Diabetes mellitus describes diseases of abnormal carbohydrate metabolism that are characterized by hyperglycemia. Patients usually present from asymptomatic, classical symptoms (e.g. polyuria, polydipsia, polyphagia, weight loss) to diabetic ketoacidosis and complications. There are a lot of advancement in the treatment of diabetes recently. Type 1 diabetes has traditionally been treated with insulin and type 2 diabetes has been treated with oral agents, such as sulfonylureas or metformin, alone or in combination with insulin (1).

There are several new categories of medications approved for the treatment of diabetes, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors, an amylin analogue, and sodium-glucose cotransporter-2 (SGLT-2). Recently, the was a complaint case in Medical Council about the use of these novel anti diabetes medication and patient was presented with DKA in A&E. (2) Emergency providers will inevitably encounter both patients taking these medications and patients presenting with adverse effects and overdose from them. This articles will focus on the novel agent for diabetes.

Insulin Sensitizers

e.g. thiazolidinediones, rosiglitazone and pioglitazone

Mechanism of action

The insulin sensitizers are also known as Peroxisome Proliferator Activated Receptor agonists (PPARs). These receptors are of three sub-types i.e. PPARα, δ and γ. The mechanism of action is to increase insulin sensitivity by acting on adipose tissue and muscle to increase glucose utilization through altering the transcription of multiple genes involved in glucose and lipid metabolism (3) PPARγ agonists are generally thiazolidinedione and are known as “glitazones” is specific for glucose metabolism. Recently dual PPARα/γ agonists was found to have synergistic action and maintains the lipid metabolism, insulin sensitivity and inflammation control. (4)

Additional Benefit

Pioglitazone showed additional benefits in improving the lipid profile of patients in the PROactive Study, independent of the beneficial effect of glycaemic control. (8)

Potential side effects

Rosiglitazone is rarely used (and is no longer widely available) because of the increased risk of heart failure and concern for increased risk of atherosclerotic cardiovascular events.(7) Pioglitazone was found to have increased risk of bladder cancer (5,6) Thiazolidinediones should not be used in patients with heart failure or any evidence of fluid overload, active or history of bladder cancer.

Incretin mimetics

eg, GLP-1 receptor agonists, dual-acting GLP-1 and glucose-dependent insulinotropic polypeptide [GIP] receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibitors

Mechanism of action

Glucagon- like peptide (GLP) and Glucose dependent Insulinotropic polypeptide (GIP) are the incretins or peptides derived from gut. It works by increasing insulin secretion and inhibiting glucagon release, thus have blood glucose-lowering effects which help to reduce HbA1c levels.(9) The half-life of GLP-1 is about 1-2 minutes due to rapid metabolism by dipeptidyl peptide – IV (DPP – IV) enzymes. DPP-4 inhibitors work by preventing the inactivation of the incretin hormone. There are many formulations of GLP-1 agonists (Lixisenatide and liraglutide, albiglutide, dulaglutide, semaglutide), all of which historically were injectable and administered subcutaneously due to poor oral bioavailability. Recently, the FDA approved an oral formulation of semaglutide.

https://www.sciencedirect.com/science/article/pii/S075333222030901X#bib0380

Additional benefit

DDP-4 inhibitor’s potential to lower HbA1c is in the range of 0.5 and 1.0% and their safety profile is favorable (11). They have no intrinsic hypoglycaemia risk and are body weight neutral. Another favorable characteristic of the DPP-4 inhibitors is their efficacy and safety profile in patients with impaired renal function.

Results of a meta-analysis of clinical studies (12) demonstrated 0.42-071% of HbA1c improvement with different GLP-1 receptor agonist. They are associated with modest weight loss and reduction in ASCVD outcomes.

Potential side effects

Acute pancreatitis has been reported in association with GLP-1 receptor agonist treatment. In rodent studies, diagnosis of pancreatitis should be considered if patient presented with abdominal pain when taking GLP-1 receptor agonist. Liraglutide and dulaglutide were associated with benign and malignant thyroid cell tumors (13). Overall, DPP-4 inhibitors are well tolerated.

Sodium-glucose co-transporter 2 inhibitors

e.g. empagliflozin, canagliflozin, and dapagliflozin

The SGLT2 is expressed in the proximal tubule and mediates reabsorption of approximately 90 percent of the filtered glucose load. SGLT2 inhibitors promote the renal excretion of glucose and thereby modestly lower elevated blood glucose levels in patients with type 2 diabetes.

Addition Benefit

SGLT2 inhibitors improves HbA1c by 0.4 to 1.1 %(15). They can promote weight loss and decrease the time to first cardiovascular event or death, less heart failure hospitalizations (HFH), and reduced MACE. They can also improve renal function with reduction of the need of RRT (16,17)

Potential Side effect

The use of use of SGLT2 inhibitors has been associated with frequent bacterial urinary tract infections or genitourinary yeast infections (18). Case report of Urosepsis and pyelonephritis and Necrotizing fasciitis of the perineum (Fournier's gangrene) has been reported with the use of SGLT2 inhibitors. SGLT2 inhibitors appear to increase the risk of diabetic ketoacidosis (DKA). The patient is usually presented with Euglycemic DKA We should be vigilant in any patient with nausea, vomiting, or malaise while taking SGLT2 inhibitors

Overall, these advances in diabetes pharmacotherapy offer new options for managing diabetes and improving long-term outcomes for patients. Other newer options including synthetic insulin, closed-loop insulin delivery systems are increasingly dispensed by endocrinologists. Emergency providers should be aware of these medications and their potential benefits and risks, in order to provide the best possible care for patients with diabetes.

Reference

1) National Diabetes Education Initiative, Diabetes management guidelines. Available at: http://www.ndei.org/ADA-diabetes-management-guidelines-pharmacologic-therapy-for-type-2-diabetes.aspx.html. Accessed March 17, 2017.

(2)https://www.hk01.com/%E7%A4%BE%E6%9C%83%E6%96%B0%E8%81%9E/864997/%E5%BC%B5%E5%81%89%E6%88%90%E4%B8%8D%E7%95%B6%E8%99%95%E6%96%B9%E8%97%A5%E7%89%A9%E8%87%B4%E7%97%85%E4%BA%BA%E9%9C%80%E6%B7%B1%E5%88%87%E6%B2%BB%E7%99%82-%E9%86%AB%E5%A7%94%E6%9C%83%E5%88%A4%E5%81%9C%E7%89%8C6%E5%80%8B%E6%9C%88%E7%B7%A9%E5%88%91

3) Yki-Järvinen H Thiazolidinediones.N Engl J Med. 2004;351(11):1106.

4) P. Balakumar, N. Mahadevan, R. SambathkumarA Contemporary Overview of PPARα/γ Dual Agonists for the Management of Diabetic Dyslipidemia Curr. Mol. Pharmacol., 12 (2019), pp. 195-201,

5) Huilin Tang Weilong Shi, Shuangshuang el Fu Pioglitazone and bladder cancer risk: a systematic review and meta‐analysis Cancer Med. 2018 Apr; 7(4): 1070–1080.

6) Lewis JD, Habel LA, Quesenberry CP et al Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. JAMA. 2015 Jul;314(3):265-77.

7) European Medicines Agency. European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim - September 23, 2010.

8) Peter Gæde Hans-Henrik Parving Oluf Pedersen PROactive study Lancet. 2006 Jan 7;367(9504):23-4

9) H. Rang, M. Dale, J. Ritter, P. MoorePharmacology (ninth ed.) (2003), pp. 408-419

Churchill Livingstone, Edinburg

(10) J. Holst From the Incretin Concept and the Discovery of GLP-1 to Today’s Diabetes TherapyFront. Endocrinol., 10 (2019),

11) Craddy P, Palin HJ, Johnson KI Comparative effectiveness of dipeptidylpeptidase-4 inhibitors in type 2 diabetes: a systematic review and mixed treatment comparison. Diabetes Ther. 2014;5(1):1. Epub 2014 Mar 25.

12) Kayaniyil S, Lozano-Ortega G, Bennett HA, et al.. A network meta-analysis comparing exenatide once weekly with other GLP-1 receptor agonists for the treatment of type 2 diabetes mellitus. Diabetes Ther 2016;7:27–43

13) Bjerre Knudsen L, Madsen LW, Andersen S Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151(4):1473. Epub 2010 Mar 4.

14) Sean M. Brady, Michael P. Kane , Robert S. Busch GLP-1 Agonist Use in a Patient With an Explainable Cause of Pancreatitis Volume 2, Issue 2, Spring 2016, Pages e82-e85

15) Clar C, Gill JA, Court R, Waugh N Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open. 2012;2(5) Epub 2012 Oct 18.

16) Shafaat Raza,1 Stephen Osasan,1 Sudiksha Sethia A Systematic Review of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors and Sympathetic Nervous System Inhibition: An Underrated Mechanism of Cardiorenal Protection Cureus 2022 Jun 25;14(6):e26313. doi: 10.7759/cureus.26313. eCollection 2022 Jun.

17) Zelniker TA, Wiviott SD, Raz I Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus. Circulation. 2019;139(17):2022.

18) Nyirjesy P, Zhao Y, Ways K, Usiskin K Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. Curr Med Res Opin. 2012 Jul;28(7):1173-8. Epub 2012 Jun 14.

19) Marilly E, Cottin J, Cabrera N SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials balancing their risks and benefits. Diabetologia. 2022;65(12):2000. Epub 2022 Aug 4.