Efficacy of Diabetes-Specific Formulas as Meal Replacements in DiabeticPatients: An Overview

Diabetes-specific formulas have shown to be effective at improving glucose control with additional nutritional benefits. The aim of this review is to assess the current knowledge on the different types of DSF (Diabetes-Specific Formulas) and how they affect the weight, HbA1c (glycosylated hemoglobin), glucose, insulin and lipid profiles. Database research was made with diabetes and nutritional formulas as keywords. From over 60,000 titles retrieved from 2005 to 2020, only 34 were chosen based mainly on their methodology and results. Results show that for glycemia control, high fiber carbohydrates are more effective as well as high protein formulas. For HbA1c, oat seemed to be less effective than Meal Replacement (MR) and a protein-rich formula proved to be effective in the long-term. One of the most researched benefits in MR plans is weight loss, evidences show up to a 5-10% decrease in interventions with DSF formulas. Other advantages of this approach include greater glycemic control, insulin sensitivity and lower postprandial secretion, which consequently lead to a decrease in morbidity and mortality associated with cardiovascular causes. About lipid profile values; HDL, LDL and Total cholesterol, existing evidence differ from one another, so it is necessary to investigate further to reach a consensus. Nevertheless, not all DSF formulas are created equal, nor is their effectiveness at short and long term. That is why the aim of this review is to give an overlook of the effects of DSF formulas (as meal replacements) on blood glucose, insulin, HbA1c, lipid profile and weight of these patients [6].


Introduction
Worldwide prevalence of diabetes has increased over the last 40 years from 4.7% to 8.5% of the adult population, especially those in 2016, around 1.6 million deaths occurred as a direct consequence of diabetes, making it the 7 th leading cause of death in that same year [1]. Poor glycemic control and dyslipidemia are very important aspects of the type 2 diabetic patient follow up, mainly because of the systemic consequences high blood glucose and dyslipidemia have proven to promote [2]. Many comorbidities such as hypertension, which affects at least 65% of diabetic patients, is also linked to other fatalities like coronary artery disease, myocardial infarction, stroke and congestive heart failure [3].
Additionally, microvascular complications as neuropathy, retinopathy and nephropathy play an important role in advanced diabetes mellitus. This is all possible because hyperglycemia promotes irregularities in the protein kinase C, polyol and hexosamine pathways, along with the free radical damage from Reactive Oxygen Species (ROS) and glycated end products which can produce endothelial dysfunction. Because of all this, the therapeutic target of diabetes is to keep blood glucose levels as low and as stable as possible, so that damage can be partially, if not completely, prevented [4]. DSF formulas have shown to help maintain glucose and lipid profiles at adequate levels when used for short periods of time [5].

Effect of meal replacements on blood glucose
When replacing one meal, a lower glycemic index has been linked with the consumption of DSF formulas with extended-release carbohydrates, if compared with the same amount of carbohydrates from a reference food, such as bread or glucose. This means that a lower glycemia was observed in subjects consuming DSF formulas [7,8]. Something similar happened when patients were given an oral nutritional formula based on a protein blend, fiber and a fat blend high on oleic oil. Researchers compared it with those receiving a cornflakes and milk isocaloric meal and found that the area under the curve for post-meal glycemia was significantly lower in the experimental group at 30 min (p=0.003), 60 min (p=0.0001), 120 min (p=0.0001), and 180 min (p 0.0001) [9].
Likewise, postprandial glycemia was also significantly lower and got back to baseline faster when experimenting with two DSF formulas versus an isocaloric amount of oatmeal for breakfast. This could be explained by the low glycemic index of the formulas and macronutrient composition [10]. Another study compared two DSF formulas vs. a standard control formula for a two-year follow-up period, results in plasma glucose levels showed that compared with the standard control formula, both DSF lowered insulin requirements, improving capillary glycemia (146.1 ± 45.8 mg/dL, p<0.001) [11].
Taking a high-energy, high-protein DSF formula and substituting the maltodextrin for isomaltose from an oral nutrition supplement resulted in an attenuated postprandial glucose level. However, postprandial peak glucose concentration in both formulas did not differ significantly (p=0.107) [12]. Another hyper-protein but very lowcarbohydrate nutrition formula was tested against a standard protein formula. The first one showed to keep blood glucose concentrations within very small variations when followed up from 30 to 150 min. These could be very helpful in malnourished patients suffering from muscle wasting or sarcopenia, given the fact that most DSF formulas tend have a higher lipid content and normoprotein distribution [13].
A higher fat and fiber content, as well as lower carbohydrate and the presence of fructose in DSF oral nutritional formulas has shown to contribute to a significantly lower glycemic index and glycemic control when compared to standard nutritional formulas. Although, it is important to note that a high-fat content meal could promote weight gain and lipid distortions among diabetic patients despite of its effects on blood glucose. In the Look AHEAD study, findings showed significant reduction in weight and blood glucose levels on those type-2 diabetes patients under MR plans with DSF in comparison to others carrying on standard diets with equal caloric count [14].

Effect of meal replacements on HbA1c
When diabetic patients were given a high fiber meal replacement for breakfast containing rice, soybean, resistant starch and oat dietary based meal, was measured as a long-term glycemic control variable. For patients who took the oat-based meal, HbA1c increased by 0.3% (95% CI, 0.1% to 0.5%, p=0.005). In contrast to those who took the high fiber breakfast replacement, whose HbA1c diminished by Open Access Journal -0.2% (95% CI, -0.38% to -0.07%, p=0.004). This suggests further consideration when recommending oat-based meals for the long term to these patients [15].
On the other hand, in this 12-week trial, patients replaced three meals a day with a protein-rich formula during week 1. In weeks 2-4, both dinner and breakfast were replaced and finally from week 5 through 12, only dinners were exchanged. After 8 weeks, HbA1c decreased from initially 8.8% to 7.7% (1.1%) (p=0.002). At the end of the study there was a slight increase of HbA1c to 8.1%, which was still statistically significantly lower than the reference [0.8% (1.4%); p=0.048], proving the effectiveness of the protein-rich meal replacement formula in long term control of glycemia [16].
An intervention consisting of a personalized diet, regular motivation and meal replacement with a low carbohydrate formula was able to decrease HbA1c to a mean of [95% confidence interval] -0.97% [-1.21 to -0.74] just as the previous studies demonstrated. Nevertheless, it is difficult to point out which of the elements of the intervention contributed the most to the lowering of HbA1c, which could diminish the clinical significance of the results from this study [17]. Other data demonstrate that three-month interventions following a 1 or 2 meal replacements daily program lead to a great decrease (0.11%) in HbA1c [18]. In the Look AHEAD trial study, individuals exposed to the intervention had better odds to lost >10% of their initial weight after the 1-year period of follow up, at the same time, this group also got lower results in HbA1c (6.1% ± 0.7 men, 6.3% ± 1.0 women) compared to their baseline data (7.0% ± 1.1) ; p (<0.0001) [19].

Effect of meal replacements on weight
Different studies have shown that weight loss of approximately 5-7% is a determining factor in reducing the mortality rate due to cardiovascular reasons; sleep apnea; female sexual dysfunction; hospital stay and urinary symptoms in overweight patients with typess 2 diabetes [20].
The Look AHEAD initiative, focused on Intensive Lifestyle Intervention (ILI), consists of a program that integrates Meal Replacements (MR) with physical activity, and its results reported that after 1 year the experimental group participants lost approximately 8.6 kg (P<0.001) compared to the control group that followed a dietary scheme with the same amount of calories per day. The most relevant data showed a positive correlation between weight loss and the quantity of meals replace by a nutritional formula per day (r=0.32, p<0.001), also, likewise data analysis demonstrated that same candidates were 4 times more likely to achieve a weight loss greater than 10% at the end of the study. Finally, the consumption of meal replacements was the third most influential factor to reach the goal of weight loss, followed by greater self-reported physical activity [21].
Interventions such as; Slim-Fast and Weight Watchers (both dietary plans calculated by energy intake for achieving weight loss), low carb diet and combined diet-exercise plan; have demonstrated effectiveness in decreasing some anthropometric measures of participants, specifically the perimeter of waist and weight [22]. Looking into a short MR intervention performed on 2009, diabetic patients (BMI 33-44 kg/m 2 ), were randomized in counseling sessions and hypocaloric diet (60%) reduction of subgroups. Those patients treated with the specific formula Glucerna SR developed a greater and sustained weight loss over time. This formula provides 206 calories per serving distributed in 9 g protein, 25 g carbohydrate and 24 other compounds. Specifically, maltodextrin; sunflower oil; soy oil, fructose; minerals (such as potassium, magnesium, sodium, copper, zinc and ferrous sulfate); vitamins B, A, K1, D2, antioxidants, taurine and L-carnitine [23]. Another study, followed a sample of patients for 8 weeks, where breakfast, lunch and dinner were replaced by a specific liquid formula composed of equal parts of proteins and carbohydrates; and 5% fat, the final data showed a marked decrease in weight (-9.6 Kg) and percentage of body fat (-7.6%) in the participants [24].
The standard Soy-Yoghurt-Honey (SYH) formula known as almased for commercial purposes; is composed mainly by soy and milk protein, in addition to antioxidants, enzymes and oligofructose from honey. In order to quantify its efficacy this formula was implemented during a controlled trial conducted in 88 diabetic and overweight subjects, randomized in two groups; meal replacements formulas and conservative therapy (lifestyle modifications). The high protein formula was administrated for 6 weeks, obtaining better results in terms of weight reduction (180% more) and fat mass (p<0.01) in comparison to lifestyle group. With that in mind experts have approved the meal replacement diet approach as an effective strategy to lose weight in diabetic patients, especially if it is part of the initial phase in the therapeutic program [25]. Another soy-based formula showed similar results in a longer intervention, where weight loss in female patients was greater (-7.6 ± 7.9 kg) (p<0.001) than the control group [26].

Effect of meal replacements on fasting insulin
Commonly used nutritional formulas are composed of high percentages of carbohydrates and/or proteins. Additionally, specific features of DSF include their low glycemic index, normoproteic and normocaloric balance, as well as 100% PHGG (partially hydrolyzed guar gum) soluble fiber, target population are diabetics who need to maintain this type of diet for long amounts of time. An experimental therapy was carried out in a clinical trial on 15 patients, achieving a lower average in the concentration of serum insulin (p=0.039) compared to the subgroup that took the standard polymeric nutritional formula. Specifically, insulin levels in the 60 and 90 minutes of the curve showed lower insulin requirements [27].
The Soy-Yoghurt-Honey (SYH) formula, was a standard weightloss formula used to replace breakfast in a group of patients during a randomize trial, obtaining post-prandial glycemic and insulinemic responses lower than the traditional breakfast group [25]. Other meal replacement therapies also showed significant decreases in serum insulin levels (14.1 ± 1.3 IU/ml, p<0.05) compare to 29.3 ± 10.9 IU/ ml in groups that had other diet programs [24]. Another specific formula with similar effects is Glucerna SR, which was incorporated into a randomized, crossover clinical trial, within 14 obese patients. Upon completion of the intervention, participants showed an increase in insulin sensitivity coupled with a decrease in insulin secretion [28].
When it comes to comparing standard formulas vs. Oral Nutritional Supplements for Diabetic patients (ONS-D), the latter demonstrate lower glycemic response and greater control in postprandial appetite. These outcomes are presumably because ONS-D such as Glucerna and Diasip are composed of sucrose analogs; sucromalt and isomaltulose respectively. Both components are low digesting carbohydrates that provoke increase GLP-1 secretion, which consequently might lower GIP and insulin concentration. On the other hand, blood glucose levels after ingesting ONS-D returned to baseline in approximately 150 minutes in contrast to standard nutritional supplements (180 minutes), which proves that ONS-D promotes a healthier metabolic profile in diabetic patients [29]. and HDL are also observed [30]. An example of this was evidenced in a multicenter, controlled trial, where the experimental group of patients received once a day the formula of meal replacement 'Once Pro' composed of 40% carbohydrate, 20% protein and 40% fat added to a controlled diet, and the other subgroup only followed a dietary regimen. At the end of 3 months both groups obtained lower HDL cholesterol values, but only the MR group had lower LDL and total cholesterol values [31]. In another intervention, using the Glucerna formula similar results were obtained, post analysis data showed decreased values in C-HDL-C, VLDL-C and triglycerides [32] [ Tables  1 and 2].

Recommendations and Conclusion
In overweight patients, DSF should be taken 2-3 times per day together with a reduced calorie meal plan, either as a calorie replacement for a meal, as a partial meal or as a snack. The calorie goal for this group of patients is as follows: patients <250 lb=1,200 to 1,500 calories, while patients >250 lb=1500 to 1800. The approach in normal weight patients varies if the diabetes is controlled (HbA1c ≤ 7%) or uncontrolled (HbA1c>7%). For patients with controlled diabetes, the use of DSF depends on the physician criteria an the patients' characteristics. However, for patients with uncontrolled diabetes, DSF should be incorporated 1-2 times per day into a meal plan, either as a calorie replacement for a meal, as a partial meal or as a snack. In underweight patients, is recommended to use 1-3 units of DSF per day, depending on management goals [33].
Standard formulas have been associated with adverse effects such as hyperglycemia, osmotic diuresis and loss of electrolytes, so they are not ideal for diabetic patients. To cover this sector of the population,  A randomized cross-over study consisting of a short-term, intensive dietary modification.
-Fasting glucose concentrations were not affected by prior diet, but postprandial glucose concentrations were (P = 0.018), with significantly higher values after the high-fat than the highsugar diet (P = 0.03).   -At 150 min, ET presented a higher glucose concentration than DSF (p < 0.001), but no significant differences were found in insulin concentration between DI and GS (p = 0.976). At 150 min, value of this incretin was significantly higher for GS when compared with both, ET (p < 0.001) and DI (p < 0.001). -The AUC0-180 min in insulin response was significantly lower in GS when compared with the other supplements (p < 0.001) -The maximum peak of this incretin was observed at 90 min with ET and DI, which was higher when compared to GS levels (p < 0.05).
specific formulas for diabetics have been developed in the last decade.
With the aim of being used with multidisciplinary weight management programs as meal replacements [28]. DSF provide a controlled caloric intake, minimizing postprandial glucose response; even in cases where patients are resistant to traditional weight loss therapy, adding the approach of meal replacements with these formulas has proven to be effective, improving weight loss to -5.4 kg in some studies [18,23].
Meanwhile standard formulas are well known and have been used over the past few decades, the used of DSFs is still controversial. Diverse studies have shown the important role of DSF for type-2 diabetic patients management in fields such as glycemic control (both capillary and plasma glucose), lowering insulin requirements, effective weight loss as well as reducing the risk of acquired infections in hospitalized patients [32]. Compared to standard formulas, DSF have lower glycemic index and its components are targeting a population who needs normoprotein-caloric diet [34]. An ideal nutritional formula for all types of diabetic patients has not yet been developed. For this reason, integrated therapy remains the best option [30]. One of the elements, exercise, is an irreplaceable component to achieve long-term maintenance of lost weight and reduce the risk of deaths from cardiovascular diseases in diabetics. The goal of achieving up to 10% of weight loss in obese diabetic patients brings long-term benefits such as reducing the need for hypoglycemic agents and better glycemic control [21].
On the other hand, there are still many aspects of topic pending for investigation, including comparison of the effects of protein-rich and fat-rich DSF on short-term and long-term. In addition, the scientific community still lacks enough clinical trials to investigate the impact of different therapies on morbidity and mortality among diabetic adults [20].