Neither metformin nor lifestyle interventions reduce risk of major adverse CV outcomes in pre-diabetics

1st June 2022

Use of either metformin or lifestyle interventions was unable to reduce the risk of a major adverse cardiovascular (CV) event in patients with pre-diabetes.

This was the key finding from a 21-year follow-up study by the Diabetes Prevention Program Research Group.

A 2018 global review of cardiovascular disease (CVD) in patients with type 2 diabetes found a prevalence of 32.2% and noted that CVD mortality accounts for approximately half of all deaths in these patients. In 1998, results from the UK Prospective Diabetes Study showed that metformin use reduced all-cause mortality by 36%.

Moreover, a study of the long-term effects of lifestyle interventions in people with impaired glucose tolerance found that such interventions delayed the onset of type 2 diabetes, as well as reducing the incidence of cardiovascular and all-cause mortality.

With a potential cardiovascular and mortality benefit from both metformin or lifestyle interventions aimed at weight reduction and increased physical activity, the Diabetes Prevention Program Research Group examined the value of each intervention in a randomised trial (the Diabetes Prevention Program (DPP) study) which was published in 2002.

The study assigned 3234 non-diabetic participants with elevated fasting and post-load plasma glucose concentrations, to either placebo, metformin (850mg twice daily), or a lifestyle-modification programme. The results showed that both metformin and lifestyle interventions, reduced the incidence of diabetes in persons at high risk by 58% and 31% respectively over an average of 2.8 years.

Based on these findings, the researchers invited pre-diabetic participants from the original DPP to enrol in a follow-on study to determine whether metformin and lifestyle interventions could reduce the incidence of adverse cardiovascular outcomes.

Participants continued with the same dose of metformin (850mg twice daily) and the lifestyle intervention. The primary outcome was the first occurrence of a major cardiovascular event which was pre-specified as non-fatal myocardial infarction, non-fatal stroke or fatal CVD.

Metformin or lifestyle interventions and CVD outcomes

A total of 3234 individuals with a baseline mean age of 51 years (68% women) and with a mean fasting blood insulin level of 160 pmol/L, were followed for a median of 21 years and of whom, 1073 were assigned to placebo, 1082 metformin and 1079 a lifestyle intervention.

During the period of follow-up, 310 individuals experienced an adverse cardiovascular event; 101 for patients assigned to metformin and 111 to the lifestyle intervention. These events did not differ significantly compared with placebo (hazard ratio, HR = 1.03, 95% CI 0.78 – 1.37, p = 0.81, metformin vs placebo) and a hazard ratio of 1.14 (95% CI 0.87 – 1.40, p = 0.34) for lifestyle vs placebo.

When considering non-fatal myocardial infarctions and strokes separately, there no significant differences for either intervention compared to placebo.

The authors concluded that despite the value of each intervention to reduce the risk of developing overt type 2 diabetes, neither was associated with a reduced risk of cardiovascular events in pre-diabetic patients.

Citation
Goldberg RB et al. Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study Circulation 2022

Anti-hypertensive use combined with healthy lifestyle significantly reduces mortality risk

14th February 2022

Anti-hypertensive drug use in combination with a healthy lifestyle is associated with the greatest reduction in all causes of death

The use of anti-hypertensive drugs when combined with healthy lifestyle measures appears to be the best strategy to reduce all-cause and cause-specific mortality. This is according to a study by Chinese researchers from the Department of Epidemiology and Biostatistics, School of Public Health, Huazhong University of Science and Technology, Hubei, China.

Hypertension significantly increases the risks of heart, brain, kidney and other diseases and according to the World Health Organization, an estimated 1.28 billion adults aged 30-79 years worldwide have hypertension, most of whom are living in low- and middle-income countries.

Furthermore, a 2019 analysis calculated that a high systolic blood pressure accounted for approximately 10·8 million deaths which was 19.2% of all recorded deaths in 2019. Hypertension is managed with a range of different classes of medicines, yet non-adherence to anti-hypertensive treatment affects 10%–80% of hypertensive patients and is one of the key drivers of suboptimal BP control.

With respect to lifestyle modification, there is strong evidence supporting the benefits of regular physical activity and exercise for the prevention and management of hypertension. However, whether the combination of anti-hypertensive medication and healthy lifestyle measures yields additional benefits and if adoption of healthy lifestyle measures after a diagnosis of hypertension provides a mortality benefit remains uncertain.

For the present study, the Chinese team examined the relationship between anti-hypertensive use and lifestyle measures and the effect of this on all-cause and cause-specific mortality among hypertensive patients.

They used data from the Dongfeng-Tongji cohort, which prospectively followed hypertensive patients for a median of 7.3 years. The team assessed specific lifestyle factors including body mass index, smoking status, diet, physical activity and sleep duration and computed an overall lifestyle score based on these five attributes, with higher scores (ranging from 0 to 10) indicating a healthier lifestyle.

In addition, participants were categorised into the following subgroups: favourable lifestyle (scores 8 – 10), intermediate (5- 7) and unfavourable (0 – 4). The use of anti-hypertensive medication was dichotomised into yes or no.

Anti-hypertensive use and subsequent mortality

A total of 14,392 participants with a mean age of 65.6 years (50.6% male) using anti-hypertensive medicines were included in the analysis. Over a median of 7.3 years, there were 2015 deaths including 761 due to cardiovascular disease and 525 from cancer.

Taking individuals not using anti-hypertensives and following an unfavourable lifestyle as the reference group, individuals using anti-hypertensives and with a favourable lifestyle had the lowest risk of all-cause mortality (hazard ratio, HR = 0.32, 95% CI 0.25 – 0.42). This was also true for cardiovascular mortality (HR = 0.33) and death due to cancer (HR = 0.30).

Interestingly, when using the same reference group, individuals who were not using anti-hypertensives but adopted a favourable lifestyle, also had a lower risk of all-cause mortality (HR = 0.34), cardiovascular (HR = 0.40) and cancer mortality (HR = 0.33).

In fact, there was a linear association with lifestyle score and mortality, such that regardless or anti-hypertensive medication use, each 1-point increase in lifestyle score was associated with a 17% lower risk of all-cause mortality, with similar reductions for cardiovascular and cancer deaths.

There was also a reduced mortality risk through the adoption of lifestyle measures after a diagnosis of hypertension. For example, compared to those with a consistently low lifestyle score between baseline and the first follow-up, those who instigated a change in lifestyle score from low to high also had a significantly reduced risk for all-cause (HR = 0.52), cardiovascular (HR = 0.53) mortality although the reduced risk of cancer mortality was non-significant.

The authors concluded that the combined effect of anti-hypertensive medication and adoption of a healthy lifestyle resulted in a significantly reduced risk of all and specific cause mortality.

Citation
Lu Q et al. Association of Lifestyle Factors and Antihypertensive Medication Use With Risk of All-Cause and Cause-Specific Mortality Among Adults With Hypertension in China JAMA Netw Open 2022