The Cardio Diabetology Era. A Concise and Illustrated Review: Four Phenotypes and Three New Evidence-Based and Practical Therapeutic Algorithms

Abstract

Type 2 diabetes mellitus (T2DM) has undergone therapeutic approaches evolving from glucocentricity towards holism, in which it is currently considered a microvascular and macrovascular risk condition determined by multiple variables beyond glucose. These include visceral adiposity, metaflammation, insulin resistance with its hemodynamic (endothelial dysfunction and hypertension) and metabolic (mixed dyslipidemia) surrogates; together with other metabolic regulation system dysfunction such as the incretin system, sodium, and glucose cotransporters at the intestinal and renal level, and the intestinal microbiota, among the most studied. Therefore, the current treatment of this risk condition called T2DM, includes the control of all its determining factors: adiposity through a healthy diet, aerobic physical activity, and/or drugs such as glucagon-like peptide-1 receptor agonists (GLP1-RA) or bariatric surgical procedures. Inflammation remains a therapeutic target under investigation, although it has not yet been transferred to clinical practice guidelines. Insulin resistance and its hemodynamic and metabolic subrogates are the therapeutic targets of multiple pharmacological interventions, essentially insulin sensitizers, inhibitors of the renin-angiotensin-aldosterone system, facilitators of the transformation and elimination of lipoproteins with apo-B100 as omega-3 ultra-purified fatty acids, fibrates, antisense oligonucleotides (ASO) against apoC3, ASO and monoclonal antibodies (mAbs) anti-ANGPTL3, statins, ezetimibe, mAbs and small interfering RNA (siRNA) anti-PCSK9, among others. In the last 14 years, drugs such as the dipeptidyl peptidase 4 (DPP-4) inhibitors, GLP1-RA, and, more recently, the dual GIP-GLP-1 analogs, have been incorporated to correct the dysfunction of the incretin system, as well as many others that inhibit the intestinal and renal reabsorption of sodium and glucose as sodium–glucose co-transporter-2 and 1 (SGLT2/1) inhibitors. Surprisingly, new drugs have emerged between the GLP1-RA and the SGLT2/1 inhibitors that, beyond their essential therapeutic effect (glucose control), have shown brain, cardiac, and renal protection of variable magnitude. Finally, manipulating the intestinal microbiota is a strategy under extensive investigation and incipient clinical application. From this summary, it is clear that the current therapeutic landscape in T2DM has expanded dramatically, from a “gluco-panorama” focused on glucose control with insulin, sulfonylureas, metformin, and glitazones, to a “holo-panorama” incorporating five new therapeutic classes and at least eighteen new "anti-diabetic" drugs, in addition to a similar number of medications for hypertension and dyslipidemia control.