About 500,000 patients with newly diagnosed type 2 diabetes were followed on average for 6 years. Cardio-protective effects of Metformin were seen immediately and maintained during the whole study when compared to lifestyle changes alone. Findings imply starting metformin at onset of diagnosis, in addition to expected lifestyle modifications. It would be difficult to commonly recommend this approach without evidence from prospective randomized clinical trials.

Medicine (Baltimore)

Population Based

July 2017

Background: Early type 2 diabetes mellitus (DM) may only require lifestyle modifications for glycemic control without the need for oral hypoglycemic agents (OHAs). Metformin is believed to improve cardiovascular outcomes in patients with DM, and it is considered to be a first-line therapy. However, it is unclear whether metformin is beneficial for patients with a new diagnosis of DM compared to those who do not need OHAs for glycemic control.

Methods: Data were obtained from a population-based health care database in Taiwan. Patients with a new diagnosis of DM were enrolled if they received metformin monotherapy only between 1999 and 2010. A 4:1 propensity score-matched cohort of patients with a new diagnosis of DM who did not take OHAs or insulin during follow-up was also enrolled. The primary study endpoint was the occurrence of major adverse cardiovascular events (MACEs). The time to the endpoints was compared between groups using Cox proportional hazards models.

Results: A total of 474,410 patients with DM were enrolled.

During a mean 5.8 years of follow-up, the incidence of MACEs was 1.072% (1072 per 100,000 person-years) in the metformin monotherapy group versus 1.165% in the lifestyle modification group (those who did not take OHAs) (P < .001).

After adjusting for confounders, metformin independently protected the DM patients from MACEs (HR 0.83, P < .001). The metformin group also had an improved MACE-free survival profile from year 1 to year 12 (P < .001).

Conclusion:

In addition to lifestyle modifications, the patients with a new diagnosis of DM treated with metformin monotherapy had a lower MACE rate than those who did not take OHAs. Our findings suggest that metformin may be given early to patients with a new diagnosis of DM, even when they do not need OHAs for glycemic control.

More from the publication:

The global prevalence of type 2 diabetes mellitus (DM) is 9% among adults, causing millions of deaths.The primary goal of DM treatment is to reduce the progression of cardiovascular complications through optimal glycemic control. Virtually all patients with early DM are advised to modify their lifestyle such as with appropriate diet control and exercise as initial glycemic control with or without oral hypoglycemic agents (OHAs). OHAs may not be administered for the patients in whom glycemic control is optimal after lifestyle modifications.

Metformin is recommended as first-line therapy in patients without contraindications based on reports demonstrating the reduction of major adverse cardiovascular events (MACEs) in various diabetic populations, including patients with atherothrombosis, myocardial infarction, and heart failure, and patients who have undergone coronary interventions. Large trials conducted by the UK Prospective Diabetes Study have validated the safety profile of metformin for its early use in diabetic patients, and demonstrated the overall cost effectiveness. A recent trial also demonstrated that early metformin treatment improved the distribution of lipoprotein. However, in addition to lifestyle modifications, it is unclear whether metformin montherapy is beneficial for patients with a new diagnosis of DM compared to those who do not need OHAs for glycemic control. Therefore, we conducted this propensity score-matched nationwide study to investigate this issue.

The main findings of this long-term population-based retrospective cohort study of 474,410 diabetic patients are as follows: in addition to lifestyle modifications, metformin was associated with a decreased risk of MACEs in patients with type 2 diabetes who had not previously used anti-diabetic medications and a metformin-associated protective effect was observed at treatment onset, which remained for at least 2 years while taking metformin. To date, this is the largest cohort observational study comparing the incidence of MACEs between patients with DM who received metformin monotherapy and those with only lifestyle modifications.

In this large population-based cohort study, we found that for patients with newly diagnosed type 2 DM, in addition to lifestyle modifications, metformin monotherapy was associated with fewer MACEs compared to lifestyle modifications alone without any hypoglycemic agents. To the best of our knowledge, this is the largest cohort study comparing MACEs between these 2 groups of patients.

Lifestyle modifications are advised for all patients with newly diagnosed type 2 DM for glycemic control. Several landmark randomized controlled clinical trials have demonstrated that strict glycemic control reduces the risk of the microvascular and neurological complications associated with diabetes, but not cardiovascular complications. Therefore, strict glycemic control with OHAs is not frequently recommended for these patients.

Metformin has many pleiotropic effects, including decreased hyperglycemia, hypoinsulinemia, higher peripheral muscle glucose uptake, decreased hepatic glyconeogenesis, reduced hypercoagulability, improved lipid profile, and increased nitric oxide-mediated vasodilatation. Metformin has also been demonstrated to have cardioprotective effects in patients with myocardial infarction, heart failure, and atrial fibrillation. The mechanism of this proposed protective effect is beyond the scope of this study.

The protective effects of metformin seemed to be sustained for only the first 2 years. This suggests that the early use of metformin in patients with newly diagnosed type 2 DM (i.e., the first 2 years) is associated with more favorable cardiovascular outcomes. The MACE rate after the third year was similar between the metformin and lifestyle change groups. This may be because the severity of hyperglycemia in diabetes progresses with age, and therefore more patients would take hypoglycemic agents as the disease advances with time but were not included in this study. In our cohort, the patients who could sustain lifestyle changes alone for long duration (>2 years) should have had milder hyperglycemia, and we speculate that these patients would be associated with fewer cardiovascular events than those with more severe hyperglycemia who needed OHAs. Therefore, the beneficial effect of metformin is likely to be ameliorated by the severity of hyperglycemia in the metformin monotherapy group.

In this nationwide population-based study, in addition to lifestyle modifications, metformin montherapy was independently associated with a lower risk of MACEs in patients with type 2 DM. The beneficial effects of metformin for patients with pre- or early diabetes may require large, prospective, and randomized trials.