There are far more options to treat diabetes now, than about 15-20 years ago. Among the newer agents, glucagon-like peptide 1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium-glucose cotransporter 2 inhibitors (SGLT-2i), are in common use. While their benefits extend far beyond the management of hyperglycemia, some pose concerns, and challenges to the anesthesia providers. Retained gastric contents due to slow gastric emptying is a significant drawback of GLP-1RA. It benefits the patient in losing weight; however, increases the risk of aspiration and can surprise an unsuspecting anesthesia provider. National associations have issued statements in an effort the mitigate the risk. Recommendations range from withholding of GLP-1RA for a predefined period of time, gastric ultrasound to evaluate the gastric contents and modification of anesthesia management especially with regards to the airway and cancellation of a scheduled (elective) surgery/procedure. SGLT-2i are known to increase the risk of euglycemic ketoacidosis. Duration of preprocedural withholding of SGLT-2i varies with the drug. Use of both GLP-1RA and SGLT-2i extends beyond the treatment of diabetes. While SGLT-2i are being extensively used to treat obesity, they are also used in the management of heart failure. A new insulin formulation of basal insulin that can be administered once weekly to achieve similar blood sugar control as once daily formulation has become available in some countries. Labelled as icodec, this is as yet not approved by the FDA because of severe hypoglycemia concerns. Imeglimin is a variant of metformin with unique mechanisms of action. It is approved for clinical use for type 2 diabetes in Japan and India. Another, as yet investigational product is IcoSema, a once-weekly combination of insulin icodec plus semaglutide. A discussion of all aspects of these drugs is warranted.

The objective of this study is to investigate how different therapies modulating insulin resistance, either causally or consequently, affect metabolic parameters in treatment-naive subjects with T2DM. A total of 212 subjects were assigned to receive either a tight Japanese diet (n=65), pioglitazone at doses ranging from 15-30 mg/day (n=70), or canagliflozin at doses ranging from 50-100 mg/day (n=77) for a duration of three months. Correlations and changes (Δ) in metabolic parameters relative to insulin resistance were investigated. Across these distinct therapeutic interventions, ΔHOMA-R exhibited significant correlations with ΔFBG and ΔHOMA-B, while demonstrating a negative correlation with baseline HOMA-R. However, other parameters such as ΔHbA1c, ΔBMI, ΔTC, ΔTG, Δnon-HDL-C, or ΔUA displayed varying patterns depending on the treatment regimens. Participants were stratified into two groups based on the median value of ΔHOMA-R: the lower half (X) and upper half (Y). Group X consistently demonstrated more pronounced reductions in FBG compared to Group Y across all treatments, while other parameters including HbA1c, HOMA-B, TC, TG, HDL-C, non-HDL-C, TG/HDL-C ratio, or UA exhibited distinct regulatory responses depending on the treatment administered These findings suggest that 1) regression to the mean is observed in the changes of insulin resistance across these therapies. 2) modulation of insulin resistance with these therapies, either causally or consequentially, results in differential effects on glycemic parameters, beta-cell function, specific lipids, body weight or UA.

Nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome in the kidney and the heart is increasingly being suggested to play a key role in mediating inflammation. In the kidney, NLRP3 activation has been associated with the progression of diabetic kidney disease. In the heart, activation of the NLRP3 inflammasome has been related to enhanced release of interleukin-1β (IL-1β) and the subsequent induction of atherosclerosis and heart failure. Apart from their glucose-lowering effects, SGLT-2 Inhibitors have been documented to attenuate activation of the NLRP3, thus, resulting in the constellation of an anti-inflammatory milieu. In this review, we will focus on the interplay between SGLT-2 Inhibitors and the inflammasome in the kidney, the heart and the neurons in the context of diabetes mellitus and its complications.