The results of the summarized study indicated that a 5:2 diet was more effective than antidiabetic medications for reducing HbA1c. This finding is primarily a consequence of greater weight loss in the 5:2 diet group (–21.4 lbs, −9.7 kg) than the metformin group (–12.1 lbs, −5.5 kg) and the empagliflozin group (–12.8 lbs, −5.8 kg).

Previous evidence indicates that weight loss reduces HbA1c in a dose-dependent manner, with each kilogram of weight loss equating to a 0.1% reduction in HbA1c, on average.^[1] Furthermore, greater amounts of weight loss lead to a greater likelihood of achieving T2D remission, defined as an HbA1c of less than 6.5% measured at least 3 months after stopping the use of antidiabetic medication.^[2]

In the DiRECT trial (an intervention involving 3 months of a very low-calorie liquid formula-based diet followed by a structured program for long-term weight loss maintenance), 34% of participants who lost 5–10 kg (11–22 lbs), 57% of participants who lost 10–15 kg (22–33 lbs), and 86% of participants who lost at least 15 kg (33 lbs) achieved T2D remission.^[3] In a similar study, known as the DIADEM-I trial, a weight loss of approximately 12 kg (26.4 lbs), on average, resulted in 61% of the participants achieving T2D remission.^[4]

The relationship between HbA1c and body weight is consequent of the etiology of T2D, or the set of factors involved in the development of the condition. Excess body fat is the primary cause of T2D because it results in the infiltration of fat into the liver and pancreas.^[5]

Factors that contribute to the development of type 2 diabetes

Adapted from Capoccia, et al., 2024, Acta Diabetol.

According to the twin cycle hypothesis, chronic excess calorie intake leads to the accumulation of fat in the liver, which decreases the liver cells’ response to insulin and results in liver-specific insulin resistance. This leads to high blood levels of insulin and glucose, which enhances de novo lipogenesis, or the synthesis of fatty acids in the liver. Due to an overproduction of very-low-density lipoprotein triglycerides by the liver, there is increased uptake and storage of these fatty acids in the pancreas. These fatty acids damage the beta cells (the cells in the pancreas that synthesize, store, and secrete insulin), and thus sustained exposure over time causes the beta cells to become dysfunctional.^[6]

However, excess body fat does not necessarily mean obesity. Once the storage capacity of subcutaneous fat is exceeded, ectopic fat accumulates, including in the liver and pancreas. The personal fat threshold posits that the storage capacity of subcutaneous fat varies between individuals, and thus T2D can develop in anyone — independent of BMI — given the accumulation of too much fat in the liver and pancreas.^[7]

A recent trial tested this theory and found that in participants with T2D and an average BMI of 24.8, a meal replacement intervention that produced an average weight loss of 7.7 kg (about 17 lbs, or 11% of initial body weight) resulted in diabetes remission in 70% of the participants.^[8]

The twin cycle hypothesis

Type 2 diabetes develops as a consequence of chronic excess calorie intake, resulting in the accumulation of liver fat and subsequently, liver insulin resistance. Elevated liver fat causes the liver to increase the export of very low-density triglycerides, which build up in the pancreas and cause damage to beta cells. Adapted from Taylor, et al., 2021, BMJ.

As evidenced by the findings discussed above, not everyone who achieves substantial weight loss also achieves T2D remission. The recovery of beta-cell function is pivotal to T2D remission, and in the context of long-standing T2D and/or other conditions, the damage to beta cells can be so severe that beta cell dysfunction is irreversible.^[9]

Notably, the participants in the summarized study had a short T2D duration (diagnosed within the past year), were not using medications, and had a relatively (compared to other people with T2D) low baseline HbA1c, all of which are associated with an increased likelihood of achieving T2D remission.^[9] Overall, 80% of the participants in the 5:2 diet group achieved an HbA1c of less than 6.5%, whereas only 55%–60% did in the antidiabetic medication groups.

Considering the importance of weight loss for T2D remission and the success of the 5:2 diet in the summarized study, the main question is whether there’s reason to believe that this particular diet is better than others. Although evidence indicates that the 5:2 diet is an effective option for reducing weight and HbA1c,^[10] there’s a lack of evidence indicating that it is superior to other hypocaloric diets.

In fact, in general, there’s a lack of evidence to indicate that any particular diet or macronutrient distribution is best for people with T2D.^[11] Consequently, the diet should be tailored to the individual’s preferences^[11] because personalization should result in greater adherence to an energy deficit, and thus greater weight loss and greater likelihood of achieving T2D remission.

While details like macronutrient distribution and meal frequency don’t seem to have much of an effect on clinical outcomes on average, though they can still make a notable difference at the individual level, there is a robust body of evidence indicating that meal replacements are particularly effective for weight loss.^[12]

Meta-analyses of randomized controlled trials have reported that diets involving meal replacements produce greater reductions in weight and HbA1c than traditional low-calorie diets or conventional diets for T2D,^[13]^[14] with greater effects observed in studies involving total meal replacement than partial meal replacement.^[13]

In summary, the 5:2 diet was more effective than taking antidiabetic medications for reducing HbA1c in the summarized study. This was due to the 5:2 diet producing greater weight loss, which is essential to achieving T2D remission, as weight loss corresponds to reductions in liver fat and pancreas fat, and elevations in these fat stores cause T2D. The 5:2 diet is a viable approach to achieve the magnitude of weight loss needed for T2D remission (at least 22 lbs or 10 kg, typically), but there’s a lack of evidence to support that it’s superior to other hypocaloric diets. On the other hand, the use of meal replacements in the 5:2 diet is notable, as evidence suggests that weight-loss diets involving meal replacements typically induce greater weight loss than conventional food-based diets.

Intermittent fasting vs. antidiabetic drugs for blood sugar control Original paper