Subject: SMART Study - Selection of coMbinAtion theRapies in Type 2 diabetes
India has the second largest number of people with diabetes in the world and only a quarter achieve glycaemic targets. A number of pathophysiological mechanisms are involved in type 2 diabetes, often referred as the ominous octet. As multiple pathophysiological defects cannot be managed by monotherapy, there is a need for combination therapy to target all pathophysiological pathways of T2DM and euglycemia. While achievement of euglycemia is important (gluco-centric approach), it is also equally critical that drug therapy should aim at reversal of known pathogenic abnormalities and demonstrate improvement in the overall metabolic health rather than simply reduce glycosylated hemoglobin (HbA1c) levels.
Type 2 diabetes being a progressive condition and as a result of increasing dysfunction and apoptosis of insulin-secreting pancreatic β-cells, most patients fail to achieve optimal glycaemic control with monotherapy, and hence, combination therapy (by adding another OAD) is required in most patients. Combination therapy offers several potential benefits over monotherapy. Early intensive glycaemic control, which typically requires the use of more than 1 glucose-lowering agent, may be associated with a legacy effect, and some evidence suggests that this approach may preserve β-cell function.
Major guidelines support the use of combination therapy for diabetes. The American Association of Clinical Endocrinologists’ recommendation specifically recommends the initiation of dual therapy if HbA1c targets are not achieved after 3 months of monotherapy, or if entry HbA1c >7.5% (with symptoms). Furthermore, AACE also recommends initiation of triple combination therapy if HbA1c targets are not achieved after 3 months of dual combination therapy, or if entry HbA1c >9% (without symptom).
SGLT2 inhibitors and DPP-4 inhibitors have complementary mechanisms of action that address several of the underlying pathophysiological abnormalities present in T2DM without overlapping drug toxicities. The combination of these 2 agents has several advantages, including a low risk of hypoglycaemia, the potential for weight loss, the ability to co-formulate into a pill with once-daily administration, and the possibility to use with other classes of glucose-lowering agents. Cardiovascular outcomes trials support the safety of the DPP-4 class and cardioprotective and reno-protective effects for SGLT2 inhibitors. The combination of an SGLT2 inhibitor/DPP-4 inhibitor is an attractive treatment option for a wide range of patients with T2DM, including those who are unable to obtain adequate glycaemic control with metformin, who cannot tolerate metformin or in whom metformin is contraindicated, and those with concerns about hypoglycaemia and weight gain. In addition, this combination therapy is appropriate for patients with a higher baseline HbA1c (>7.5%), and can be given in combination with other classes of oral glucose-lowering agents, including insulin.
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