SGLT2 Inhibitors in the Early Treatment of Type 2 Diabetes
Given the complex nature of T2DM, there is agreement that drug treatment should be tailored to each patient, according to their individual glycaemic target (i.e. HbA1c) and other factors, such as duration and stage of disease, life expectancy, risk of hypoglycaemia and risk of cardiovascular disease (CVD). The recommended glycaemic target for many non-pregnant adults with T2DM is < 7.0%. This can be individualised so that a more stringent target (e.g. < 6.5%) is applied to a newly diagnosed person with no complications (e.g. without CVD). Some clinicians believe the target HbA1c should be reduced further to ≤ 6.0% in newly diagnosed T2DM patients with no CVD. Conversely, a less stringent target (e.g. < 8.0%) could be applied to T2DM patients with advanced CVD, reduced life expectancy and multiple comorbidities. Whatever the precise goal, it is also well established that early and effective intervention in T2DM provides a greater opportunity to reduce the risks of long-term diabetes complications.
As described in a recent review by DeFronzo and colleagues, an individual has already lost approximately 80% of their beta-cell function by the time a diagnosis of T2DM is made; thus, drug therapy must be started promptly to compensate for the progressive beta-cell failure that is already well established in such individuals. They suggest treatment should be based on the reversal of known pathogenic abnormalities (beta-cell failure and insulin resistance) and not simply on HbA1c reductions. To accomplish this, they proposed early combination therapy with thiazolidinediones (TZDs) and glucagon-like peptide 1 receptor (GLP-1R) agonists added to metformin, as these agents improve and preserve beta-cell function, and TZDs are also potent insulin sensitizers while GLP-1R agonists promote weight loss. However, these drugs have limitations; for example, TZDs are associated with weight gain, fluid retention and bone fractures, whereas GLP-1R agonists are given via subcutaneous injection, and are associated with gastrointestinal side effects. Dipeptidyl peptidase-4 (DPP-4) inhibitors provide an alternative incretin-based option to GLP-1R agonists, but are weight-neutral rather than associated with weight loss. Thus, there remains a need for additional treatment options in the early stages of T2DM.
Early Intervention in T2DM
Given the complex nature of T2DM, there is agreement that drug treatment should be tailored to each patient, according to their individual glycaemic target (i.e. HbA1c) and other factors, such as duration and stage of disease, life expectancy, risk of hypoglycaemia and risk of cardiovascular disease (CVD). The recommended glycaemic target for many non-pregnant adults with T2DM is < 7.0%. This can be individualised so that a more stringent target (e.g. < 6.5%) is applied to a newly diagnosed person with no complications (e.g. without CVD). Some clinicians believe the target HbA1c should be reduced further to ≤ 6.0% in newly diagnosed T2DM patients with no CVD. Conversely, a less stringent target (e.g. < 8.0%) could be applied to T2DM patients with advanced CVD, reduced life expectancy and multiple comorbidities. Whatever the precise goal, it is also well established that early and effective intervention in T2DM provides a greater opportunity to reduce the risks of long-term diabetes complications.
As described in a recent review by DeFronzo and colleagues, an individual has already lost approximately 80% of their beta-cell function by the time a diagnosis of T2DM is made; thus, drug therapy must be started promptly to compensate for the progressive beta-cell failure that is already well established in such individuals. They suggest treatment should be based on the reversal of known pathogenic abnormalities (beta-cell failure and insulin resistance) and not simply on HbA1c reductions. To accomplish this, they proposed early combination therapy with thiazolidinediones (TZDs) and glucagon-like peptide 1 receptor (GLP-1R) agonists added to metformin, as these agents improve and preserve beta-cell function, and TZDs are also potent insulin sensitizers while GLP-1R agonists promote weight loss. However, these drugs have limitations; for example, TZDs are associated with weight gain, fluid retention and bone fractures, whereas GLP-1R agonists are given via subcutaneous injection, and are associated with gastrointestinal side effects. Dipeptidyl peptidase-4 (DPP-4) inhibitors provide an alternative incretin-based option to GLP-1R agonists, but are weight-neutral rather than associated with weight loss. Thus, there remains a need for additional treatment options in the early stages of T2DM.
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