Should sodium glucose co-transporter-2 inhibitors (SGLT2-i) be the first choice in the treatment of diabetes type 2?

Jan Willem Elte The Netherlands

For many years metformin has been the first choice drug in the treatment of diabetes type 2  after, of course, life style modifications have been applied.

Recently, however, new classes of diabetes drugs have been investigated.  A new consensus report on the management of hyperglycemia in type 2 diabetes developed and published by the joint scientific associations of diabetes in Europe (EASD) and the United States (ADA) has appeared (published in Diabetes Care 2022).

This report now recommends that patients with cardiorenal (heart and kidney ) risks should start with a SGLT2-i or a GLP1-RA ( glucagonlike peptide1-receptor agonist) with proven CVD (cardiovascular disease) benefit. In heart failure (HF) SGLT2-i is prefered. A combination of SGLT2-i and GLP1-RA may also be considered in patients with a very high atherosclerotic cardiovascular disease (ASCVD) risk. Use of both agents is recommended independent of HbA1,c, even if not on metformin. It should, however, be realized that the agents (GLP1-RA even more than SGLT2-i) are expensive.

Before going into somewhat more detail, it is good to define what is meant by high risk for ASCVD. This is defined as diabetes in a patient aged 55 years or older with two additional risk factors such as hypertension, lipid disorders, obesity etc. Chronic kidney disease (CKD) is defined as an estimated glomerular filtration rate < 60 ml/min/1.73 m² or albumin to creatinine ratio > 30.

With no cardiorenal risk metformin remains a reasonable first choice. Several other classes of hypoglycemic agents may be used in combination with metformin in diabetes type 2 patients without risk.

SGLT2-i are oral medications that reduce plasma glucose by enhancing urinary excretion of glucose (and thus calories), thereby lowering blood glucose and body weight. Examples are: empaglifozine, sotaglifozine, dapaglifozine,  canaglifozine.

SGLT2-i are efficient in reducing the risk of composite Major Adverse Cardovascular Events (MACE), cardiovascular death, myocardial infarction, hospitalization for heart failure HHF) and all-cause mortality. PAD (Peripheral Artery Disease) patients do derive benefits too. They also improve renal outcomes in individuals with type 2 diabetes and established risk of CVD and they lower blood pressure. They act neutrally as far as stroke is concerned.

All SGLT2-i effects are  independent of their glucose-lowering effect and their effects are not different in the elderly. Adverse effects of SGLT2-i are limited and usually treatable. There is an increased risk of mild mycotic genital infections and an even lower risk of diabetic keto-acidosis (DKA). For this last side effect, it is advised to temporary discontinue the drug during prolonged fasting, acute illness and peri-operatively.

If SGLT2-i are contra-indicated or not tolerated, GLP1-RA treatment may be considered. These drugs also reduce MACE and its components in CVD patients and are beneficial in heart failure and CKD patients. They reduce weight and blood pressure. Most GLP1-RA are administered as subcutaneous injections weekly. Examples are: dulaglutide, liraglutide, lixisenatide, semaglutide. Semaglutide is the only one which can also been given as an oral agent, but this dosage form is not yet registered everywhere. Side-effects are mainly gastro-intestinal (nausea, vomiting, diarrhea) mainly self-limiting and in the beginning.

If compared, SGLT2-i are superior to GLP1-RA in reducing hospitalization for heart failure (HHF), and improving composite kidney outcome. GLP1-RA are superior to SGLT2-i in reducing the risk for stroke and reducing weight.

It is important to realize that no agent or drug class has a notable beneficial effect on cardiovascular events in low risk individuals with diabetes.

Insulin treatment in type 2 diabetes patients is only indicated in case of a very high HbA1c, catabolic conditions (weight loss) and in acute disorders.

It should be kept in mind that glucose lowering should be integrated as part of a holistic, multifactorial approach to type 2 diabetes patients that includes weight, blood pressure and lipid management.

 A recent study, published in The Lancet, showed that effects of SGLT2-i are not only beneficial in type 2 diabetes patients at high CVD risk, but also in patients with CKD or HF, irrespective of diabetes status, primary kidney disease or kidney function.

So, in conclusion, individuals with diabetes type 2 and CVD should be preescribed SGLT2-i (or GLP-1 RA), as well as those with CKD (eGFR < 60 ml/min/1.73 m² or UACR > 3.0 mg/mmol).