5:2 lifestyle intervention outflanks two antidiabetics for EARLY T2D

In the EARLY* trial, a 16-week intervention consisting of a 5:2 intermittent fasting meal replacement (5:2 MR) diet trumps two antidiabetic agents in improving glycaemic control and weight loss, as well as BP, TG, and HDL-C** levels in overweight or obese Chinese individuals with newly diagnosed type 2 diabetes (T2D).

Week 16 saw markedly greater reductions in HbA_1c (least-squares mean [LSM], -1.9 percent vs -1.6 percent; p=0.011) and mean weight loss (LSM, -9.7 vs -5.5 kg; p<0.0001) with 5:2 MR vs metformin. This treatment effect was similarly seen in the comparison between 5:2 MR and empagliflozin (LSM, -1.9 percent vs -1.5 percent; p=0.0001 and -9.7 vs -5.8 kg; p<0.0001, respectively).

Nearly 90 percent of individuals on 5:2 MR achieved HbA_1c level <7 percent as opposed to those on metformin (73.9 percent; p=0.002) and empagliflozin (70.6 percent; p<0.001). [JAMA Netw Open 2024;7:e2416786]

Achieving HbA_1c <6.5 percent

There were also more patients on 5:2 MR who achieved HbA_1c level <6.5 percent vs those on metformin and empagliflozin by week 16 (80 percent vs 60.4 percent and 55.1 percent; p<0.001 for both).

Of note, the duration of the intervention was less than the recommended 6-month minimum. This implies that the achievement of HbA_1c <6.5 percent is feasible with 5:2 MR within a period shorter than the recommended duration.

Moreover, almost 80 percent of those on 5:2 MR sustained their HbA_1c level <6.5 percent by the end of the 8-week follow-up. “[This indicates] that the 5:2 MR approach significantly and sustainably improves HbA_1c levels in patients with early T2D,” the researchers noted.

As per the ADA*** recommendations, individuals with HbA_1c <6.5 percent for at least 6 months after initiating lifestyle interventions are considered to have achieved diabetes remission. [Diabetes Care 2021;44:2438-2444]

Metabolic parameters, safety

Compared with patients on metformin, those on 5:2 MR had significant reductions in systolic BP (SBP; -6.7 vs -1.6 mm Hg; p=0.001), diastolic BP (DBP; -3.5 vs -1.0 mm Hg; p<0.0001), TG (-0.74 vs -0.13 mmol/L; p=0.007), and HDL-C (0.24 vs 0.13 mmol/L; p=0.02).

A similar trend was seen in the comparison between 5:2 MR and empagliflozin (-6.7 vs -2.1 mm Hg; p=0.002 [SBP], -3.5 vs -0.8 mm Hg; p=0.015 [DBP], -0.74 vs -0.12 mmol/L; p=0.006 [TG], and 0.24 vs 0.2 mmol/L; p=0.024 [HDL-C]).

According to the investigators, these findings suggest a potential cardiovascular protective effect with 5:2 MR.

The incidence of any adverse event (AE) was highest with metformin (n=36), with the most common being diarrhoea (n=13) and hypoglycaemia (n=8). Of the 11 AEs reported with empagliflozin, five were hypoglycaemia events.

In the 5:2 MR group, eight of the nine AEs were hypoglycaemia likely tied to the low-energy diet. The researchers underscored that it is important to prevent hypoglycaemia with low-energy diets. “However, compared with medications, the 5:2 MR demonstrates favourable safety.”

Two patients on empagliflozin had serious AEs (severe rash and elevated blood ketones requiring hospitalization), but these resolved following treatment.

Foundational treatment for T2D

Globally, China ranks first in terms of the number of adults with diabetes, with the figures jumping from 90 million in 2011 to 140.9 million by 2021. It is estimated to jump to almost 175 million by 2045. [https://diabetesatlas.org/idfawp/resource-files/2021/07/IDF_Atlas_10th_Edition_2021.pdf, accessed July 16, 2024]

In T2D patients, weight loss may lead to better glycaemic control and reduction in antidiabetic drug dosing. [Diabetes Care 2022;45:S113-S124] However, achieving weight loss could be challenging, hence the need for lifestyle interventions, the researchers noted.

The study included 405 individuals (mean age 45.5 years, 65.4 percent men, mean BMI 29.5 kg/m², mean HbA_1c level 7.9 percent) with newly diagnosed T2D but had not used antidiabetics in the 3 months prior. Participants were randomized 1:1:1 to receive 5:2 MR, metformin 0.5 g BID (increased to 2 g/d if initial dose was well tolerated), or empagliflozin 10 mg QD. Treatment ran for 16 weeks, with an 8-week follow-up thereafter.

The 5:2 MR regimen required participants to consume a low-energy MR product. There were 2 non-consecutive days within a week wherein the three regular meals were replaced with one serving of MR product A. For the remaining 5 days, participants were free to choose breakfast and lunch but were instructed to consume one serving of MR product B for dinner. They were encouraged to monitor their calorie intake.

“[F]or the first time, to our knowledge, [our study] directly compared 5:2 MR with two widely used antidiabetic medications, providing evidence for the 5:2 MR approach as an effective initial lifestyle intervention [and an alternative to metformin and empagliflozin] for Chinese patients with early-stage T2D,” the researchers concluded.

The findings also align with the 2020 China Guidelines, which stipulate that lifestyle intervention is the foundational treatment for T2D, and that medications shall only be initiated if glycaemic control is not achieved with the intervention. [https://rs.yiigle.com/cmaid/1315505, accessed July 16, 2024]

The investigators called for further studies to ascertain whether the glycaemic improvement is driven by the weight loss or the 5:2 MR intervention. They also recommended evaluating the intervention in patients taking antidiabetics or those with higher baseline HbA_1c. Longer studies are also warranted to determine the long-term efficacy and durability of 5:2 MR.