Is It Time for a New Algorithm for the Pharmacotherapy of Steroid-Induced Diabetes?

Abstract

Glucocorticoids (GS) are widely used in multiple medical indications due to their anti-inflammatory, immunosuppressive, and antiproliferative effects. Despite their effectiveness in treating respiratory, skin, joint, renal, and neoplastic diseases, they dysregulate glucose metabolism, leading to steroid-induced diabetes (SID) or a significant increase of glycemia in people with previously diagnosed diabetes. The risk of adverse event development depends on the prior therapy, the duration of the treatment, the form of the drug, and individual factors, i.e., BMI, genetics, and age. Unfortunately, SID and steroid-induced hyperglycemia (SIH) are often overlooked, because the fasting blood glucose level, which is the most commonly used diagnostic test, is insufficient for excluding both conditions. The appropriate control of post-steroid hyperglycemia remains a major challenge in everyday clinical practice. Recently, the most frequently used antidiabetic strategies have been insulin therapy with isophane insulin or multiple injections in the basal-bolus regimen. Alternatively, in patients with lower glycemia, sulphonylureas or glinides were used. Taking into account the pathogenesis of post-steroid-induced hyperglycemia, the initiation of therapy with glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors should be considered. In this article, we present a universal practical diagnostic algorithm of SID/SIH in patients requiring steroids, in both acute and chronic conditions, and we present a new pharmacotherapy algorithm taking into account the use of all currently available antidiabetic drugs.

Keywords: diabetes; glucagon-like peptide 1 agonists; glucocorticoids; pharmacotherapy algorithm; steroid-induced diabetes.

Figure 1

Mechanisms of GS impact on glucose metabolism and the potential pharmacological target points to reduce glycemia. GLP-1: glucagon-like peptide-1; DPP-4: inhibitors-dipeptidyl peptidase 4 inhibitors; SGLT2i: sodium glucose cotransporter-2 inhibitors.

Figure 2

Glycemic patterns during therapy with intermediate-acting glucocorticoids based on [38] and authors’ own experiences.

Figure 3

A diagnostic algorithm for SID and SIH based on the present medical history and laboratory markers of diabetes. DM: diabetes mellitus, OGTT: oral glucose tolerance test; FPG: fasting plasma glucose level; GS: glucocorticoids; SID: steroid-induced diabetes; SIH: steroid-induced hyperglycemia; PCOS: polycystic ovarian syndrome.

Figure 4

The effects of GLP-1A (GLP-1 agonists)/GLP1-RA activation on different tissues and organs affecting insulin resistance. cAMP: cyclic AMP; PKA: protein kinaseA; GLP1-R: Glucagon-like peptide 1 receptor; TNF-a: tumour necrosis factor-a; CREB-cAMP: responsive element binding; PGC-1a: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PI3K: Phosphoinositide3-kinase; AKT/PKB: protein kinaseB; ROS: reactive oxygen species;PDK1: Phosphoinositide dependent protein kinase-1;AMPK-AMP: activated protein kinase; IRS: Insulin receptor substrate 1; SIRT1:sirtuin 1; GLUT: glucose transporter; mTOR: mammalian target of rapamycin; HIF-1a: Hypoxialnducible Factor 1 alpha; ADAM10: ADAM metallopeptidase domain 10; Hsp70: heat-shock protein 70; MEK: mitogen activated protein kinase kinase; ERK1/2: extracellular signal-regulated kinases; BCI2: B-cell lymphoma 2; MAPK: Mitogen-activated protein kinase; Pax6: paired box 6 protein; SCFA: short-chain fatty acids; RUNX2: Runt-related transcription factor 2; SP7: Transcription factor Sp7; OPN: Osteopontin; ALP: Alkaline phosphatase; OPG: Osteoprotegerin; BGLAP: Osteocalcin gene,COL1-Type-1 collagen; gloglucose; ins-insulin; LPL: Lipoprotein lipase; PPARy: Peroxisome proliferator- activated receptory; ATGL: adipose trigliceride lipase; FABP4: fatty acid binding protein 4; SREBP1: sterol regulatory element-binding transcription factor 1.

Figure 5

Proposed new algorithm of SID pharmacotherapy with the usage of the newest antidiabetic agents, own modification based on [26]. SID: steroid-induced diabetes; SIH: steroid-induced hyperglycemia; GLP-1RA: glucagon-like-peptide 1 receptor agonists; DLPH: drugs with low potency of lowering postprandial glucose; DHPH: drugs with high potency of lowering postprandial glucose; SU: sulphonylureas; SGLT2i: sodium-glucose cotransporter-2 inhibitors; DPP-4: inhibitors- dipeptidyl peptidase 4 inhibitors.

Figure 6

Proposed new algorithm of SIH pharmacotherapy with the usage of the newest antidiabetic agents, own modification based on [1]. DM: diabetes mellitus; SID: steroid-induced diabetes; SIH: steroid-induced hyperglycemia; GLP-1RA: glucagon-like-peptide 1 receptor agonists; DLPH: drugs with low potency of lowering postprandial glucose; DHPH: drugs with high potency of lowering postprandial glucose; SU: sulphonylureas; SGLT2i: sodium-glucose cotransporter-2 inhibitors; DPP-4: inhibitors- dipeptidyl peptidase 4 inhibitors.