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Metformin is a classic first-line hypoglycemic drug for patients with type 2 diabetes and an essential drug in combination regimens. However, as the evidence is updated, the concept of drug choice for first-line treatment is changing. For patients with type 2 diabetes who have atherosclerotic cardiovascular disease (ASCVD) or are at high risk for ASCVD and who have heart failure and/or chronic kidney disease, GLP-1 agonists and SGLT-2 inhibitors with or without metformin (as required for glycemic management) have also been recommended by several guidelines as appropriate starting treatment.

So, can the cardio-renal benefits of these new hypoglycemic drugs in clinical trials be translated into practical applications, and can their first-line treatment effects stand the test of the real world?

Recently, a research team from Harvard Medical School published a study in the authoritative medical journal Annals of Internal Medicine:

1. Compared with metformin, SGLT-2 inhibitors as first-line treatment can significantly reduce the risk of heart failure hospitalization by 22%.

2. For patients with previous cardiovascular disease, the risk of myocardial infarction was also significantly reduced.

3. However, SGLT-2 inhibitors failed to reduce stroke or all-cause mortality.

Study Data: Specific Effects on Cardiovascular Outcomes

This study is based on two medical databases in the United States, covering data on patients with type 2 diabetes treated with SGLT-2 inhibitors (9334 people) and metformin (819973 people) as first-line treatment between April 2013 and March 2020, respectively. These patients did not have HIV/AIDS, had no end-stage renal disease, and had not undergone kidney or other organ transplantation.

After adjusting for confounders and propensity score matching of the two groups 1:2, there were 8613 participants in the SGLT-2 inhibitor group and 17226 in the metformin group. SGLT-2 inhibitors include canagliflozin, empagliflozin or dapagliflozin.

Huateng Pharma is a leading pharmaceutical intermediates supplier. We have three SGLT-2 inhibitors in development, they are Dapagliflozin, Canagliflozin and Empagliflozin. We can also provide intermediates of Sitagliptin, Alogliptin, Linagliptin, Liraglutide and Semaglutide which used for diabetes treatment.

“Looking ahead, sales of SGLT-2 inhibitors are expected to grow further.” said the R&D director of Huateng Pharma.”Huateng Pharma will focus on reducing the cost of manufacturing these drugs and improving the quality of intermediates and drugs.”

Before treatment, the SGLT-2 inhibitor group and metformin group had diabetic nephropathy (4.6% vs 4.8%), cardiovascular disease (26.2% vs 26.2%), hyperlipidemia (71.2% vs 71.7%), hypertension ( 71.9% vs 72.4%), chronic kidney disease (7.0% vs 6.9%) and other comorbidities were similar.

The mean follow-up time in the SGLT-2 inhibitor group and metformin group was 10.7 months and 12.2 months, respectively. The results show:

1. There was no significant difference between the SLGT-2 inhibitor group and the metformin group in the composite endpoint of myocardial infarction hospitalization, stroke hospitalization, or all-cause mortality (incidence 15.0/1000 person-years vs 16.2/1000 person-years).

2. For the composite end point of hospitalization for heart failure and all-cause mortality, patients who received SLGT-2 inhibitors as first-line therapy had a significantly lower risk of 20% (18.3 vs. 23.5 per 1000 person-years), with the benefit becoming apparent approximately 6 months after initiation of treatment.

3. Analysis of specific cardiovascular events showed that compared with metformin, the risk of hospitalization for heart failure was significantly reduced by 22% in the SGLT-2 inhibitor group (HR 0.78, 95%CI 0.63-0.97). The risk of myocardial infarction (MI) showed a 30% trend but was not statistically significant (HR 0.70, 95%CI 0.48 to 1.00). Stroke and all-cause mortality were similar between the two groups.

Subgroup analyses showed that overall outcomes remained similar regardless of whether patients had coexisting cardiovascular disease.

However, in patients with cardiovascular disease, SGLT-2 inhibitors are more effective in preventing myocardial infarction risk, reducing the risk by 60%; for the improvement of heart failure hospitalization, the effect is more obvious in patients without cardiovascular disease. 37% lower.

The overall safety profile of first-line treatment with SGLT-2 inhibitors and metformin was similar, with the exception of more genital infections in the SGLT-2 inhibitor group (54.1/1000 person-years vs 23.7/1000 person-years; HR 2.19). There were no significant differences between the two groups in events such as acute kidney injury, fractures, severe hypoglycemia, diabetic ketoacidosis, and lower-extremity amputations.

How to make sense of these findings?

The research team noted that the real-world HF benefits of SGLT-2 inhibitors were consistent with findings from the Cardiovascular Outcomes Trial, in which SGLT-2 inhibitors reduced the risk of HF hospitalization compared with placebo27 %~35%. Regarding the impact of myocardial infarction, the research team pointed out that the current findings are consistent with the results of a 2019 meta-analysis (including 3 cardiovascular outcome trials), which significantly reduced the risk of myocardial infarction by 11%, but not the risk of stroke.

Professor Simeon I. Taylor, University of Maryland, commented, "This study confirms the conclusions of existing randomized clinical trials in general and provides strong support for the benefit of reducing the risk of hospitalization for heart failure in particular."

"But the results do not fully support the advantages of SGLT-2 inhibitors in myocardial infarction, stroke and cardiovascular death." Professor Taylor's analysis believes that one of the potential reasons is that several cardiovascular benefits of SLGT-2 inhibitors are shown. While the trials were placebo-controlled, this real-world study compared metformin. "From this perspective, it may not be surprising that this study did not demonstrate a robust benefit of SGLT-2 inhibitors in reducing MACEs (major adverse cardiovascular events)."

In addition, the follow-up time of the current study was only about 1 year, which is also limited. "A period of 1 year may be sufficient to assess the effects of certain pharmacological mechanisms, for example, the potential beneficial effects of promoting urinary sodium excretion to reduce the risk of heart failure. However, 1 year may not be enough time to observe a beneficial effect on atherosclerosis. "Statins, for example, often show efficacy in cardiovascular adverse events after years of treatment."

"From a cardiovascular outcome perspective, our findings may support the use of SGLT-2 inhibitors as first-line treatment for type 2 diabetes, but randomized clinical trials are warranted to obtain stronger evidence." Corresponding author, Harvard Medical School Researcher Dr. HoJin Shin said the study is just the beginning. "High-quality evidence can help doctors and patients make better decisions about drug selection. Which patients will benefit more has not been analyzed."

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