety-related disorders: an updated review of clinical features, physiological characteristics, and psychological and neurobiological mechanisms.
38 : Impact of insomnia and obstructive sleep apnea on the risk of acute exacerbation of chronic obstructive pulmonary disease.
39 : Nighttime blood pressure in normotensive subjects with chronic insomnia: implications for cardiovascular risk.
41 : Insomnia with objective short sleep duration and risk of incident cardiovascular disease and all-cause mortality: Sleep Heart Health Study.
43 : Insomnia with objective short sleep duration is associated with type 2 diabetes: A population-based study.
45 : Prevalence of sleep disturbances in patients with chronic non-cancer pain: A systematic review and meta-analysis.
47 : Short-term improvement in insomnia symptoms predicts long-term improvements in sleep, pain, and fatigue in older adults with comorbid osteoarthritis and insomnia.
53 : Risk of dementia in patients with primary insomnia: a nationwide population-based case-control study.
58 : Consequences of comorbid insomnia symptoms and sleep-related breathing disorder in elderly subjects.
59 : Pharmacotherapeutic failure in a large cohort of patients with insomnia presenting to a sleep medicine center and laboratory: subjective pretest predictions and objective diagnoses.
60 : Pharmacotherapeutic failure in a large cohort of patients with insomnia presenting to a sleep medicine center and laboratory: subjective pretest predictions and objective diagnoses.
61 : The relationship between insomnia and health-related quality of life in patients with chronic illness.
64 : The economic burden of insomnia: direct and indirect costs for individuals with insomnia syndrome, insomnia symptoms, and good sleepers.
68 : Special report from a symposium held by the World Health Organization and the World Federation of Sleep Research Societies: an overview of insomnias and related disorders--recognition, epidemiology, and rational management.
80 : Insomnia symptoms and risk of cardiovascular diseases among 0.5 million adults: A 10-year cohort.
81 : Associations of Sleep-disordered Breathing and Insomnia with Incident Hypertension and Diabetes. The Hispanic Community Health Study/Study of Latinos.
85 : Efficacy and safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, double-blind, crossover study.
86 : Assessment of sympathetic neural activity in chronic insomnia: evidence for elevated cardiovascular risk.