Will Metformin Be Replaced By SGLT-2 Inhibitors

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

So, can the heart-kidney benefits of these new hypoglycemic drugs in clinical trials be translated into practical applications, and can their first-line therapeutic effects stand up to real-world testing?

In May 2022, the Harvard Medical School research team published a paper entitled Cardiovascular Outcomes in Patients Initiating First-Line Treatment of Type 2 Diabetes With Sodium-Glucose Cotransporter-2 Inhibitors Versus Metformin : A Cohort Study in the Annals of Internal Medicine, a leading medical journal, showing that:

1. Compared with metformin, SGLT-2 inhibitors as first-line treatment can significantly reduce the risk of hospitalization for heart failure 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 was carried out based on two medical databases in the United States, covering the data of 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. These patients did not have HIV/AIDS, end-stage renal disease, kidney transplantation or other organ transplantation.

After adjusting for confounding factors and matching the two groups with propensity scores of 1:2, there were 8613 participants in the SGLT-2 inhibitor group and 17,226 in the metformin group. SGLT-2 inhibitors include canagliflozin, empagliflozin, or dapagliflozin.

Before treatment, the SGLT-2 inhibitor groups and metformin groups had a similar proportion of patients with comorbidities, 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%) and chronic kidney disease (7.0% vs 6.9%).

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

There was no significant difference between the SLGT-2 inhibitor group and the metformin group in the composite end point of hospitalization for myocardial infarction, hospitalization for stroke, or all-cause mortality (morbidity 15.0/1000person-year vs 16.2/1000person-year).

For the composite end point of hospitalization and all-cause mortality for heart failure, patients receiving a SLGT-2 inhibitor as first-line therapy had a significant 20% reduction in risk (18.3/1000 person-year vs 23.5/1000 person-year), a benefit that began to be clearly observed approximately 6 months after initiation of therapy.

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

Subgroup analysis showed that overall outcomes remained similar regardless of whether patients had cardiovascular disease or not.

However, in patients with cardiovascular disease, SGLT-2 inhibitors were more effective in preventing myocardial infarction, reducing the risk by 60%. Improvements in hospitalization for heart failure were more pronounced in patients without cardiovascular disease, with a 37 percent reduction in risk.

The safety of SGLT-2 inhibitors and metformin first-line therapy was similar overall, except that more patients in the SGLT-2 inhibitor group had genital infections (54.1 vs 23.7 per 1000 person-years; HR 2.19). There were no significant differences between the two groups in the incidence of acute kidney injury, fractures, severe hypoglycemia, diabetic ketoacidosis, and lower extremity amputation.

How To Understand These Findings?

The research team pointed out that the heart failure benefits of SGLT-2 inhibitors in the real world are consistent with the findings of cardiovascular outcome trials. In previous clinical trials, SGLT-2 inhibitors reduced the risk of heart failure hospitalization by 27% to 35% compared with placebo. Regarding the impact of myocardial infarction, the research team pointed out that the current findings are consistent with the results of a meta-analysis (including 3 cardiovascular outcome trials) in 2019. The risk of myocardial infarction was significantly reduced by 11%, but the risk of stroke was not reduced.

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

"However, the results of the study do not fully support the advantages of SGLT-2 inhibitors in terms of myocardial infarction, stroke and cardiovascular death." According to Professor Taylor's analysis, one of the potential reasons is that there are few indications of cardiovascular benefits of SLGT-2 inhibitors. While the previous trials were placebo-controlled, this real-world study was compared with metformin. " From this perspective,, it may not be surprising that this study did not demonstrate a robust benefit of SGLT-2 inhibitors in reducing MACE (major adverse cardiovascular events)."

In addition, the follow-up time of the current study was only about 1 year, which is also limited. "One year may be sufficient to assess the effects of certain pharmacological mechanisms, for example, a potential beneficial effect by promoting natriuresis to reduce the risk of heart failure. However, 1 year may not be long enough to observe beneficial effects on atherosclerosis. For example, it often takes years for statins to show efficacy in cardiovascular adverse events."

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

As a professional pharmaceutical intermediates and API supplier, Huateng Pharma has three SGLT-2 inhibitors in development: Dapagliflozin, Canagliflozin, Empagliflozin and their intermediates. Looking ahead, sales of SGLT-2 inhibitors are expected to grow further, and Huateng Pharma will focus on reducing the cost of manufacturing these drugs and improving the quality of intermediates and drugs.