T2D treatment goal shifts from glucose centricity to end-organ protection

28 May 2025 bởiKanas Chan
T2D treatment goal shifts from glucose centricity to end-organ protection

With the advent of disease-modifying agents such as tirzepatide, the current treatment goal for type 2 diabetes (T2D) extends beyond merely managing glycaemic levels to focusing on a broader approach that emphasizes end-organ protection.

T2D is not just about HbA1c

“T2D is a malignant cardiometabolic disease associated with reduced life expectancy,” said Professor Stephan Jacob of the Department of Endocrinology, Metabolism, and Pathobiochemistry, University of Tübingen, Germany, at HKMF 2025. Having T2D at 60 years of age is estimated to reduce life expectancy by 6 years vs no diabetes. Coexistence of early chronic kidney disease (CKD) further reduces life expectancy by 9 years, and the presence of MI or stroke reduces life expectancy by 11 years. [JAMA 2015;314:52-60]

A meta-analysis of five trials (eg, UKPDS, PROactive, ADVANCE, VADT, and ACCORD) showed that intensive glycaemic control did not reduce all-cause mortality (hazard ratio, 1.02; 95 percent confidence interval, 0.87–1.19) vs standard glycaemic control. [Lancet 2009;373:1765-1772] “T2D is not just about HbA1c, as the older approach of glucose-lowering does not help patients live longer,” Jacob commented.

Forty-two percent of patients with prediabetes before T2D diagnosis developed microvascular disease, while 30 percent had macrovascular disease. [BMJ Open Diabetes Res Care 2020;8:e001061] “In the prediabetic state, high HbA1c is unlikely to be the primary factor for developing complications. Other risk factors are involved [eg, obesity, high blood pressure (BP),” he said.

“We must wipe out the glucose-centric view. A multifactorial approach is needed,” stressed Jocob. “New cardiorenal-protective drugs offer hope, shifting the focus from glucose centricity to disease modification.”

Tirzepatide: A multifactorial treatment

Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist (RA) that exerts a multidimensional effect on regulating appetite, glucose metabolism, and fat distribution. [Cureus 2024;16:e60545]

The phase III SURPASS 2 trial evaluated the efficacy and safety of tirzepatide 5, 10 or 15 mg vs semaglutide 1 mg in 1,879 patients with T2D inadequately controlled on metformin monotherapy. [N Engl J Med 2021;385:503-515]

All tirzepatide doses were superior to semaglutide in reducing mean HbA1c: 

·       Tirzepatide 5 mg (treatment difference [TD], -0.15; p=0.02);

·       Tirzepatide 10 mg (TD, -0.39; p<0.001);

·       tirzepatide 15 mg (TD, -0.45; p<0.001).

Normoglycaemia (HbA1c, 5.7 percent) was achieved in up to 46 percent of patients receiving tirzepatide (vs 19 percent with semaglutide).

Tirzepatide was superior to semaglutide in weight reduction at all doses, with estimated TDs of -1.9 kg, -3.6 kg and -5.5 kg at the 5 mg, 10 mg and 15 mg doses, respectively (all p<0.001).

“Tirzepatide demonstrated additional benefits, including reductions of BP, liver fat content, and waist circumference,” pointed out Jacob. “A renal-protective effect was seen in patients with T2D in the SUPRESS-1 to -5 trials.”

While results of the SURPASS-CVOT trial are to be published in June 2025, a meta-analysis of  cardiovascular outcome trials of GLP-1 RAs demonstrated significant reductions in all cardiovascular and kidney events and all-cause mortality. [Am J Prev Cardiol 2024;18:100679; NCT04255433]

“The new data call for a paradigm shift,” Jocab highlighted. “We should initiate disease-modifying therapies earlier to provide cardiorenal benefits to all T2D patients, rather than waiting for a heart attack to occur before finally starting treatment.”