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In persons with type 2 diabetes without established cardiovascular complications data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to glycemic outcomes as well as microvascular and cardiovascular disease outcomes. The GRADE trial compared the ability of four glucose-lowering remedies to achieve and maintain a defined glycated hemoglobin target and to protect the participant from microvascular and macrovascular complications. In this article, we comment on the relevance of this trial with specific attention for the notion that GLP-1 receptor agonists seem to have a primary preventive effect.

A structured approach in the diagnostic process of hypoglycemia is important to find the right diagnosis. The first step is to recognize the symptoms of hypoglycemia, confirming the hypoglycemia during symptoms and dissolvement of complaints once the glucose level is restored to normal. This confirms the Whipple triad. The second step is to exclude common causes. The third, and most important, step is a diagnostic fasting test. Measurement of insulin and C-peptide during hypoglycemia will guide to exogenic or endogenic causes of hyperinsulinism. Targeted additional investigation is then required. Often the underlying cause is treatable. This justifies the need to measure a well-timed serum glucose when hypoglycemia is suspected to make a quick diagnosis.

Recent trials of two classes of glucose-lowering drugs (SGLT2 inhibitors and GLP1RAs) have shown consistent cardiovascular and renal benefits that appear independent of glycaemic control. These results have prompted the Dutch College of General Practitioners (NHG) together with the Dutch Society of Internal Medicine (NIV) to update the treatment algorithm in patients with type 2 diabetes mellitus (T2D) at very high CVD risk. The use of SGLT2 inhibitors or GLP1RAs is now recommended in 3 groups of people with T2D. 1. patients with established CVD; 2. Patients with chronic kidney disease and a moderately to high CVD risk according to KDIGO; 3. patients with heart failure with reduced ejection fraction (HFrEF). Treatment algorithms differ for drug-naïve and drug-treated patients with T2D. In both drug-naïve and drug-treated patients the use of a SGLT2 inhibitor respectively as monotherapy or add-on is recommended as first step. If HbA1c is above the individual target, metformin will be added in drug-naive patients whereas GLP1-RAs could be considered in drug-treated patients. GLP1-RAs should also be considered when SGLT2-inhibitors are contraindicated.

High glucose values are associated with vascular risk in observational studies, but glucose lowering does not automatically translate into better outcomes for patients In patients with type 2 diabetes and cardiovascular disease, cardiovascular benefits of GLP-1 receptor agonists and SGLT-2 inhibitors have been demonstrated. However, experience in clinical practice is limited and costs are high. In diabetic patients with heart failure and renal complications, SGLT-2 inhibitors may have additional beneficial effects. Metformin may have vascular benefits, but this has not been demonstrated for sulphonylurea derivatives, insulin and DPP-4 inhibitors In patients with a low cardiovascular risk, beneficial vascular effects of glucose lowering drugs have not convincingly been demonstrated. The outcomes of the recent studies will lead to a more personalized treatment strategy for type 2 diabetes. Treatment choices will depend upon patient's risk of complications, the goal of therapy, patient preferences and costs.

The metabolic syndrome is a cluster of mutually related risk factors that confers an increased risk for both type 2 diabetes mellitus and cardiovascular disease. Although the metabolic syndrome seems to have multiple aetiological factors, microvascular dysfunction is a potential explanation for the above-mentioned cluster of multiple metabolic risk factors such as hypertension, insulin resistance and glucose intolerance. Microvascular dysfunction leads not only to increased peripheral vascular resistance and blood pressure, but may also decrease the insulin-mediated glucose uptake in muscles. The different effect on the microcirculation may explain why some antihypertensive drugs (beta-blockers) lead to an increased incidence of type 2 diabetes, whereas others (angiotensin-converting enzyme (ACE) inhibitors) are associated with a decrease of that risk.