Steroid diabetesSince the advent of glucocorticoid therapy for autoimmune can i keep anadrol gains in the s, their widespread application has led to the insulin steroid induced diabetes therapy-limiting discovery of many adverse metabolic side effects. Unanticipated hyperglycemia associated with the initiation of glucocorticoids often leads to preventable hospital insulin steroid induced diabetes, prolonged hospital stays, increased risks for infection and reduced graft function in solid organ transplant recipients. Challenges in managing steroid-induced diabetes stem from wide fluctuations in post-prandial hyperglycemia and the lack of clearly defined treatment protocols. The mainstay of treatment is insulin therapy coincident with meals. This article aims to review the pathogenesis, risk factors, diagnosis and treatment principles unique to steroid-induced diabetes. Glucocorticoids are extensively used in almost every subspecialty of medicine. Indications for short-term acute steroid therapy can be seen in exacerbation of chronic obstructive pulmonary disease, acute gout, chemotherapy protocols, bacterial meningitis and in pregnant women for fetal lung maturation, to name a few.
Steroid diabetes - Wikipedia
Steroids are drugs that have been used extensively in a variety of conditions. Although widely prescribed for their anti-inflammatory and immunosuppressive properties, glucocorticoids have several side effects, being hyperglycemia one of the most common and representative.
In the present review, we discuss the main epidemiologic characteristics associated with steroid use, with emphasis on the identification of high risk populations. Additionally we present the pathophysiology of corticosteroid induced hyperglycemia as well as the pharmacokinetics and pharmacodynamics associated with steroid use. We propose a treatment strategy based on previous reports and the understanding of the mechanism of action of both, the different types of glucocorticoids and the treatment options, in both the ambulatory and the hospital setting.
Finally, we present some of the recent scientific advances as well as some options for future use of glucocorticoids. We present the pathophysiology of corticosteroid induced hyperglycemia as well as the pharmacokinetics and pharmacodynamics associated with steroid use.
Steroids are drugs that have been used extensively in a variety of conditions, both acute and chronic[ 1 ]. At supraphysiological doses, they reduce the synthesis of pro-inflammatory cytokines, T-cell function, and antibody Fc receptor expression, which activate anti-inflammatory and immunosuppressive processes, making them the cornerstone in treatment of numerous inflammatory diseases[ 2 , 3 ].
Despite their efficacy, their use is limited by the wide variety of side effects, which can be divided into three categories: Immediate effects include fluid retention, blurred vision, mood changes, insomnia, weight gain, and modulation of the immune response. The more gradual effects are those related to endocrine metabolism, especially hyperglycemia, osteopenia with subsequent osteoporosis, dyslipidemia, central obesity, and adrenal suppression.
Additionally, acne, skin thinning, and dyspepsia are considered of gradual onset. Some of the idiosyncratic effects are avascular necrosis, cataracts, open-angle glaucoma and psychosis[ 3 - 5 ]. Steroids are the main cause of drug-induced hyperglycemia[ 4 ]. Furthermore, in some populations they can precipitate acute complications such as nonketotic hyperosmolar state, and diabetic ketoacidosis[ 10 ] and in a few instances death, especially in patients with pre-existing DM.
Exacerbated and uncontrolled hyperglycemia is a common complication in patients with DM and carbohydrate intolerance as previously documented[ 11 ] Moreover, DM incidence in patients without a prior history of hyperglycemia to steroid use varies from The main risk factors that have been identified as predictors of developing diabetes are: In addition, there are population groups with a greater risk of developing hyperglycemia during treatment with steroids, among these are patients with a history of gestational DM, a family history of diabetes OR: The main associated factors related to inpatient hyperglycemia are previous history of DM, a higher prevalence of comorbidities, prolonged treatment with steroids and older age[ 9 , 23 ].
Its storage is totally dependent on the presence of insulin and the availability of the glucose transporter type 4 GLUT4 glucose transporter in the cell membrane. On the other hand, steroids are responsible for the catabolism of proteins with the subsequent increase in serum amino acids, which also interfere with insulin signaling in the muscle cell.
Finally, they increase lipolysis, resulting in an increase in serum free fatty acids and triglycerides. These promote the accumulation of intramyocellular lipids acetyl coenzyme A, diacylglycerol and ceramide , reducing the entry and storage of intramuscular glucose[ 4 ]. In the fasting state, the liver maintains euglycemia via gluconeogenesis and glycogenolysis, effects that are counteracted by insulin after food intake.
At the level of adipose tissue they promote the deposition of fat in viscera, while reducing peripheral reserves. Steroids have direct effects on various adipokines: Finally, they are responsible for increasing triglyceride hydrolysis in adipocytes[ 4 ]. These effects have the final result of increased plasma levels of non-sterified fatty acids, which accumulate within muscle cells and reduce glucose uptake by interfering with insulin signaling[ 24 , 25 ]. Additionally, they reduce insulin synthesis and it is thought that they reduce cell mass through the induction of beta cell apoptosis.
Likewise, in response to the decrease in insulin sensitivity, the pancreatic beta cell normally increases insulin secretion to maintain glucose homeostasis, but at times this increase is not sufficient to compensate for the insulin resistance resulting in hyperglycemia[ 4 , 15 ]. In healthy subjects, this mechanism is compensated by an increase in pancreatic insulin secretion, causing serum glucose levels to remain within normal range[ 14 ].
Steroids of adrenal origin are synthesized from cholesterol, and their secretion follows a circadian pattern and a pulsatile ultradian rhythm. They are metabolized in the liver and their conjugated metabolites are excreted mainly by the kidneys[ 5 , 25 , 26 ].
The development of insulin resistance is mainly postprandial and varies depending on the type of steroid used: Prednisone and methylprednisolone are classified as intermediate-acting GCs, with a peak of action h following administration.
Their effect on glucose levels is mainly during the afternoon and night without effect in fasting glucose when they are administered in a single dose. On the other hand, they cause persistent hyperglycemia when administered in divided doses. Dexametasone fits in the long-acting GCs, with a steroid hyperglycemia that lasts for more than 24 h, with a slight decline during an overnight fast[ 5 , 25 , 26 ]. The effect of steroids is usually transient and reversible.
As steroid doses are reduced, their effect on endocrine metabolism returns to baseline and drug-induced diabetes is expected to resolve; however, this is not true in all cases[ 1 , 6 ]. There are few studies that describe the effect of long-term use of GCs on pancreatic function and the development of DM. Despite its frequency, little is known about the impact of hyperglycemia associated with steroid use on clinical comorbidities and mortality.
It is known that rheumatic diseases per se represent an important cardiovascular risk factor, which makes them the leading cause of premature mortality in these patients. Therefore, it is thought that the coexistence of inflammatory diseases and steroid-induced hyperglycemia may lead to worse cardiovascular consequences[ 3 , 10 ].
Similarly the diabetic patient possesses a traditional cardiovascular risk factor for microvascular and macrovascular complications. Fluctuations in serum glucose levels have been associated with increased cardiovascular mortality associated with increased LDL cholesterol, endothelial dysfunction, activation of the coagulation cascade, increased pro-inflammatory cytokine production, and oxidative stress resulting in macrovascular disease progression[ 2 ].
Several studies have reported that transient increases in serum glucose are associated with acute inflammatory processes and endothelial dysfunction in both diabetic and non-diabetic patients[ 14 ]. In the hospitalized patient, acute hyperglycemia is associated with increased hospital stay, repeated emergency room visits, risk of admission to intensive care, higher risk of infection rates, poor wound healing and higher hospital mortality rates[ 9 , 23 , 28 ].
In susceptible populations such as the elderly, persistent hyperglycemia associated with GC use can precipitate hyperglycemic hyperosmolar states, which would require frequent hospital admissions for aggressive hydration and insulin therapy, as well as increased complications related to inpatient hyperglycemia[ 19 ]. Additionally, steroid hyperglycemia represents a strong predictor of graft failure in the transplant population with a fold increased risk of fatal and non-fatal cardiovascular events as compared with non-diabetic patients[ 29 , 30 ].
All patients who are started on steroid treatment should have a baseline glucose, as well as education on daily self-monitoring of glucose[ 6 , 8 ]. The diagnosis of steroid hyperglycemia is similar to the current criteria established by the American Association of Diabetes: Based on the pathophysiology and pattern of GC-induced hyperglycemia it seems that some of the current criteria for diagnosis of DM underestimate the diagnosis itself.
Since steroid-induced diabetes is detected mainly in the postprandial state, we do not recommend the use of fasting glucose as well as the glucose tolerance curve as reliable diagnostic methods, because there is a high possibility of losing some of the hyperglycemic patients. The postprandial glycemia after lunch offers the greatest diagnostic sensitivity, especially when intermediate-acting GCs are administered in a single morning dose.
In hospitalized patients, monitoring should start with capillary glucose determination from the start of steroid treatment. Several protocols to detect patients at risk of steroid-induced hyperglycemia are being studied.
This is based on the hypothesis that abnormalities in insulin secretion and loss of beta cell function present in pre-diabetic individuals can be exacerbated in response to an increase in insulin requirements secondary to GC exposure. However, it is necessary to develop further studies to confirm its usefulness. Due to differences in steroid dose and the scheme used, the approach to hyperglycemia should always be individualized[ 35 ].
Algorithm for the management of glucocorticoids-induced hyperglycemia. Glargine and other analogues can be recommended in cases of nocturnal hyperglycemia associated with long-acting steroid use. Neutral protamine Hadegorn; BG: There is little information on the therapeutic efficacy of oral agents in steroid-induced hyperglycemia.
Furthermore, the action profile of oral hypoglycemic drugs throughout the day does not usually coincide with the pattern of GC induced hyperglycemia[ 13 , 25 ]. However, due to their narrow therapeutic window, prolonged use increases the risk of hypoglycemia with short-term steroids, especially where single morning doses of steroids are given[ 14 ].
In patients where intermediate-acting GCs in two or more daily doses, by long-term preparations such as dexametasone, or by intra-articular GCs are used, long acting sulfonylureas may be considered as a therapeutic option, always bearing in mind the risk of hypoglycemia in these type of drugs.
Metformin may be a good therapeutic option because of its direct effect on the improvement of insulin sensitivity; however, there are few articles that support its usefulness. On the other hand, many patients who are treated with steroids have significant co-morbidities associated with hypoxia and renal failure, that make the use of metformin contraindicated[ 13 , 14 ]. Thiazolidinediones TZDs were used for long-term treatment in patients with steroid-induced hyperglycemia.
However, their usefulness is limited by the risk of edema, heart failure, hepatotoxicity and possible cardiovascular effects[ 37 ]. They have also been associated with increased risk of fractures, which together with the osteopenic effect of steroids is an important contraindication to their use[ 1 , 14 ].
Selective inhibitors of the dipeptidyl peptidase 4 DPP-4 enzyme and glucagon-like peptide-1 have shown effectiveness in the control of hyperglycemia since they promote enhanced release of glucose dependent insulin, inhibiting glucagon secretion and enhancing uptake into peripheral tissues, in addition to increasing the speed of gastric emptying, with decreased appetite and calorie intake[ 13 , 32 , 38 ]. Regarding steroid hyperglycemia, DPP-4 have shown to decrease glycated hemoglobin in up to Continuous intravenous infusion of exenatide significantly improves GC-induced hyperglycemia in healthy individuals in association with restoration of initial insulin secretion and decreased glucagon concentrations.
Additionally, exenatide has been associated with reduced hypoglycemia and the promotion of weight loss[ 13 ]. Despite the benefits observed, their applicability in these patients is still under study.
Nevertheless, they can be recommended in patients receiving intermediate-acting corticosteroids in a single morning dose because their immediate onset of action, their predominant effect on postprandial glycemia, and their lack of risk of hypoglycemia related to glucose-dependent effects[ 25 ]. A new review has been published with this type of drugs[ 33 ]. Glinides allow minimal dose titration and have an immediate onset of action and short duration of effect, which adapts to the hyperglycaemic profile of the corticosteroids and reduces the risk of hypoglycemia in the morning, coinciding with the disappearance of the hyperglycemic action of corticosteroids[ 25 ].
Renal sodium-linked glucose transporter 2 inhibitors are new antidiabetic drugs with an insulin-independent mechanism of action. They pose one remarkable advantage compared with already established antidiabetics: Clinical trials showed promising results: Nevertheless, some safety concerns remain, such as genital mycotic infections, urinary tract infections and cardiovascular risks in vulnerable patients.
Several therapeutic schemes have been used, among which the use of prandial insulin has been included, and also based on schemes of steroid dose and the body mass index of the patient[ 14 ]. In general, hyperglycemia associated insulin resistance, present at the start of treatment with steroids, generates the need for large doses of insulin in early stages of treatment, which are gradually reduced once glucose levels are controlled[ 1 , 12 ].
The prandial insulin scheme is based on the observation that even though normal levels of fasting glucose can be present; serum glucose gradually increases throughout the day reaching a maximum concentration after meals, with a gradual reduction at night.
This mechanism could be explained by defective postprandial insulin secretion[ 14 ]. Regular insulin is recommended for people who usually eat snacks between meals and those with delayed gastric emptying; on the other hand, rapid insulin, LysPro and Aspart, are used in people who do not eat snacks between meals and who usually eat a high carbohydrate diet[ 1 , 7 ]. The initial dose is calculated at 0. If the patient continues with pre-prandial corrections the initial insulin dosage should be increased[ 1 ].
The use of basal insulin is usually considered when using high doses of steroids are used or in those patients with characteristics of diabetes prior to the start of the steroid.
Additionally, glargine can be recommended particularly in cases of nocturnal hypoglycemia[ 1 , 34 ]. In patients who receive a single daily steroid dose, generally in the morning, NPH insulin in the morning is recommended, considering that the peak and duration of action of this insulin is similar to conventional intermediate-steroids prednisone and prednisolone [ 35 ]. Clore et al[ 14 ] recommend using a scheme based on weight and steroid dose, using an initial dose of 0.
When using dexamethasone, NPH could be replaced by detemir or glargine due to their pharmacodynamic similarities[ 14 ]. In-hospital dose calculation is similar to outpatient doses, with some modifications. On the other hand, if high doses of steroids are used and the dose must be calculated empirically, the insulin dose will be calculated based on weight 0.