Introduction

Cardiovascular disease (CVD) remains a major cause of morbidity and mortality in individuals with type 2 diabetes.^1,2 In 2019, 37.1 million (14.7%) American adults had diabetes and about 96 million (38%) had prediabetes.³ While metformin and lifestyle interventions reduce the development of diabetes, their impact on improving cardiovascular (CV) outcomes remains unclear.^4–7

An analysis of the United Kingdom Prospective Diabetes Study (UKPDS) suggested possible cardioprotective benefits from metformin in overweight patients with newly diagnosed diabetes when compared to insulin or sulfonylurea therapies.⁴ In a publication by the Diabetes Prevention Program (DPP), coronary artery calcification (CAC) was lower in men who took metformin than in the placebo group after 14 years of follow-up; no CAC differences between the lifestyle and placebo groups were found.⁸

The study by Goldberg et al. evaluated the effects of metformin and lifestyle on the incidence of major CV events among individuals with prediabetes enrolled in the DPP trial and Diabetes Prevention Program Outcomes Study (DPPOS).⁹

Methods

The DPP trial was a multicenter trial administered across the 27 clinical centers in the United States between 1996-2002. It examined the ability of metformin or lifestyle to prevent or delay the development of diabetes in individuals with impaired glucose tolerance and elevated fasting plasma glucose concentrations 95-125mg/dL and body mass index (BMI) ≥24 kg/m².⁹

 A total of 3,234 participants were randomized to receive placebo or 850 mg metformin twice daily or an intensive lifestyle counseling program that aimed for 7% weight loss and 150 minutes of moderate exercise per week over 3 years. The primary outcome measure was the development of diabetes, diagnosed by fasting or 2-hour post-challenge plasma glucose concentrations using the 1997 American Diabetes Association criteria (fasting plasma glucose level ≥126 mg/dL [7.0 mmol/L] or 2-hour plasma glucose ≥200 mg/dL [11.1 mmol/L]) after a 75-gram oral glucose tolerance test (OGTT) and confirmed with a repeat test.

The original DPP study was followed by DPPOS, which conducted a long-term follow-up of all active DPP study participants (2,776 or 88% enrolled). The original lifestyle intervention group was offered lifestyle reinforcement semi-annually and the unmasked metformin was continued in the metformin group. The participants' clinicians managed CV risk factors. DPPOS evaluated the effects of the interventions on the further development of diabetes and hyperglycemia-related complications, including CVD.

The primary outcome was the first occurrence of a major CVD event defined as nonfatal myocardial infarction (MI), stroke, or fatal CVD. An extended CV event outcome comprised the first occurrence of a major event or hospitalization for heart failure or unstable angina, revascularization, coronary heart disease diagnosed by angiography, or silent MI.

Study Results

In the DPP and DPPOS studies, the development of diabetes was significantly lower in both metformin and lifestyle intervention groups than in placebo group, and CV risk factors were generally more favorable in the intervention groups than in the placebo group; 310 major CV events occurred during a 21-year median follow-up.

Neither metformin nor lifestyle intervention reduced CV events. The metformin versus placebo hazard ratio (HR) and lifestyle versus placebo HR was 1.03 (95% CI, 0.78–1.37; P = 0.81) and 1.14 (95% CI, 0.87–1.50; P = 0.34), respectively. There were fewer nonfatal stroke events in the metformin group. There was no significant heterogeneity by age, sex, race/ethnicity, or diabetes development.

Conclusion

In an ethnically diverse cohort with prediabetes, neither metformin nor lifestyle interventions reduced the occurrence of major adverse cardiovascular events despite decreasing diabetes development. Factors such as group lifestyle intervention, extensive out-of-study metformin, lipid-lowering, and antihypertensive medications likely limited the ability to identify the beneficial effects of metformin and lifestyle interventions.

Perspectives and Future Directions

Several factors may have limited the effects of interventions in this study – especially the increased use of out-of-study metformin, statins, and antihypertensive medications and intensive lifestyle modifications. The cohort had a mild degree of hyperglycemia with mean HbA1c values approximately 6.1%. Additionally, about 60% of participants developed diabetes, which may reflect the persistence of the in-trial benefit of the original DPP intensive lifestyle intervention termed the "legacy effect".

Despite favorable influences on risk factors, lifestyle interventions did not show further CV benefit in line with the Finnish Diabetes Prevention Study and the Look AHEAD trial (Action for Health in Diabetes) cohort with type 2 diabetes.^6,10 Conversely, the Da Qing study demonstrated a beneficial effect of lifestyle on major events (HR 0.74 [95% CI, 0.59–0.92]) among individual with prediabetes.⁷ Lifestyle intervention was intensive only during DPP, whereas participants in DPPOS were offered a less intensive group lifestyle intervention.

Metformin is effective, safe, inexpensive and remains the most widely prescribed medication for patients with type 2 diabetes and is the preferred first-line treatment.¹¹ It may have a beneficial impact on weight in overweight or obese individuals with impaired glucose tolerance.¹²

In DPP/DPPOS, metformin was associated with significantly lower severity and prevalence of CAC in men, but not women over 14 years of follow up,⁸ suggesting that metformin treatment may have reduced early stages of plaque development.

Based on prior analyses of DPP/DPPOS showing a more significant effect of metformin for diabetes prevention in specific subgroups such as those with a BMI ≥35 kg/m², prior gestational diabetes, or age under 60 years, it is possible that the CV effect of metformin will also be more significant in such individuals. This may be a consideration in the analysis of or selection of participants for future trials focused on the effect of metformin on events among individuals with prediabetes.

The ongoing multicenter, randomized, double-blind, secondary trial, Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular Outcomes (VA IMPACT), will clarify the CV effects of metformin. This trial is testing the hypothesis that treatment with metformin, compared with placebo, reduces CV morbidity in patients with prediabetes and established atherosclerotic CVD.¹³

In choosing a medication for diabetes prevention, it is important to consider its added effect on CV outcomes, which may enhance its cost-effectiveness. Sodium-glucose cotransporter-2 inhibitors (SGLT2i's) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have proven CV benefit. Consequently, several national and international guidelines now recommend SGLT2i's/GLP1-RAs for high-risk patients with diabetes with established CVD, kidney disease, or heart failure. GLP-1RAs have huge potential for diabetes prevention, with studies suggesting a diabetes incidence reduction as high as 79% over a 3-year period, among those with prediabetes.^14,15

Evidence from ongoing and future drug clinical trials of diabetes prevention, using metformin or drugs such as GLP-1Ras, will demonstrate whether such interventions will improve long-term outcomes.

References

1. Barrett-Connor E, Wingard D, Wong N, et al. Heart Disease and Diabetes. In: Diabetes in America. 3rd edition. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases (US); 2018 Aug. CHAPTER 18.
2. Schramm TK, Gislason GH, Køber L, et al. Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation 2008;117:1945-54.
3. Estimates of Diabetes and Its Burden in the United States (cdc.gov). 2022.  Available at: https://www.cdc.gov/diabetes/data/statistics-report/index.html. Accessed June 23, 2022.
4. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.
5. Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia 2017;60:1620-29.
6. Lindström J, Louheranta A, Mannelin M, et al. The Finnish Diabetes Prevention Study (DPS): lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care 2003;26:3230-36.
7. Gong Q, Zhang P, Wang J, et al. Morbidity and mortality after lifestyle intervention for people with impaired glucose tolerance: 30-year results of the Da Qing Diabetes Prevention Outcome Study. Lancet Diabetes Endocrinol 2019;7:452-61.
8. Goldberg RB, Aroda VR, Bluemke DA, et al. Effect of long-term metformin and lifestyle in the Diabetes Prevention Program and its outcome study on coronary artery calcium. Circulation 2017;136:52-64.
9. Goldberg RB, Orchard TJ, Crandall JP, et al. Effects of long-term metformin and lifestyle interventions on cardiovascular events in the Diabetes Prevention Program and its outcome study. Circulation 2022;145:1632-41.
10. Wing RR, Bolin P, Brancati FL, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145-54.
11. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2021. Diabetes Care 2021;44:S111-S124.
12. Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the diabetes prevention program outcomes study. Diabetes Care 2012;35:731-37.
13. National Library of Medicine (U.S.). (2016, September - ). Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes (VA-IMPACT). Identifier: NCT02915198. https://clinicaltrials.gov/ct2/show/NCT02915198.
14. le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomized, double-blind trial. Lancet 2017;389:1399-1409.
15. Wilding JPH, Batterham RI, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384:989-1002.

Clinical Topics: Cardiovascular Care Team, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Lipid Metabolism, Acute Heart Failure, Interventions and Imaging, Angiography, Nuclear Imaging, Diet

Keywords: Diabetes Mellitus, Type 2, Diabetes Mellitus, Prediabetic State, Follow-Up Studies, Cardiovascular Diseases, Overweight, Coronary Vessels, Prospective Studies, Metformin, Life Style, Insulins, Blood Glucose, Glucose Tolerance Test, Body Mass Index, Glucose Intolerance, Fasting, Weight Loss, Risk Factors, Hospitalization, Myocardial Infarction, Coronary Disease, Outcome Assessment, Health Care, Angina, Unstable, Heart Failure, Angiography, Counseling, Stroke, Antihypertensive Agents, Ethnic Groups, Lipids

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