[Management of diabetes during corticosteroid therapy].Glucocorticoids are widely used as potent anti-inflammatory and immunosuppressive drugs to treat a wide range of diseases. However, they are also associated with a number of side effects, including new-onset hyperglycemia in patients without a history of corticosteroid therapy and diabetes mellitus DM or severely uncontrolled hyperglycemia in patients with known DM. Glucocorticoid-induced diabetes mellitus GIDM is a common and potentially harmful problem in clinical practice, affecting what is dianabol cycle all medical specialties, but is often difficult to detect in corticosteroid therapy and diabetes settings. However, scientific evidence is lacking regarding the effects of GIDM, as well as strategies for prevention and treatment. Similarly to nonsteroid-related DM, the principles of early detection and annd factor modification apply. Screening for GIDM should be considered in all patients treated with medium to high doses of glucocorticoids.
Management of hyperglycaemia and steroid (glucocorticoid) therapy (October ) | Diabetes UK
Glucocorticoids are widely used as potent anti-inflammatory and immunosuppressive drugs to treat a wide range of diseases. However, they are also associated with a number of side effects, including new-onset hyperglycemia in patients without a history of diabetes mellitus DM or severely uncontrolled hyperglycemia in patients with known DM.
Glucocorticoid-induced diabetes mellitus GIDM is a common and potentially harmful problem in clinical practice, affecting almost all medical specialties, but is often difficult to detect in clinical settings. However, scientific evidence is lacking regarding the effects of GIDM, as well as strategies for prevention and treatment. Similarly to nonsteroid-related DM, the principles of early detection and risk factor modification apply.
Screening for GIDM should be considered in all patients treated with medium to high doses of glucocorticoids. Challenges in the management of GIDM stem from wide fluctuations in postprandial hyperglycemia and the lack of clearly defined treatment protocols. Together with lifestyle measures, hypoglycemic drugs with insulin-sensitizing effects are indicated. However, insulin therapy is often unavoidable, to the point that insulin can be considered the drug of choice.
The treatment of GIDM should take into account the degree and pattern of hyperglycemia, as well as the type, dose, and schedule of glucocorticoid used. Prospective studies are needed to answer the remaining questions regarding GIDM.
Glucocorticoids have been shown to be potent anti-inflammatory and immunosuppressive drugs; they started to be used for therapeutic purposes in the midth century, and are currently widely used in the treatment of many diseases [ 1 ]. At any point in time, up to 0.
Moreover, nearly one-quarter of patients may need to use corticosteroids for more than 6 months [ 2 ]. Glucocorticoids are extensively used in almost every subspecialty of medicine [ 3 ]. Although they are widely prescribed for their anti-inflammatory and immunosuppressive properties, glucocorticoids have a range of common metabolic side effects including hypertension, osteoporosis, and diabetes [ 2 ].
Glucocorticoid-induced diabetes mellitus GIDM has been recognized as a complication of glucocorticoid use for over 60 years [ 4 ].
Glucocorticoids are the drug group most often associated with the onset of hyperglycemia or diabetes mellitus [ 1 ]. Glucocorticoids exacerbate hyperglycemia in patients with diabetes mellitus, unmask undiagnosed diabetes mellitus or may precipitate the appearance of GIDM, which is an independent risk factor for other complications associated with the use of these drugs [ 2 ].
Furthermore, although it is expected that the blood glucose levels of non-diabetic patients should normalize after discontinuing glucocorticoid use, this does not always happen, and such patients require close monitoring due to the risk of developing diabetes mellitus in the future [ 5 ].
The diagnosis and treatment of GIDM are surprisingly undervalued by many health-care professionals, although GIDM results in an increased use of medical care and the development of associated morbidities that affect medical costs and patients' quality of life [ 2 ]. Despite the high prevalence of corticosteroid use in clinical practice and the strong association of glucocorticoids with new-onset hyperglycemia, limited information is available regarding the pathophysiology, frequency, and diagnosis of this condition.
Similarly, prospective studies assessing the effectiveness of preventive measures taken against this condition and comparing the effectiveness of different treatment schedules are lacking.
Therefore, the primary goal of this review article was to highlight the most recent evidence regarding the clinical aspects of GIDM. Other studies of the prevalence of GIDM associated with different diseases have reported varying results [ 7 , 8 , 9 ]. However, the exact prevalence of hyperglycemia secondary to glucocorticoid therapy is not known, making this an unpredictable challenge for general practitioners and endocrinologists alike [ 5 ].
GIDM has been reported to have an even greater prevalence among patients treated with glucocorticoids for rheumatoid arthritis [ 12 ]. A recent meta-analysis indicated that the rates of glucocorticoid-induced hyperglycemia and diabetes were The length of time on glucocorticoids, the relative potency of the glucocorticoid and the absolute dose all play a role in the occurrence of GIDM [ 14 ].
The odds ratio for presenting with new-onset diabetes after taking glucocorticoids in various studies has been reported to range from 1. It is unlikely that the development of hyperglycemia is related only to the existence of an underlying disease, because abnormalities in glucose metabolism have also been observed in experimental studies with healthy subjects.
A number of predictors of the onset of GIDM have been identified [ 1 , 2 , 9 , 15 ]. These predictors include the dose and duration of glucocorticoid treatment, age, weight, previous glucose intolerance, reduced sensitivity to insulin or impaired insulin secretion stimulated by glucose, a family history of diabetes, or race, as shown in Table 1. Gender does not seem to be a predictor and, conversely, early withdrawal from corticosteroids is a protective factor [ 1 , 2 , 9 , 15 ].
Various glucocorticoids differ in their pharmacological properties and duration of action, and can be administered in different schedules depending on the therapeutic indication.
These drugs may cause hyperglycemia when administered at supraphysiological doses by any route topical, oral, inhaled, intramuscular, intravenous, or intra-articular [ 10 ]. The effects of glucocorticoids on glucose homeostasis are complex and not completely understood. The metabolic effects of glucocorticoids on glucose metabolism are seen at numerous stages in the insulin-signaling cascade [ 5 ]. Glucocorticoids reduce peripheral glucose uptake at the level of the muscle and adipose tissue [ 19 , 20 ].
Skeletal muscle is primarily responsible for the insulin-mediated capture of postprandial glucose and corticosteroids can induce insulin resistance by interfering directly with various components of the insulin signaling cascade [ 19 , 21 ]. Chronic glucocorticoid overexposure alters body composition, including the expansion of adipose tissue depots in the trunk, and impairs metabolism and insulin action, resulting in hyperglycemia and dyslipidemia [ 16 ].
The ability of glucocorticoids to induce adipose tissue lipolysis depends on their concentration, duration of exposure, and the specific adipose tissue depot [ 16 ]. The liver plays a major role in the control of glucose metabolism, maintaining fasting euglycemia. Corticosteroids increase endogenous glucose production directly by activating numerous genes involved in the hepatic metabolism of carbohy-drates, leading to increased gluconeogenesis [ 19 , 22 ].
The abilities of glucocorticoids to induce hyperglycemia depend on their dose and the duration of exposure [ 16 , 25 ]. The mechanisms of glucocorticoid-induced hyperglycemia are summarized in Table 2.
There are several reasons why glucocorticoid-induced hyperglycemia is important in clinical practice. First, it is quite common, and the problems of hyperglycemia itself, which are often severe, may cause hospitalization, prolonged hospital stays, or repeated emergency room visits. Second, glucocorticoids increase the risk of infection due to persistent hyperglycemia, which has a deleterious effect on patients' prognoses.
Moreover, the control of transient hyperglycemia in similar situations during hospitalization has been associated with decreased mortality and complication rates [ 26 , 27 , 28 ]. It is well known that glucocorticoid therapy may provoke new-onset type 2 diabetes mellitus T2DM and invariably worsens hyperglycemia in patients with preexisting diabetes mellitus [ 10 ].
Glucocorticoids are a well-known cause of hyperosmolar hyperglycemic nonketotic syndrome [ 28 ], which requires admission to the hospital for aggressive hydration and insulin therapy. The tendency for high-risk patients to develop new-onset hyperglycemia is often not anticipated, and outpatients with new-onset GIDM frequently require hospitalization for intravenous hydration and initiation of insulin therapy.
In addition, hyperglycemia in hospitalized patients with or without diabetes has been associated with poor outcomes regardless of the underlying cause [ 17 ]. Inpatient hyperglycemia is known to be associated an increased length of stay and a greater incidence of infections [ 27 ]. In addition, sustained glucocorticoid treatment increases the potential for future cardiovascular disease through multiple pathways [ 11 ].
Glucocorticoids are administered using different schedules, doses, and methods, and it is possible that the mode of administration e. Knowledge of these hyperglycemia patterns is essential to establish the most appropriate strategy for diagnosis and therapy.
GIDM is defined as an abnormal increase in blood glucose associated with the use of glucocorticoids in a patient with or without a prior history of diabetes mellitus. The diagnosis of GIDM, as well as other types of diabetes, is set according to the criteria established by expert committees [ 29 ].
It is generally thought that glucocorticoids result mainly in an increase in postprandial blood glucose levels [ 30 ]. The use of a continuous blood glucose monitor in chronic obstructive pulmonary disease patients treated with prednisolone demonstrated that hyperglycemia predominantly occurred in the afternoon and evening, indicating that this would be the most appropriate time to screen for GIDM as well as the preferable time to implement specific treatments [ 31 ].
In patients treated with most glucocorticoids, measuring fasting blood glucose can underestimate glucocorticoid-induced hyperglycemia and diabetes, particularly in intermediate-acting treatments that are administered in single morning doses. However, given the pathophysiology and pattern of glucocorticoid-induced hyperglycemia, it can be inferred that the established criteria [ 29 ] provide a low diagnostic sensitivity in most patients with GIDM.
For most glucocorticoids, measuring fasting blood glucose can underestimate glucocorticoid-induced hyperglycemia and diabetes, especially in cases of intermediate-acting glucocorticoid treatment with single morning doses [ 11 ]. On the contrary, postprandial glycemia after lunch offers the greatest diagnostic sensitivity. Preprandial glycemia at dinner offers less sensitivity, but is easier to standardize [ 11 ].
Blood glucose monitoring should be considered for non-diabetic patients who are at high risk of developing GIDM as shown in Table 1 [ 5 ]. In addition, an OGTT should also be performed as early as to detect diabetes in those deemed to be at risk [ 32 ]. However, the OGTT does not seem suitable for the diagnosis of GIDM because, apart from the difficulties associated with its implementation, it is performed in fasting patients and may underestimate the increase in glucose levels that occurs predominantly in the evening [ 2 ].
In order to appreciate the magnitude of GIDM, one needs to consider that glucocorticoids cause predominantly postprandial hyperglycemia and therefore, using impaired fasting glucose as the sole diagnostic criterion, may underestimate the true incidence of GIDM.
In patients with pre-existing diabetes or risk factors for GIDM, screening should be performed even when low doses of corticosteroids are indicated [ 2 ]. Failure to appreciate the frequency of hyperglycemia in patients without diabetes is associated with the time course of corticosteroid action with prednisone or prednisolone given once daily [ 7 ].
No consensus exists for the optimal screening frequency. Some authors recommend screening with a once- to twice-weekly 2-hour post-lunch capillary blood glucose test in patients who are not known to be diabetic, but who are at a high risk of GIDM [ 5 ].
The American Diabetes Association further recommended that glucose monitoring be conducted in patients without known diabetes who receive therapies with a high risk of hyperglycemia, such as parenteral or enteral nutrition, glucocorticoids, immunosuppressive therapy, or octreotide [ 26 ]. The Endocrine Society recommended that all patients have blood glucose levels tested on admission, regardless of whether they have a pre-existing diagnosis of diabetes [ 27 ]. This approach is believed to be warranted by the opportunity to diagnose new diabetes and to assess glycemic control early course of hospitalization.
Therefore, continued blood glucose monitoring is advisable before meals and at bedtime in patients who exhibit hyperglycemia, and is definitely recommended for those who require anti diabetic medications. Efforts to minimize hyperglycemic episodes are beneficial for patients exposed to glucocorticoids.
Fluctuations in plasma glucose concentrations have shown an increased risk of cardiovascular mortality [ 35 ]. As is the case for diagnosis, no clear evidence exists for the establishment of therapeutic goals in patients with GIDM.
In the case of chronic treatment with glucocorticoids at more or less stable doses, the control goals and the need for drug treatment can be based on the recommended control aims for most patients with diabetes mellitus: Similarly to the recommendations for T2DM, the introduction of therapeutic measures should be progressive and additive.
The selection strategy for hypoglycemic drugs should prioritize those with a mechanism of action that fits with the pathophysiology of the process and the patient's hyperglycemic profile. In the posttransplant setting, as more studies will be conducted with these and other agents, it is essential to focus attention to on drug—drug interactions is essential. At present, no consensus guidelines exist for the optimal management of hyperglycemia secondary to glucocorticoids, although various opinions have been published by international organizations.
There is no evidence to confirm which hypoglycemic drugs and treatment regimens are more effective in achieving adequate glycemic control and lowering complication rates in patients with glucocorticoid-induced hyperglycemia [ 2 ]. Therefore, the recommendations proposed in the present review are based on the pathophysiology of the process, the mechanism of action of various hypoglycemic drugs, and few clinical studies.
First, it is important to evaluate the degree of pre-existing glucose intolerance, the patient's clinical condition, and the degree of hyperglycemia. Second, it is essential to determine the type, dose, and frequency of administration of the corticosteroid compound. Third, it is necessary to recognize the mechanism of action, pharmacokinetics, and pharmacodynamics of various hypoglycemic drugs. The final relevant aspect of addressing the treatment of GIDM is to differentiate between temporary and indefinite treatment with glucocorticoids.
All these aspects condition the selection and schedule of hypoglycemic measures, as well as the goals set in terms of glycemic control. Together with, or after, lifestyle measures, hypoglycemic drugs with insulin-sensitizing effects are indicated.
Other oral hypoglycemic drugs or insulin therapy can be considered as the second drug of choice [ 2 ]. As second drugs of choice, pioglitazone, sulfonylureas, glinides, dipeptidylpeptidase 4 DPP-4 inhibitors, glucagon-like peptide 1 GLP-1 receptor agonists or insulin therapy can be considered, taking into account their profile of action, tolerance, cost, and risk for hypoglycemia, especially at night [ 1 ].
As with all types of diabetes, the initial steps to improve glycemic control incorporate lifestyle modifications, which include exercise and dietary counseling to provide options that may reduce postprandial hyperglycemia [ 3 ].
Theoretically, of the entire range of oral agents that can be used to treat glucocorticoid-induced or glucocorticoid-exacerbated diabetes, preference should be given to agents that target postprandial hyperglycemia and have a rapid onset of action.