nutrients

Article
Comparative Evaluation of a Low-Carbohydrate Diet and a
Mediterranean Diet in Overweight/Obese Patients with Type 2
Diabetes Mellitus: A 16-Week Intervention Study
Walter Currenti 1, *,† , Francesca Losavio 2,† , Stefano Quiete 3 , Amer M. Alanazi 4 , Giovanni Messina 2 ,
Rita Polito 2 , Fabiana Ciolli 2 , Raffaela Simona Zappalà 1 , Fabio Galvano 1, * and Raffaele Ivan Cincione 2

1 Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy;
simonazappala@hotmail.com
2 Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy;
losaviofrancesca@yahoo.it (F.L.); giovanni.messina@unifg.it (G.M.); rita.polito@unifg.it (R.P.);
fabycioll@gmail.com (F.C.); ivan.cincione@unifg.it (R.I.C.)
3 Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
stefanoquiete@gmail.com
4 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University,
P.O. Box 2457, Riyadh 11451, Saudi Arabia; amalanazi@ksu.edu.sa
* Correspondence: currentiw@gmail.com (W.C.); fgalvano@unict.it (F.G.)
† These authors contributed equally to this work.

Abstract: Introduction: The worldwide prevalence of type 2 diabetes mellitus (T2DM) and obesity
has been steadily increasing over the past four decades, with projections indicating a significant rise
in the number of affected individuals by 2045. Therapeutic interventions in T2DM aim to control
blood glucose levels and reduce the risk of complications. Dietary and lifestyle modifications play
a crucial role in the management of T2DM and obesity. While conventional medical nutritional
therapy (MNT) often promotes a high-carbohydrate, low-fat Mediterranean diet as an elective treat-
Citation: Currenti, W.; Losavio, F.; ment, low-carbohydrate diets (LCDs), specifically those restricting carbohydrate intake to less than
Quiete, S.; Alanazi, A.M.; Messina, G.; 130 g/day, have gained popularity due to their multifaceted benefits. Scientific research supports the
Polito, R.; Ciolli, F.; Zappalà, R.S.; efficacy of LCDs in improving glycemic control, weight loss, blood pressure, lipid profiles, and overall
Galvano, F.; Cincione, R.I.
quality of life. However, sustaining these benefits over the long term remains challenging. This trial
Comparative Evaluation of a Low-
aimed to compare the effects of a Mediterranean diet vs. a low-carbohydrate diet (carbohydrate
Carbohydrate Diet and a
intake < 130 g/day) on overweight/obese patients with T2DM over a 16-week period. The study will
Mediterranean Diet in Overweight/
evaluate the differential effects of these diets on glycemic regulation, weight reduction, lipid profile,
Obese Patients with Type 2 Diabetes
Mellitus: A 16-Week Intervention
and cardiovascular risk factors. Methods: The study population comprises 100 overweight/obese
Study. Nutrients 2024, 16, 95. https:// patients with poorly controlled T2DM. Anthropometric measurements, bioimpedance analysis, and
doi.org/10.3390/nu16010095 blood chemistry assessments will be conducted at baseline and after the 16-week intervention period.
Both dietary interventions were hypocaloric, with a focus on maintaining a 500 kcal/day energy
Academic Editor: Susanna C. Larsson
deficit. Results: After 16 weeks, both diets had positive effects on various parameters, including
Received: 31 October 2023 weight loss, blood pressure, glucose control, lipid profile, and renal function. However, the low-
Revised: 22 December 2023 carbohydrate diet appears to result in a greater reduction in BMI, blood pressure, waist circumference,
Accepted: 23 December 2023 glucose levels, lipid profiles, cardiovascular risk, renal markers, and overall metabolic parameters
Published: 27 December 2023
compared to the Mediterranean diet at the 16-week follow up. Conclusions: These findings suggest
that a low-carbohydrate diet may be more effective than a Mediterranean diet in promoting weight
loss and improving various metabolic and cardiovascular risk factors in overweight/obese patients
Copyright: © 2023 by the authors. with T2DM. However, it is important to note that further research is needed to understand the clinical
Licensee MDPI, Basel, Switzerland. implications and long-term sustainability of these findings.
This article is an open access article
distributed under the terms and Keywords: low-carbohydrate diet; Mediterranean diet; obesity; type 2 diabetes; body composition;
conditions of the Creative Commons free-fat mass; fat mass; cardiovascular risk; cardiometabolic risk
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).

Nutrients 2024, 16, 95. https://doi.org/10.3390/nu16010095 https://www.mdpi.com/journal/nutrients

Nutrients 2024, 16, 95 2 of 14

1. Introduction
Over the past forty years, there has been a persistent rise in the worldwide prevalence
of type 2 diabetes mellitus (T2DM) and obesity. Projections indicate that by 2045, the
number of people with diabetes around the world will increase significantly, with estimates
suggesting that approximately 600 million individuals will be affected [1]. Type 2 diabetes
mellitus (T2DM) has a significant impact on public health, affecting over 3 million individ-
uals in Italy and is associated with high rates of mortality, disability, and hospitalization,
as reported by the ISTAT report on Diabetes in Italy). Therapeutic interventions in T2DM
aim to control blood glucose levels and reduce the incidence of both microvascular and
macrovascular complications. It has been reported that a 1% reduction in HbA1c levels
leads to a 35% decrease in the risk of microvascular complications and reduces the risk of
myocardial infarction and sudden death by 16% [2]. Achieving optimal blood glucose levels
is a critical therapeutic goal while concurrently addressing concomitant comorbidities, such
as dyslipidemia, hypertension, and albuminuria, which are intricately interrelated with
the pathophysiology of hyperglycemia [3–5]. The modification of dietary and lifestyle
factors represents a fundamental tenet in the treatment and management of type 2 diabetes
mellitus and obesity [6]. Dietary interventions that institute a substantial negative calorie
balance play a critical role in restoring normal pancreatic function and hepatic insulin
sensitivity [7–9]. Insulin resistance, a significant risk factor for cardiovascular disease in
patients with type 2 diabetes (T2DM), is independently linked to ischemic heart disease in
T2DM patients. Moreover, T2DM patients who suffer from ischemic heart disease display
a greater degree of insulin resistance compared to those without coronary disease, even
after controlling for other variables that may influence this association [10–13]. The conven-
tional medical nutritional therapy (MNT) for managing diabetes typically promotes the
adoption of a Mediterranean diet (MD) with high-carbohydrate (50–60% of daily energy
requirements) and low-fat regimen (no more than 30% of total energy), emphasizing caloric
restriction, increased fiber consumption, and focusing on vegetables, fruits, whole cereals,
and legumes, in addition to lean proteins from fish and poultry and healthy fats such as
extra virgin olive oil [14,15]. There is growing evidence leading to recommendations from
numerous scientific medical societies of diabetology on the use of these dietary approaches
to intervene against type 2 diabetes [16–18] and overall protection against cardiovascular
diseases [19]. However, contemporary literature reviews assessing the comparative effects
of carbohydrate restricted diets versus low-fat control diets in overweight/obese patients
with type 2 diabetes mellitus have shown divergent and inconclusive results regarding
the impact on glycated hemoglobin, weight loss, and cardiovascular risk factors [20–26].
Dietary fats, particularly saturated fatty acids (SFAs), have been implicated as the cause
of the significant rise in obesity and its related diseases [24]. On the contrary, several
systematic reviews challenge the link between total SFA intake with cardiovascular disease
and recent studies showed that short-chain saturated fatty acids (SCSFAs) especially from
dairy foods [27–30] may exert potential beneficial effects both on metabolic and mental
health outcomes [31–33].
Thus, the aim of this study was to compare the effects of a Mediterranean diet versus
a low-carbohydrate diet (carbohydrate intake < 130 g/day) on overweight/obese patients
with T2DM over a 16-week period. The study will evaluate the differential effects of these
diets on glycemic regulation, weight reduction, lipid profile, and cardiovascular risk factors.

2. Materials and Methods

2.1. Study Population
A total number of 100 overweight/obese patients with type 2 diabetes mellitus, with
a median duration of diabetes of 5 years (54 females and 46 males, with an average age
of 63; BMI 34,4 kg/m2 ; HA1c 8.5%), equally divided in two groups, where one group
followed a low-carbohydrate dietary approach (50 patients, 24 men, 26 women) and the
other group had a Mediterranean diet (50 patients, 22 men, 28 women) were recruited at
the University Service of Dietetic Therapy, Diabetology and Metabolic Diseases, Policlinico
Nutrients 2024, 16, x FOR PEER REVIEW 3 of 16

followed a low-carbohydrate dietary approach (50 patients, 24 men, 26 women) and the
Nutrients 2024, 16, 95 3 of 14
other group had a Mediterranean diet (50 patients, 22 men, 28 women) were recruited at
the University Service of Dietetic Therapy, Diabetology and Metabolic Diseases,
Policlinico Riuniti Hospital of Foggia, Puglia, Italy, as reported in Figure 1. All the women
Riuniti Hospital of Foggia, Puglia, Italy, as reported in Figure 1. All the women recruited
recruited were in the post-menopause stage. The inclusion criteria were age > 18 and < 75
were in the post-menopause stage. The inclusion criteria were age > 18 and < 75 years,
years, BMI > 25 Kg/m2, a poorly controlled type 2 diabetes mellitus with HA1c >8.5%, a
BMI > 25 Kg/m2 , a poorly controlled type 2 diabetes mellitus with HA1c >8.5%, a stable
stable body weight, and no physical activity during the 90 days preceding the study (less
body weight, and no physical activity during the 90 days preceding the study (less than
than 1.6 METS in 24 h). Furthermore, no physical activity was allowed throughout the
1.6 METS in 24 h). Furthermore, no physical activity was allowed throughout the study.
study. Exclusion criteria included: pregnancy or lactation, previous gout or
Exclusion criteria included: pregnancy or lactation, previous gout or hyperuricemia, neo-
hyperuricemia, neoplastic disease, corticosteroids, hypoglycemic therapy with drugs
plastic disease, corticosteroids, hypoglycemic therapy with drugs other than metformin,
other thanrenal
impaired metformin,
functionimpaired
with a serum renalcreatinine
function ≥ with a serumabnormal
1.5 mg/dL, creatinineliver
≥1.5function
mg/dL,
abnormal
with liver
alanine function with alanine
aminotransferase aminotransferase
and aspartate and aspartate
aminotransferase levels aminotransferase
surpassing three
levels surpassing three times the standard upper limit, heart
times the standard upper limit, heart diseases such as unstable angina, and diseases such as unstable
unstable heart
angina, and unstable heart failure. None of the enrolled patients
failure. None of the enrolled patients experienced chronic complications of diabetesexperienced chronicor
complications
previous of diabetes
cardiovascular or previous
events. cardiovascular
The comorbidities events. The
are represented by comorbidities
hypertension and are
represented byFinally,
dyslipidemia. hypertension
to assessand thedyslipidemia.
comparative Finally,
effects oftoonly
assess
twothetypes
comparative effects
of diet, i.e., the
of only two types of diet, i.e., the Mediterranean diet versus a low-carbohydrate
Mediterranean diet versus a low-carbohydrate diet, all anti-hypertensive, cholesterol low- diet, all
anti-hypertensive, cholesterol lowering, and hypoglycemic drugs were suspended
ering, and hypoglycemic drugs were suspended during the study. Before taking part in the during
the study.
study, Before taking
all subjects providedpartwritten
in the study, all subjects
permission and it provided writteninpermission
was conducted accordanceand with it
was conducted in accordance
the Declaration of Helsinki. with the Declaration of Helsinki.

Figure 1. Flowchart of participant selection.

2.2. Study Design

A single-center, prospective, longitudinal, two parallel arm, non-randomized di-
etary pilot trial was conducted to test the effects of a Mediterranean diet versus a low-
Nutrients 2024, 16, 95 4 of 14

carbohydrate dietary approach in overweight/obese patients with uncontrolled T2DM. The

study lasted a total of 16 weeks. Anthropometric measurements, bio-impedance analysis,
and blood chemistry assessments were performed at the beginning of the study, time 0 (T0),
and at the end of the 16 weeks, time 1 (T1).

2.3. Dietary Intervention

A registered dietitian provided instructions to participants in both groups regard-
ing the implementation of the two diets. Those assigned to the low-carbohydrate diet
(LCD) received a personalized dietary plan with a maximum of 20 E (energy value of the
diet)% from carbohydrates (primarily complex and water soluble), 50–60 E% from fat, and
25–30 E% from protein. The consumption of monounsaturated fatty acids (MUFAs) and
polyunsaturated fatty acids (PUFAs) was encouraged. During the first visit, they were
carefully trained on recognizing foods containing carbohydrates and nutritional education
materials were provided. On the other hand, participants allocated to the mediterranean
diet (MD) were instructed to adhere to the official Italian society of Diabetology dietary
recommendations, which entail 50–60 E% carbohydrates, mainly derived from fruits, veg-
etables, and whole-grain sources, 20–30 E% fat, where less than 10 E% should be from
SFA, and 20–25 E% from protein. For the low-carbohydrate diet, as per definition [29], a
quantity of carbohydrates less than 130 g was administered, while for the Mediterranean
diet, a quantity of carbohydrates, as per definition, exceeding 45% (about 55%) [15] was
administered. Firstly, the individual calorie requirement was calculated by estimating
the basal metabolic rate (BMR) through Mifflin-St George equations, which consider the
individual’s sex, age, weight, and height of overweight/obese subjects [34]. Total daily
energy expenditure (TDEE) was calculated by multiplying the obtained BMR by the lower
physical activity factor derived from LARN (Italian Reference Intake Levels of Nutrients
and Energy). Both dietary interventions were subjected to a 500 kcal/day energy deficit.
Patients have been instructed to have five meals in a day. The typical balanced daily energy
distribution was: 20–25 E% at breakfast, 5–10 E% for snacks, 30–35 E% for lunch, and
25–30 E% for dinner. Adherence to the diet was monitored every four weeks by phone
calls conducted by trained research staff dietitians. During the telephone calls, patients
were asked to report a typical day’s food intake, including details about meals, snacks, and
beverages. The researcher engaged in a supportive and motivational discussion with the
participants. Patients received guidance on how to overcome specific dietary challenges or
navigate social situations that could impact adherence.

2.4. Body Composition Assessment

After verifying compliance with the inclusion criteria, anthropometric analysis, bio-
electric impedance analysis (BIA), and urine and blood samples were collected before
and at the end of the dietary program. The following anthropometric parameters were
measured: height, weight, body mass index (BMI = body weight (kg)/height2 (m)2 , waist
circumference, hips and waist–hip ratio (waist–hip ratio = waist circumference/hips).
Through bio-electric impedance analysis (InBody 770. Co., Ltd., Seoul, South Korea), we
evaluated the body composition of patients by detecting the following parameters: FM (fat
mass) expressed in kilograms, FFM (fat-free mass), muscle mass expressed in kilograms,
total body water expressed in kilograms and in percentage.

2.5. Urine and Blood Samples

Fasting samples of venous blood and urine were collected and analyzed at the cen-
tralized laboratory of the Policlinico Universitario Riuniti di Foggia to evaluate glucose,
glycosylated hemoglobin (Hb1Ac), total cholesterol, HDL cholesterol, LDL cholesterol,
triglycerides, creatinine, albuminuria, and e-Gfr, calculated using CKD-EPI equations for
the glomerular filtration rate [35]. Insulin was measured by the immunochemiluminescent
method, blood glucose by the enzymatic method with hexokinase, HbA1c by immunoas-
say measurement, and total cholesterol, HDL, LDL, and triglycerides by the enzymatic
Nutrients 2024, 16, 95 5 of 14

colorimetric assay. Serum creatinine was measured by the enzymatic assay. To deter-
mine cardiovascular risk, the cardiovascular risk index (calculated by dividing the total
cholesterol values by the HDL cholesterol values) and the cardiovascular (expressed as a
percentage of the probability of undergoing a first major cardiovascular event in the next
10 years), were assessed.

2.6. Statistical Analysis

We based the power of calculation on the findings of a prior investigation [20], in which
the anticipated absolute reduction in HbA1c levels between the LCD and Mediterranean
diet cohorts was 0.5%, accompanied by a standard deviation (SD) of 0.408%. Utilizing a
two-tailed 5% significance level, a power (1-ß) of 80%, and assuming a follow-up loss of
20%, the calculated sample size required for the study was 80 patients. For the variables
considered at T0 and T1 in the two diet groups, the main descriptive statistics (means
and standard deviations) were then compiled. The chi-squared test was performed to
demonstrate homogeneity between the two groups, while for age the t-test for indepen-
dent samples was performed. To test the difference between T0 and T1 for each variable,
paired-sample t-tests were performed separately for the two groups. The delta % variable
(i.e., delta percent) was constructed to estimate the time differences of each parameter
between the start and the end of treatment and assessed according to the following formula:
∆% = [(Z − W)/W] × 100 where ∆% is the percentage variation of each parameter, calcu-
lated as the ratio of an absolute margin of variation from the base value. Subsequently,
t-tests with independent samples were performed to verify the differences between the
two diets on delta % variable. The level of significance considered is p < 0.01. The analyses
were conducted with SPSS v28.

3. Results
3.1. Baseline Parameters
Except for height and waist–hip ratio, there were no significant differences between
the participants in the two dietary groups by age, gender, BMI, blood pressure, lipid
profile, renal markers, and glucose homeostasis parameters (fasting glycemia and HbA1c)
at baseline as reported in Table 1.

Table 1. Background characteristics of the study population.

All Patients Low-Carbohydrate Mediterranean

No. (100) No. (50) No. (50) p Value
Sex, n (%)
Men 53% 24 22
Women 47% 26 28
Age, (SD) 63.2 (6.8) 63.4 (6.9) 63 (6.8) 0.770
Weight, kg (SD) 94.6 (19.7) 91.3 (19.8) 97.9 (19.3) 0.094
Height, m (SD) 1.65 (0.1) 1.63 (0.1) 1.68 (0.1) 0.012
BMI, kg/m2 (SD) 34.4 (5.8) 34 (6.2) 34.7 (5.4) 0.575
Systolic blood pressure, mmHg (SD) 126.7 (9.5) 125.7 (9.9) 127.7 (9) 0.294
Diastolic blood pressure, mmHg (SD) 85.5 (8.6) 84.8 (8.9) 86.3 (8.3) 0.387
Waist circumference, cm (SD) 111 (16.3) 113.6 (15.3) 108.4 (16.9) 0.110
Hip circumference, cm (SD) 120.7 (13.4) 118.5 (13.8) 122.9 (12.8) 0.105
Waist–hip ratio, cm (SD) 0.92 (0.1) 0.96 (0.01) 0.88 (0.1) <0.001 *
Fat mass (FM), kg (SD) 39 (13.8) 36.4 (14.1) 41.7 (13.2) 0.058
Fat-free mass (FFM), kg (SD) 55.9 (9) 55.2 (9.3) 56.6 (8.9) 0.429
Total body water, kg (SD) 40.7 (8.4) 39.8 (8) 41.6 (8.7) 0.297
Nutrients 2024, 16, 95 6 of 14

Table 1. Cont.

All Patients Low-Carbohydrate Mediterranean

No. (100) No. (50) No. (50) p Value
Blood glucose, mg/dL (SD) 174.7 (47.8) 178 (57.7) 171.3 (35.4) 0.482
Hemoglobin A1c (HbA1c), % (SD) 8.6 (0.7) 8.6 (0.7) 8.6 (0.6) 0.954
Blood cholesterol, mg/dL (SD) 208.6 (21.8) 205.4 (18.9) 211.8 (24.1) 0.144
HDL cholesterol, mg/dL (SD) 45.4 (8.4) 44.5 (8.8) 46.2 (8.1) 0.339
Cardiovascular Index, (SD) 4.75 (0.98) 4.78 (1) 4.72 (0.96) 0.783
% CV risk, (SD) 15.28 (11.9) 14.53 (9.2) 16 (14.1) 0.531
Triglycerides, mg/dL (SD) 173.3 (58) 171.9 (58.3) 174.6 (58.4) 0.815
LDL cholesterol, mg/dL (SD) 128.6 (20.5) 126.5 (17.6) 130.7 (23) 0.306
Albuminuria, mg/dL (SD) 52.1(49.4) 51.1 (50) 53.1 (49.3) 0.840
Serum creatinine level, mg/dL (SD) 0.98 (0.2) 0.99 (0.3) 0.98 (0.2) 0.770
e-Gfr, mL/min (SD) 74 (18.2) 72.4 (18.6) 75.5 (17.8) 0.396
Data are presented as the mean ± standard deviation with * p < 0.01. Abbreviations: BMI (body mass in-
dex); FM (fat mass); FFM (fat-free mass); HDL (high-density lipoprotein); LDL (low-density lipoprotein);
CV (cardiovascular); e-Gfr (estimated glomerular filtration rate).

3.2. Anthropometric and Body Composition Parameters

Both the low-carbohydrate and Mediterranean diets showed positive effects on weight
loss. However, when comparing the effects of the two dietary treatments, the low-
carbohydrate diet resulted in a greater reduction in BMI, waist circumference, waist–hip
ratio, fat mass, and total body water with no statistically significant differences in free-fat
mass, although there is a greater loss of muscle mass in the Mediterranean diet than the low-
carbohydrate diet as reported in Table 2. There are no statistically significant gender-related
differences in any of the variables considered.

Table 2. Anthropometric and body composition parameters of the patients at baseline and at the
16-week follow up.

∆% ∆%
LC Diet p MD p Value p Value ∆%
Parameters MD Diet LC Diet
LC Diet Value Baseline MD Diet Baseline between Diet
Mean ± SD Baseline Baseline
to 16 Week to 16 Week Groups
to 16 Week to 16 Week
Weight, kg (SD) 91.3 (±19.8) 97.9 (±19.3)
Baseline
p < 0.001 p < 0.001 −8.20 (±5.7) −10.1 (±4.3) 0.062
82.2 (±18.6) 90.3 (±20.8)
16 wk
BMI, kg/m2 (SD) 34 (±6.2) 34.7 (±5.4)
p < 0.001 p < 0.001 −8.20 (±5.7) −10.11 (±4.3) 0.062
Baseline 30.6 (±5.8) 32 (±6.1)
16 wk
Waist circumference, cm (SD) 113.6 (±15.3) 108.4 (±16.9)
Baseline
p < 0.001 p < 0.001 −6.2 (±4.7) −8 (±3.7) 0.010
103.8 (±13.5) 101.9 (±19)
16 wk
Hip circumference, cm (SD) 118.5 (±13.8) 122.9 (±12.8)
Baseline
p < 0.001 p < 0.001 −5.3 (±4.3) −4.1 (±2.9) 0.101
113.6 (±12.3) 116.4 (±13.6)
16 wk
Waist–hip ratio, cm (SD) 0.96 (±0.01) 0.88 (±0.1)
Baseline
p < 0.001 p < 0.001 −1 (±3) −4.6 (±3) <0.001 *
0.92 (±0.01) 0.87 (±0.1)
16 wk
Fat mass (FM), kg (SD) 36.4 (±14.1) 41.7 (±13.2)
Baseline
p < 0.001 p < 0.001 −16.5 (±12.4) −25.4 (±12.8) <0.001 *
27.8 (±12.8) 35.6 (±14.6)
16 wk
Fat-free mass (FFM), kg (SD) 55.2 (±9.3) 56.6 (8.9)
Baseline
p < 0.001 p < 0.001 −2.47 (±2) −1.81 (±3.7) 0.269
54.2 (±9.3) 55.2 (8.9)
16 wk
Total body water, kg (SD) 39.8 (±8) 41.6 (±8.7)
Baseline
p < 0.001 p < 0.001 −3.4 (±2.6) −2 (±3.4) 0.022
39 (±7.9) 40.2 (±8.7)
16 wk

Data are presented as the mean ± standard deviation and as ∆% with * p < 0.01. Abbreviations: BMI (body mass
index); FM (fat mass); FFM (fat-free mass); LC (low-carbohydrate diet); MD (Mediterranean diet).

3.3. Metabolic Parameters and Cardiovascular Risk Factors

Positive outcomes were observed in both the low-carbohydrate and Mediterranean
dietary approaches on blood pressure, glucose control, lipid profile, cardiovascular risk,
and renal function after 16 weeks. In assessing the effects of the dual dietary strategies, it is
Nutrients 2024, 16, 95 7 of 14

revealed that the implementation of a low-carbohydrate diet leads to a greater reductions

in various health markers including systolic blood pressure, diastolic blood pressure,
blood glucose levels, hemoglobin A1c percentage, total blood cholesterol levels, HDL
cholesterol levels, cardiovascular index, percentage of cardiovascular risk, LDL cholesterol
levels, albuminuria, serum creatinine levels, and e-Gfr over a 16-week period as reported
in Table 3. There are no statistically significant gender-related differences in any of the
variables considered. To calculate the probability of a first major cardiovascular event in
the next 10 years, we used the UKPDS risk engine, which is a specific risk calculator for
type 2 diabetes based on 53,000 patients years of data from the UK Prospective Diabetes
Study [36–38].

Table 3. Metabolic parameters and cardiovascular risk factors of the patients at baseline and at the
16-week follow up.

LC Diet p MD Diet p ∆% ∆%
p Value ∆%
Parameters Value Value MD Diet LC Diet
LC Diet MD Diet between
Mean ± SD Baseline to Baseline Baseline Baseline
Diet Groups
16 Week to 16 Week to 16 Week to 16 Week
Blood glucose, mg/dL (SD) 178 (±57.7) 171.3 (35.4)
Baseline
p < 0.001 p < 0.001 −21 (±7.9) −37.6 (±13.9) <0.001 *
104.7 (±17.9) 134.7 (±28.4)
16 wk
Hemoglobin A1c (HbA1c), % (SD) 8.6 (±0.7) 8.6 (±0.6)
Baseline
p < 0.001 p < 0.001 −13.5 (±3.2) −23.2 (±5) <0.001 *
6.6 (±0.7) 7.4 (±0.6)
16 wk
Blood cholesterol, mg/dL (SD) 205.4 (±18.9) 211.8 (±24.1)
Baseline
p < 0.001 p < 0.001 −13 (±8.6) −18 (±6.6) 0.002
168.1 (±18) 182.9 (±17.4)
16 wk
HDL cholesterol, mg/dL (SD) 44.5 (±8.8) 46.2 (±8.1)
Baseline
p < 0.001 p < 0.001 7.1 (±7) 12.8 (±13.4) 0.009
50 (±10.2) 49.2 (±7.9)
16 wk
Triglycerides, mg/dL (SD) 171.9 (±58.3) 174.6 (±58.4)
Baseline
p < 0.001 p < 0.001 −36.9 (±18.9) −41 (±17.7) 0.268
96.7 (±30.1) 106.5 (±43.5)
16 wk
LDL cholesterol, mg/dL (SD) 126.5 (±17.6) 130.7 (±23)
Baseline
p < 0.001 p < 0.001 −12.6 (±14.2) −21.6 (±12.5) 0.001
98.7 (±19.1) 112.4 (±19)
16 wk
Albuminuria, mg/dL (SD) 51.1 (±50) 53.1 (±49.3)
Baseline
p < 0.001 p < 0.001 −21.7 (±16.1) −48.4 (±25.6) <0.001 *
26.3 (±27.9) 41.6 (±40.6)
16 wk
Serum creatinine level, mg/dL (SD) 0.99 (±0.25) 0.98 (±0.23)
Baseline
p < 0.001 p < 0.001 −5.7 (±4.9) −22.3 (±8.8) <0.001 *
0.76 (±0.15) 0.92 (±0.20)
16 wk
e-Gfr, mL/min (SD) 72.4 (±18.6) 75.5 (±17.8)
Baseline
p < 0.001 p < 0.001 6.5 (±6.1) 29.7 (±22.7) <0.001 *
90.4 (±12.4) 79.8 (±16.9)
16 wk
Cardiovascular Index, (SD) 4.78 (±1) 4.72 (±0.96)
Baseline
p < 0.001 p < 0.001 −18.3 (±10.8) −26.4 (±10) <0.001 *
3.5 (±0.8) 3.83 (±0.88)
16 wk
% CV risk, (SD) 14.53 (±9.2) 16 (±14.1)
Baseline
p < 0.001 p < 0.001 −20.2 (±8.9) −32.6 (±14.7) <0.001 *
9.5 (±6.5) 12.9 (±11.7)
16 wk
Systolic blood pressure, mmHg (SD) 125.7 (±9.9) 127.7 (±9)
Baseline
p < 0.001 p < 0.001 −4.2 (±3) −7 (±4.2) <0.001 *
116.6 (±6) 122.1 (±6)
16 wk
Diastolic blood pressure, mmHg (SD) 84.8 (±8.9) 86.3 (±8.3)
Baseline
p < 0.001 p < 0.001 −4.62 (±3.7) −9.15 (±5) <0.001 *
76.7 (±5.5) 82.1 (±6.2)
16 wk

Data are presented as the mean ± standard deviation and as ∆% with * p < 0.01. Abbreviations: HDL (high-density
lipoprotein); LDL (low-density lipoprotein); e-Gfr (estimated glomerular filtration rate); CV (cardiovascular).

3.4. Compliance with Treatment

The selection of patients with similar anthropometric (BMI, weight, body composition)
and clinical characteristics (years of disease, glucometabolic control status, renal function,
dyslipidemia, kidney function, hypertension, and cardiovascular risk), has been predeter-
mined in order to assess the comparative efficacy of the two dietary treatments alone, and
thus avoiding any potentially confounding elements. This type of selection and allocation
in the two groups has allowed, from the beginning, for the identification and recruitment
of the most motivated patients to follow the diet. Preselection before starting the study
resulted in achieving total compliance without any dropouts and a homogeneous balance
between the two groups in anthropometric and clinical terms.
Nutrients 2024, 16, 95 8 of 14

4. Discussion
The current study aimed to assess and compare the effects of a low-carbohydrate
diet (LCD) and a Mediterranean diet (MD) on various anthropometric, clinical, body com-
position, and metabolic parameters in overweight/obese patients with type 2 diabetes
mellitus (T2DM). The increasing worldwide prevalence of T2DM and obesity has raised
significant public health concerns, with projections indicating a continuing rise in the
number of affected individuals and associated morbidity and mortality rates. This under-
scores the urgent need for effective therapeutic interventions to manage these conditions
successfully [39]. Dietary and lifestyle modifications are essential in the treatment and
management of T2DM and obesity, making it vital to identify the most effective nutri-
tional strategies to achieve and maintain positive clinical outcomes. Conventional medical
nutritional therapy often advocates for the adoption of a Mediterranean diet, which is
rich in fruits, vegetables, whole grains, legumes, nuts, seeds, olive oil, and fish, while
reducing red meat and sweets. Numerous studies have demonstrated the beneficial effects
of adherence to the MD on glycemic parameters in individuals with T2DM. For instance, a
cross-over study found that greater adherence to the Mediterranean diet was associated
with better glycemic control, including lower HbA1c levels and reduced fasting glucose
levels [40]. Additionally, systematic reviews and meta-analyses reported that the MD was
effective in reducing fasting blood glucose levels and glycated hemoglobin (HbA1c) in
individuals with T2DM [41,42]. The MD’s beneficial effect on diabetes is derived from its
nutrient profile, which is particularly rich in fiber, complex carbohydrates, monounsatu-
rated fats, antioxidants, and anti-inflammatory compounds [43,44]. However, the MD diet
is a dietary approach characterized by high-carbohydrate intake (50–60% of daily energy
requirements at the expense of proteins and fats) and, as known, carbohydrates are the
primary macronutrient that significantly affects glycemic control in subjects with diabetes.
In this context, a low-carbohydrate diet (LCD) has gained attention as a potential alternative
to the Mediterranean diet [45], particularly in the short term, due to its ability to facilitate
greater initial weight loss [46–48], promote satiety and reduce hunger [49], decrease liver
fat content [50–52], improve glycemic control and reduce the need for glucose lowering
drugs in patients with T2DM [23,53–57].
Although there are numerous studies on the potential beneficial effects of low-
carbohydrate diets on overweight diabetic patients, there is a paucity of scientific literature
that directly compares the effects of an MD versus an LCD as seen in our study [58]. First,
in line with a recent review and meta-analysis of Ajala et al. [59], our study showed that
both MD and LCD diets resulted in a significant reduction in weight loss and improvement
in blood pressure, glucose control, lipid profile, cardiovascular risk, and renal function
after 16 weeks of treatment. This result may be attributable firstly to the caloric restriction
induced by both diets (about −500 kcals from TDEE) and the adherence to a structured
food plan monitored by qualified personnel. Remarkably, when comparing the effects of
the two diets, the low-carbohydrate diet resulted in a greater reduction in several critical
parameters at 16 weeks, including BMI, systolic blood pressure, diastolic blood pressure,
waist circumference, waist−hip ratio, fat mass, total body water, blood glucose, hemoglobin
A1c %, blood cholesterol, HDL cholesterol, cardiovascular index, % cardiovascular risk,
LDL cholesterol, albuminuria, serum creatinine levels, and e-Gfr.
These results may be explained firstly by the fact that low-carbohydrate diets per-
form better on weight loss in the short term (less than 6 months) especially on visceral
adiposity [60]. The reduction in adipose tissue decreases the release of proinflammatory
adipokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which
contribute to a low-grade systemic inflammation and insulin resistance [61]. By also reduc-
ing carbohydrate intake, LCDs result in decreased glucose availability, leading to lower
postprandial glucose excursions and overall blood glucose levels [62]. LCDs thus promote
a reduced demand for insulin secretion, facilitating improved glycemic control [63] and
reducing glucose toxicity, oxidative stress, and inflammation which can affect beta-cell
function [56]. The decreased insulin levels promote the activation of hormone-sensitive li-
Nutrients 2024, 16, 95 9 of 14

pase (HSL) that facilitates the breakdown of stored triglycerides in adipose tissue, releasing
fatty acids into the bloodstream for energy utilization [64,65]. This process contributes to a
decrease in circulating triglycerides and an increase in fatty acid oxidation.
Additionally, low-carbohydrate diets promote the expression of genes involved in
lipid metabolism, such as peroxisome proliferator-activated receptor alpha (PPARα),
which enhances fatty acid oxidation and contributes to the improvement in blood lipid
profiles [66,67]. Moreover, low-carbohydrate diets may enhance the activity of enzymes
involved in HDL metabolism, such as lecithin-cholesterol acyltransferase (LCAT), leading
to increased HDL cholesterol synthesis and clearance [68]. Therefore, the effects of LCD on
blood lipids are mixed [69,70]; it usually appears that LDL cholesterol tends to increase,
while triglycerides are drastically lowered and HDL cholesterol rises [71]. A recent random-
ized controlled trial involving 71 patients with type 2 diabetes showed that LCD does not
adversely affect endothelial function and markers of inflammations as interleukin-6 (IL-6)
or high-sensitivity C-reactive protein (hsCRP), demonstrating that this dietary approach
does not increase the risk of cardiovascular disease [72]. In our study, the LCD group
showed a reduction in LDL cholesterol and an increase in HDL, while the decrease in
triglycerides levels did not reach statistical significance among groups. Different study
results on blood lipids are probably derived from the variable macronutrient composition
of low-carbohydrate diets, especially the amount of saturated fats and the carbohydrate
reduction. A carbohydrate restricted diet increases the LDL peak particle size, thus be-
coming less atherogenic and decreases the numbers of total and small LDL particles [73],
which may be a more relevant indicator of cardiovascular risk than total LDL cholesterol
levels alone [74].
Significantly lower insulin levels have also beneficial effects on blood pressure through
the reduction in sodium reabsorption [75], norepinephrine [76], and angiotensin II re-
lease [77]. Regarding the kidney, insulin has been shown to affect the integrity and function
of the glomerular filtration barrier through the synthesis and release of endothelial nitric
oxide, a vasodilator, which helps maintain the dilation of the afferent arteriole. This dilation
enhances renal blood flow and contributes to the maintenance of the normal glomerular
filtration rate (GFR). Insulin also regulates the synthesis and distribution of key components
of the glomerular basement membrane, such as type IV collagen and laminin, which are
essential for maintaining the integrity of the filtration barrier. Alterations in insulin signal-
ing can disrupt these processes and contribute to glomerular dysfunction and increased
permeability, leading to the leakage of albumin into the urine and alterations in creatinine
levels [78,79].
Our study highlights the potential benefits of a low-carbohydrate diet as a dietary
strategy for managing obesity and T2DM. Therefore, to date, our study is one of the first
to compare the Mediterranean diet and the moderate low-carbohydrate diet. Consider-
ing both anthropometric and clinical parameters, several potential limitations need to be
highlighted. First, a limitation of the present study is the small sample size. A larger
sample size would have increased the statistical power to detect changes in the variables
measured. Second, the duration of the interventions, which is 16 weeks, is a very short
period of time to assess the long-term beneficial metabolic effects and sustainability of
LCD. Third, there is no consensus on the ideal low-carbohydrate diet for the treatment of
T2DM, particularly with regards to the optimal carbohydrate intake for an individual, as it
may vary based on factors such as gender, age, and level of physical activity. In scientific
literature, a disparity exists in the definition of low-carbohydrate diets as the level of carbo-
hydrate intake varies and the classification of carbohydrates load ranges from moderate
to low, making comparisons with other studies difficult. This demonstrates the need for a
standard definition and a more rigorous examination of the effects of low-carbohydrate
diets on various health outcomes. Nevertheless, to date, there is no shared and common
approach. In fact, different dietary strategies for the management of type 2 diabetes are
proposed by various international medical scientific associations. The American Diabetes
Association (ADA) in 2023 Standards of Medical Care in Diabetes [80], and previously
Nutrients 2024, 16, 95 10 of 14

the British Diabetic Association in 2021 position statement, along with the Scientific Advi-
sory Committee on Nutrition (SACN) report on lower carbohydrate diets for adults with
type 2 diabetes [81], advocate for the effectiveness of a low-carbohydrate eating pattern
in managing patients with type 2 diabetes or prediabetes who are not achieving glucose
targets or require glucose lowering medications. Additionally, achieving remission of type 2
diabetes is deemed possible through weight loss and intensive dietary changes [82]. This is
supported by a joint consensus statement in 2021 from the American Diabetes Association
(ADA), the Endocrine Society, the European Association for the Study of Diabetes, and
Diabetes UK [62]. The statement suggests that remission can occur at least six months after
initiating a lifestyle intervention and can persist for three months or more without the use
of glucose lowering medications, resulting in the maintenance of normal blood glucose
levels with HbA1c levels below 6.5% (48 mmol/mol). Conversely, as of the current date, the
Italian Society of Diabetology (SID) and the Association of Medical Diabetologists (AMD)
recommend a balanced nutritional therapy, such as the Mediterranean diet, instead of a low-
carbohydrate approach for the nutritional treatment of type 2 diabetes, as outlined in their
2023 standards of care. The lack of consensus regarding the appropriate low-carbohydrate
diet for managing type 2 diabetes mellitus (DM) is apparent. This uncertainty mostly
stems from the varying opinions on the most suitable carbohydrate intake for individuals,
which can be influenced by characteristics such as gender, age, and degree of physical
activity [63]. However, in our 16-week study, a low-carbohydrate diet seems to be superior
to the Mediterranean diet for each investigated outcome, but it is necessary to consider the
sustainability and long-term compliance of this type of diet. In fact, the restrictive nature
of low-carbohydrate diets, particularly those that severely limit carbohydrate intake, may
lead to cravings, social challenges, and difficulty in maintaining dietary variety. While
low-carbohydrate diets may restrict certain carbohydrate-rich foods, it is crucial to focus
on nutrient-rich sources of carbohydrates, such as vegetables, fruits, and whole grains.
Adequate intake of essential nutrients, including fiber, vitamins, and minerals, should
be prioritized to maintain optimal health while following a low-carbohydrate approach.
Finally, the long-term sustainability of these effects and the optimal carbohydrate intake for
individual patients warrant further investigation. The findings of this study contribute to
the ongoing discussion regarding dietary interventions in the management of T2DM and
provide valuable insights for healthcare providers and individuals seeking effective dietary
approaches for T2DM management.

5. Conclusions
In this study, the results indicate that a low-carbohydrate diet might have superior
efficacy compared to a Mediterranean diet in facilitating weight loss and enhancing several
metabolic and cardiovascular outcomes among individuals with type 2 diabetes who are
overweight or obese. Nevertheless, it is crucial to emphasize that additional research is
essential to comprehend the clinical implications and assess the long-term viability of
these findings.

Author Contributions: Conceptualization and methodology, R.I.C. and F.L.; data curation and formal
analysis, R.I.C. and F.L.; writing—original draft preparation, R.I.C., F.L. and W.C.; writing—review
and editing, R.I.C., F.L., W.C., A.M.A., F.C., F.G., R.S.Z., G.M., S.Q. and R.P.; supervision, F.G and
G.M.; poject administration and funding acquisition, A.M.A. and F.G. All authors have read and
agreed to the published version of the manuscript.
Funding: This work was supported by the Distinguished Scientist Fellowship Program (DSFP) at
King Saud University, Riyadh, Saudi Arabia.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration
of Helsinki. The study was approved by the local Ethics Committee 22 May 2018, n◦ 440/DS-.
Informed Consent Statement: Informed consent was obtained from all subjects involved in
the study.
Nutrients 2024, 16, 95 11 of 14

Data Availability Statement: The data that support the findings of this study are available upon
reasonable request.
Conflicts of Interest: The authors declare no conflicts of interest. The funders had no role in the
design and reporting of the study.

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