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3: Glucocorticoid, Mineralocorticoid, and Immunomodulatory Agents

DOI: 10.2337/9781580406192.03

Glucocorticoid Steroids

In people with diabetes, systemic glucocorticoid steroid therapy impairs glycemic control via multiple mechanisms. Glucocorticoids induce insulin resistance, inhibit peripheral glucose utilization, stimulate lipolysis, and increase hepatic glucose production.^1–3 In addition, these steroids inhibit insulin secretion and insulin biosynthesis, stimulate glucagon release, and induce endoplasmic reticulum stress and β-cell apoptosis following prolonged exposure (Figure 3.1).^2,4–6 In people with prediabetes and those at high risk for type 2 diabetes (T2D), prolonged steroid therapy could worsen glucose tolerance and induce diabetes. There is significant heterogeneity in individual susceptibility to glucocorticoid-induced dysglycemia. Accurate data on the exact magnitude of risk are lacking, and the tendency to report mostly fasting glucose levels might mask the true prevalence of the problem.

Figure 3.1—Constellation of the diabetogenic actions of glucocorticoids. ER, endoplasmic reticulum.

In one nested case control study based on a family practice database, the adjusted odds ratio for diabetes associated with three or more oral glucocorticoid prescriptions was 1.36 (95% confidence interval [CI] 1.10–1.69; P = 0.005).⁷ Thus, the risk of treatment-emergent diabetes was increased by 36% following oral steroid exposure.⁷ The diabetes risk is dependent on the dose and duration of glucocorticoid therapy, but even single doses of potent agents, such as dexamethasone, can induce transient hyperglycemia.⁸ Genetic factors play a prominent role in determining susceptibility: in one study, a family history of diabetes increased the risk of steroid-induced diabetes tenfold.⁹ Other risk factors for steroid-induced diabetes include the potency of steroid preparation, age, weight, decreased β-cell capacity, and a history of gestational diabetes (Table 3.1).^10,11 Compared with systemic therapy, inhaled or topical glucocorticoids or glucocorticoid eye drops have not been consistently associated with hyperglycemia.^6,7,12

Table 3.1—Risk Factors for Steroid-Induced Diabetes

• Family history of diabetes

• Type, dose, and duration of steroid therapy

• History of gestational diabetes

• Overweight or obesity

• Older age

• Decreased insulin secretory capacity

High doses of topical steroids, however, can sometimes induce hyperglycemia.¹⁰ Reports are conflicting on the effects of intra-articular steroid injection on blood glucose levels.^13–15 Overall, the reported glucose excursions tend to be transient, returning to baseline within a few hours to 5 days following the injection of steroids into inflamed joints.^15,16

Approach to Risk Reduction

When systemic glucocorticoid therapy is unavoidable, as in patients with acute severe asthma or transplant recipients, blood glucose levels should be monitored frequently and the antidiabetic regimen should be optimized. Insulin sensitizer drugs and insulin augmentation, alone or in combination, can help restore glycemic control in most patients with steroid-induced diabetes.¹⁷ Because the metabolic effects of glucocorticoids are dose related, use of the minimum effective dose for treatment of the primary condition is recommended. For people with prediabetes and those at high risk for T2D, lifestyle modification (Table 3.2) has been shown to be effective in preventing diabetes and should be advocated empirically, although there are no specific data for the steroid-treated population. In experimental animals, treatment with etomoxir (an inhibitor of fatty acid oxidation) improves insulin sensitivity and reverses glucocorticoid-induced insulin resistance.¹⁸

Table 3.2—Approach to Prevention of Glucocorticoid-Induced Diabetes

• Identify risk factors for diabetes (age, family history, overweight/obesity, etc.)

• Monitor blood glucose frequently in high-risk subjects

• Recommend lifestyle modification for high-risk people

• Use minimum effective dose of glucocorticoid steroid

• Consider alternate-day regimen, if feasible

• Consider metformin for people with prediabetes (impaired fasting glucose and impaired glucose tolerance)

The possible prophylactic use of insulin sensitizers (e.g., thiazolidinediones [TZDs] and metformin) to prevent diabetes during prolonged steroid therapy is somewhat appealing.¹⁹ Such an approach, however, would be an off-label use of metformin and TZDs; additionally, the judicious selection of appropriate candidates for such an intervention requires an exact treatment-emergent diabetes risk prediction capability that currently is elusive. Absent data from randomized controlled trials, the efficacy of prophylactic antidiabetes therapy is unknown, as are the number needed to treat, and the merit of such an approach over that of careful monitoring and lifestyle modification. On the basis of the aggregation of diabetes risk factors, underlying ailments, and the glucocorticoid regimen, patients deemed to be at particularly high risk for steroid-induced diabetes (Table 3.1) may be considered for training in ambulatory self–blood glucose monitoring. The training should include instructions on the expected range of fasting and nonfasting blood glucose values, and out-of-range values that should trigger contact with the treating physician. The record of home blood glucose measurement should be reviewed during clinic visits, to determine whether a pattern of dysglycemia is discernible. As a pragmatic compromise, metformin can be considered in addition to lifestyle modification in high-risk patients who show evidence of prediabetes (impaired glucose tolerance [IGT] and impaired fasting glucose [IFG]) before or during prolonged steroid therapy, to prevent progression to diabetes.²⁰

The mechanism of action of glucocorticoids involves binding to the intracellular glucocorticoid receptor and subsequent interaction with nuclear targets. At the genomic level, the anti-inflammatory actions of glucocorticoids are mediated by transrepression of target genes, whereas the metabolic effects are mediated mostly by transactivation of genes. Thus, novel compounds in development (selective glucocorticoid receptor agonists [SEGRAs]) might be successful in selectively targeting inflammation, while avoiding adverse metabolic effects of glucocorticoids.²¹ The future availability of SEGRAs would be a great advance in the prevention of glucocorticoid-induced diabetes.²²

Although there are individual variations of therapeutic needs and response patterns, patients who develop hyperglycemia during treatment with glucocorticoids frequently require insulin therapy for optimal glycemic control.²³ A detailed discussion of the management of breakthrough hyperglycemia during glucocorticoid therapy is beyond the scope of this work. Flexibility is required, however, so that the intensity of insulin treatment can be governed by the ambient glucocorticoid regimen, including consideration of the pharmacodynamics of the specific glucocorticoid in use. Some effective insulin regimens for control of steroid-induced diabetes in hospitalized patients are available.^24,25

Mineralocorticoids: Aldosterone and Glucoregulation

In his pioneering studies that described the syndrome of hyperaldosteronism in the 1950s, Dr. Conn observed an increased risk of diabetes in affected patients.²⁶ Although not fully understood, the mechanisms linking hyperaldosteronism to glucose intolerance and diabetes include hypokalemia, activation of reactive oxygen species and inflammatory cytokines, and impaired insulin secretion.^4,27,28 Hypokalemia induced by aldosterone activation of the mineralocorticoid receptor was once thought to be the dominant mechanism for dysglycemia through its negative effect on insulin secretion. Potassium repletion only partially restores insulin secretion and glucose tolerance, however. To explain the latter finding, direct inhibitory effects of aldosterone on glucose-stimulated insulin secretion have been observed in isolated pancreatic islets cells, probably through activation of reactive oxygen species.²⁸ Similar inhibitory effects of aldosterone on insulin signaling have been demonstrated in adipocytes and skeletal muscle cells. Thus, multiple mechanisms (including hypokalemia, mineralocorticoid receptor–mediated activation of reactive oxygen species and proinflammatory cytokines, insulin resistance, and impaired insulin secretion) link hyperaldosteronism to glucose intolerance and hyperglycemia. Interestingly, mineralocorticoid receptor blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation, all of which should ameliorate the deleterious effects of aldosterone on glucoregulation.²⁷

The mineralocorticoid agent, fludrocortisone (Florinef), is prescribed widely for patients with primary adrenal insufficiency and conditions associated with aldosterone deficiency, hyperkalemia, orthostatic hypotension, and type IV renal tubular acidosis. To date, the clinical use of Florinef has not been associated with diabetes risk in published reports. As noted, mineralocorticoid antagonists, spironolactone and eplerenone, have been associated with improved insulin sensitivity and insulin secretion.²⁷

Immunomodulatory Agents

Calcineurin Inhibitors and Post-Transplant Diabetes

Organ transplantation is an expanding area of modern medical practice, and diabetes is being increasingly diagnosed in organ recipients. Post-transplant diabetes (also known as new-onset diabetes after transplantation [NODAT]) refers to the occurrence of diabetes in subjects who previously did not have diabetes following transplantation. The development of NODAT is associated with adverse clinical outcomes, including renal allograft loss, post-transplant infections, cardiovascular disease, and increased mortality.^29–31 Variable incidence rates of NODAT have been reported over variable intervals among recipients of different organ transplants. The estimated rates of NODAT at 12 months or longer post-transplant are ~20% for kidney transplants, 9% to 21% for liver transplants, and ~20% for lung transplants.^32–34 Most of the data in this field are derived from analysis of renal transplants, because information on other types of transplants is limited. The peak incidence of NODAT appears to occur around 3 months post-transplant, but the risk of diabetes persists for much longer.

The clinical presentation of NODAT is consistent with T2D, and studies have identified insulin resistance and impaired β-cell function as the underlying mechanisms.³⁵ The insulin resistance can be induced in subjects who previously were normoglycemic and can be aggravated in subjects who have prediabetes, following organ transplantation. Medications used for post-transplant immunosuppression have been implicated in the pathogenesis of NODAT. The calcineurin inhibitors (tacrolimus and cyclosporine) and steroids have been the most documented drugs associated with the induction of NODAT. The agents, however, also are the most widely used immunosuppressive agents in the transplant population, and many other risk factors appear to influence the development of NODAT (Table 3.3).^32,36

Table 3.3—Risk Factors for Post-Transplant Diabetes Mellitus

Nonmodifiable	Modifiable
Age >45 years Race Ethnicity	• Immunosuppressive regimen - Tacrolimus - Glucocorticoid steroids - Combined tacrolimus and steroid • Acute rejection • Prediabetes (impaired fasting glucose or impaired glucose tolerance) • Body mass (BMI > 25 kg/m2 ) • Cadaveric organ • Hepatitis-C infection