From glucose lowering agents to disease/diabetes modifying drugs: a "SIMPLE" approach for the treatment of type 2 diabetes

Abstract

During the last decade we experienced a surge in the number of glucose lowering agents that can be used to treat patients with type 2 diabetes. Especially important are the discoveries that sodium glucose co-transporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve patients' cardiovascular and renal outcomes. Accordingly, various medical associations have updated their guidelines for the treatment of diabetes in this new era. Though not agreeing on every issue, these position-statements generally share a detailed and often complex workflow that may be too complicated for the busy and overworked primary care setting, where the majority of patients with type 2 diabetes are managed in many countries. Other guidelines, generally those from the cardiology associations focus primarily on the population of patients with high risk for or pre-existing cardiovascular disease, which represent only the minority of patients with type 2 diabetes. We believe that we should re-define SGLT2i and GLP-1 RA as diabetes/disease modifying drugs (DMDs) given the recent evidence of their cardiovascular and renal benefits. Based on this definition we have designed a SIMPLE approach in order to assist primary care teams in selecting the most appropriate therapy for their patients. We believe that most subjects newly diagnosed with type 2 diabetes should initiate early combination therapy with metformin and a prognosis changing DMD. The decision whether to use GLP-1 RA or SGLT2i should be made based on specific patient's risk factors and preferences. Importantly, DMDs are known to have a generally safe side-effect profile, with lower risk for hypoglycemia and weight gain, further promoting their wider usage. Early combination therapy with DMDs may improve the multiple pathophysiological abnormalities responsible for type 2 diabetes and its complications, thus resulting in the greatest long term benefits.

Keywords: Clinical approach; Diabetes/Disease Modifying Drugs (DMDs); Type 2 Diabetes.

Fig. 1

Changes in the treatment of patients with type 2 diabetes over the last two decades. GLA Glucose Lowering Agents, CV Cardiovascular, FDA Food and Drugs Administration, DPP4i Dipeptidyl peptidase-4 inhibitors, SGLT2i Sodium glucose co-transporter type 2 inhibitor, GLP-1 RA Glucagon-like peptide-1 receptor agonists, DMD Disease/Diabetes modifying drug, MACE major adverse cardiovascular events. Until the early 2000s treatment of type 2 diabetes focused on glucose control. The main GLAs in use were insulin, metformin and sulfonylureas. In 2008, the FDA started to require pharmaceutical companies to confirm the CV safety of their newly developed GLAs, compared with placebo or other GLA, in patients with high CV risk [82]. Members of the DPP4i and thiazolidinediones classes were found to have CV non-inferiority, without CV superiority, in MACE-based outcomes [, –86]. Starting in 2015, several members of the SGLT2i and GLP-1 RA classes were found to exert cardiorenal protection [–, –17, 48, 56], defining them as disease/diabetes modifying drug (DMDs)

Fig. 2

The choice of glucose lowering agents. Established ASCVD: Prior proven coronary artery disease, cerebrovascular disease or peripheral arterial disease. Risk factors for ASCVD: Older age (male > 50, female > 55) and one or more risk factor(s) for cardiovascular disease - HTN, hyperlipidemia, (current) smoker. HF: Prior clinical or imaging diagnosis of HFrEF. Risk factors for HF: According to TIMI risk-score [47]. CKD: eGFR < 90 ml/min/1.73 m² and/or UACR ≥ 30 mg/g. Obesity: BMI > 30 kg/m². ASCVD Atherosclerotic cardiovascular disease, HTN Hypertension, HF Heart failure, HFpEF Heart failure with preserved ejection fraction, HFrEF Heart failure with reduced ejection fraction, CKD Chronic kidney disease, eGFR estimated glomerular filtration rate, UACR Urinary albumin to creatinine ratio, BMI Body mass index, SGLT2i Sodium glucose co-transporter type 2 inhibitor, GLP-1 RA Glucagon-like peptide-1 receptor agonists, DMD Disease/Diabetes modifying drug (either SGLT2i or GLP-1 RA)

Fig. 3

Choosing injectable drugs for patients with type 2 diabetes. OAD Oral antidiabetic drug, GLP-1 RA Glucagon-like peptide-1 receptor agonist