Discussion
The major finding of the present study is that, despite excellent glycemic control, as evident by HbA1c<6.5% throughout the 6-year follow-up in all participants, as well as optimal control of blood pressure and LDL cholesterol, both atherosclerotic disease, as evidenced by progression of cIMT, and hepatic steatosis and fibrosis continued to progress in patients receiving vonventional therapy (ie, metformin, sulfonylurea and then insulin), while both were markedly attenuated in subjects receiving initial triple therapy (metformin plus pioglitazone plus GLP-1 RA).
HbA1c was maintained <6.5% in all subjects during the entire study period (6 years) and was comparable in both treatment groups. Consistent with the important role of hyperglycemia in the development of microvascular complications, both groups were free of diabetic retinopathy at 6 years and had comparable renal function.
Despite comparable and optimal control of glucose, blood pressure, and LDL cholesterol, and the lack of microvascular complications in both study groups, both atherosclerosis, as evident by an increase in cIMT, and hepatic fat accumulation and fibrosis continued to progress in subjects receiving conventional therapy, while both were attenuated in subjects receiving triple therapy. Although there was a small non-significant difference in HbA1c between subjects receiving conventional therapy versus triple therapy (6.0% vs 5.7%), it is unlikely that such a small difference in this range of HbA1c is responsible for the change in cIMT. Because body weight was comparable in both groups and because patients in both treatment arms received metformin therapy, the difference between the two treatment arms can be attributed to the combination of pioglitazone plus GLP-1 RA in the triple therapy group versus sulfonylurea plus insulin in the conventional therapy group. These results, although in a relatively small group of patients (n=55) and need to be validated in a larger prospective multiethnic randomized trial, provide strong evidence that maintaining HbA1c<6.5% (plus controlling other CV risk factors) is not sufficient to prevent all T2DM complications in newly diagnosed patients with T2DM who are free of cardiorenal complications. Another limitation of the study is that not all CV risk factors were measured in the study, for example, smoking. However, because the study was a randomized trial, it is unlikely that a bias in other CV risk factors has influenced the results. The results of the present study, together with the results of recent CV and renal outcome trials in patients with T2DM,4–8 they strongly support the concept that, with regard to the metabolic benefits and prevention of all T2DM complications, not all glucose-lowering agents are equal and that maintaining the HbA1c at target (ie, <6.5%) with metformin, sulfonylurea, and insulin in patients with new-onset diabetes who are free of complications may reduce the risk of microvascular complications but has little influence on the development of other metabolic abnormalities commonly present in T2DM, for example, liver steatosis/fibrosis and carotid intima–media thickening, a well-documented measure of CV disease. Inclusion of pioglitazone plus GLP-1 RA in the treatment regimen, in addition to achieving optimal glycemic control and thus reducing microvascular risk, also prevented the progression of cIMT and attenuated the development of hepatic steatosis and fibrosis. Thus, the choice of glucose-lowering agent(s) has the potential to markedly influence the risk of developing other diabetes complications, for example, progression of atherosclerosis and MASLD, in newly diagnosed patients with T2DM who are free of complications at the time of diabetes diagnosis. Therefore, despite similar glucose-lowering ability, not all antidiabetic agents are equal with respect to other non-glycemic metabolic benefits. Therefore, agents with additional non-glycemic metabolic benefits (GLP-1 RAs, and pioglitazone) should be favored over those which only lower plasma glucose (eg, metformin, sulfonylureas, and insulin) in patients with T2DM with and without established CV, hepatic or renal disease.
Leave a Reply