Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC pST3Zdm3fcYBFfmj9Vq6WcF S0066-782X2023000400303 00303 10.36660/abc.20220606 Artigo Original Papel do Jejum Intermitente e da Dieta Restrita em Carboidratos na Prevenção de Doenças Cardiovasculares em Pacientes Pré-Diabéticos 0000-0002-6105-9300 Khalfallah Mohamed 1 Concepção e desenho da pesquisa e Análise estatística Análise e interpretação dos dados Revisão crítica do manuscrito quanto ao conteúdo intelectual importante 0000-0002-5569-5781 Elnagar Basma 1 Obtenção de dados Redação do manuscrito Soliman Shaimaa S. 2 Análise e interpretação dos dados Redação do manuscrito Eissa Ahmad 3 Obtenção de dados Análise e interpretação dos dados Allaithy Amany 1 Redação do manuscrito Revisão crítica do manuscrito quanto ao conteúdo intelectual importante Tanta University Faculty of Medicine Cardiovascular Department Egito Cardiovascular Department, Faculty of Medicine, Tanta University – Egito Menoufia University Faculty of Medicine Public Health and Community Medicine Department Egito Public Health and Community Medicine Department, Faculty of Medicine, Menoufia University – Egito Tanta University Faculty of Medicine Internal Medicine Department Egito Endocrinology, Internal Medicine Department, Faculty of Medicine, Tanta University – Egito Correspondência: Mohamed Khalfallah Faculty of medicine, Tanta University – El-Geish Street, Tanta – Egito. E-mail: khalfallah@yahoo.com

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 07 04 2023 2023 120 4 e20220606 27 08 2022 02 12 2022 14 12 2022 This is an open-access article distributed under the terms of the Creative Commons Attribution License Resumo Fundamentos:

Pacientes pré-diabéticos têm alto risco de doenças cardiovasculares e complicações microvasculares e macrovasculares. O Jejum Intermitente (JI) e a dieta restrita em carboidratos (dieta low-carb, DLC) são estratégias dietéticas promissoras nesse grupo.

 Objetivos:

Analisar os benefícios da combinação do JI com DLC sobre desfechos microvasculares e macrovasculares em pacientes pré-diabéticos.

 Métodos:

O estudo incluiu 485 pacientes pré-diabéticos sem história de doença cardiovascular. Os pacientes foram divididos em dois grupos: grupo I (n = 240) submetidos ao JI (16 horas de JI, F 3-4 dias por semana) combinado com DLC (<130 g de carboidratos por dia), e grupo II (n = 245) que consumiram alimentos à vontade (grupo controle). Os dois grupos foram acompanhados por dois anos para avaliação de complicações macrovasculares e microvasculares. Um valor p < 0,05 foi considerado estatisticamente significativo.

 Resultados:

Houve uma redução significativa no peso corporal, índice de massa corporal, porcentagem de gordura corporal e hemoglobina glicada no grupo I. A incidência de progressão de pré-diabetes para diabetes foi significativamente menor no grupo I (2,1%) que no grupo II (6,9%) (p = 0,010). Ainda, um aumento significativo na incidência de complicações microvasculares e macrovasculares foi observado no grupo II, incluindo retinopatia, neuropatia e angina instável. A análise de regressão multivariada revelou que peso corporal aumentado, e níveis elevados de glicemia de jejum, hemoglobina glicada e lipoproteína de baixa densidade foram fatores de risco independentes de desfechos microvasculares e macrovasculares.

 Conclusões:

Em pacientes pré-diabéticos, o JI, combinado com DLC, associou-se com menor progressão para diabetes mellitus e menor incidência de complicações microvasculares e macrovasculares.

 Palavras-chave: Estado Pré-diabético Jejum Dieta Doenças Cardiovasculares Principais resultados do estudo; JI: jejum intermitente; DLC: dieta restrita em carboidratos (dieta low-carb). Introdução

As doenças cardiovasculares (DCVs) ainda são causa importante de morte em todo o mundo, sendo responsáveis por aproximadamente 20% das mortes.1 Apesar dos avanços no tratamento das DCVs, sua morbidade e sua mortalidade são significativamente altas, que levam a encargos econômicos. Assim, a detecção e o tratamento precoce dos fatores de risco modificáveis para DCVs são de fundamental importância. Os principais fatores de risco modificáveis incluem sobrepeso, dislipidemia, hipertensão e hiperglicemia.2 A pré-diabetes é caracterizada por um estado hiperglicêmico, abaixo do nível utilizado para a definição de diabetes mellitus (DM), com alta probabilidade de progredir para DM. Pacientes pré-diabéticos têm risco elevado de disfunção endotelial, resultando em complicações microvasculares e macrovasculares associadas com maior morbidade e mortalidade cardiovascular.3 A incidência de pré-diabetes tem aumentado e está associada à elevação dos níveis de obesidade em todo o mundo.4

Vários estudos validaram intervenções no estilo de vida como métodos efetivos de prevenir ou retardar a progressão do DM tipo 2 (DM2) bem como diminuir o risco cardiovascular em pacientes pré-diabéticos.5,6 A redução do peso por meio de mudança no estilo de vida, plano alimentar, intervenções farmacológicas e/ou cirúrgicas tem um impacto benéfico sobre o status hiperglicêmico.

O Jejum Intermitente (JI) é um plano dietético caracterizado por uma redução na ingestão energética usando um período de jejum alternando com um consumo livre de alimentos. A forma mais comum consiste em horas de jejum seguidas de horas de ingestão livre em um mesmo dia.7 Outra intervenção dietética, principalmente no estado hiperglicêmico, é conhecida como dieta com restrição de carboidratos, ou dieta low-carb (DLC). De acordo com o consumo de carboidratos e sua porcentagem do total de energia ingerida, a DLC é classificada como muito baixa em carboidratos (20-50 g/dia ou <10% da ingestão energética), baixa em carboidratos (< 130 g/dia ou < 26% ingestão energética), e moderada em carboidratos (26-44% da ingestão energética).8

Nos anos recentes, o JI e as DLCs foram aprovadas e se tornado cada vez mais populares para a redução de peso.9 No entanto, seu impacto sobre a saúde humana, especialmente sobre desfechos cardiovasculares em pacientes diabéticos e pré-diabéticos ainda está sob investigação. Este estudo teve como objetivo investigar o impacto do JI e da DLC sobre desfechos microvasculares e macrovasculares em pacientes pré-diabéticos.

Pacientes e métodos

Este é um estudo prospectivo do tipo coorte, conduzido com 485 participantes atendidos no ambulatório de doenças cardiovasculares do hospital da Universidade de Tanta, Egito, entre junho de 2019 e junho de 2020, com um período de acompanhamento de dois anos. O estudo foi aprovado pelo comitê de ética da faculdade de medicina da Universidade de Tanta, Egito, e conduzido de acordo com os princípios da Declaração de Helsinki II. Todos os pacientes incluídos assinaram um termo de consentimento e um código foi atribuído a cada paciente. Os pacientes incluídos foram randomizados utilizando-se um gerador computadorizado de números aleatórios para a seleção aleatória dos blocos permutados, que possuíam tamanho dois e razão idêntica de alocação. A alocação foi feita de maneira sigilosa, usando envelopes opacos numerados selados, os quais foram abertos após os participantes assinarem o termo de consentimento e serem incluídos nos grupos respectivos.

 Critérios de inclusão e exclusão

Todos os participantes tinham idade acima de 30 anos e abaixo de 70 anos, com diagnóstico confirmado de pré-diabetes por hemoglobina glicada (HbA1c) 5,7-6,4 %, e/ou glicemia de jejum de 100–125 mg/dL, e /ou glicemia duas horas pós-prandial de 140–199 mg/dL.9 Pacientes com história prévia de DM, DCVs (acidente vascular cerebral, doença cardíaca isquêmica, insuficiência cardíaca, e doença arterial periférica), doença renal ou hepática avançada, e doença inflamatória crônica foram excluídos.

Os participantes foram separados aleatoriamente em dois grupos de acordo com seu plano dietético; grupo I (JI-DLC): submetido ao JI (16/8: 16 horas de jejum seguido de oito horas de ingestão livre por 3-4 dias por semana), e DLC (menos que 130 g/dia de carboidrato e < 26% da ingestão energética total, sem aumento da ingestão de gordura por sete dias da semana); grupo II (grupo controle): os pacientes continuaram seu padrão dietético diário, sem restrição energética. Todos os pacientes foram submetidos a uma anamnese detalhada, envolvendo fatores de risco cardiovasculares – tabagismo, hipertensão, dislipidemia, história familiar de doenças cardiovasculares – e manifestações de complicações vasculares do DM (por exemplo, dor torácica, visão embaçada e dormência). Estresse psicossocial em todos os participantes foi estimado usando a escala de estresse percebido de 0 a 40 (escore < 14 indicam ausência ou baixo estresse), e escores ≥ 14 indicam status de estresse considerável.10,11 A atividade física dos participantes foi avaliada de acordo com o tipo e a duração da atividade física semanal; participantes que realizavam pelo menos 150 minutos de atividade física moderada, ou pelo menos 75 minutos de atividade física vigorosa foram considerados fisicamente ativos.12 Os participantes também foram interrogados quanto a seguro saúde, estresse psicossocial, e uso e adesão a medicamentos anti-hipertensivos, hipolipemiantes e antiplaquetários. Ainda, foram avaliados status socioeconômico incluindo nível educacional, renda dos pacientes, local de residência, estado civil e de emprego.

Medidas antropométricas e exames físicos foram realizados, incluindo medida da altura, circunferência da cintura, circunferência do quadril, e razão cintura-quadril usando uma fita métrica. O peso corporal, o índice de massa corporal (IMC) e a composição corporal por análise de bioimpedância elétrica foram aferidos por um aparelho InBody230. Medidas de pressão arterial e frequência cardíaca, e avaliação neurológica completa também foram realizadas. Medidas laboratoriais de rotina incluindo glicemia (jejum e duas horas pós-prandial), colesterol total, lipoproteína de baixa densidade (LDL), lipoproteína de alta densidade (HDL), proteína C reativa, creatinina sérica e taxa de filtração glomerular estimada (TFGe) também foram analisadas. Uma amostra de urina foi coletada pela manhã para análise de albuminúria e razão albumina/creatinina. Ainda, o índice tornozelo-braquial é calculado pela razão entre a pressão arterial sistólica mais alta do tornozelo e a pressão arterial sistólica mais alta da artéria braquial. A espessura da camada íntima média da artéria carótida foi obtida por ultrassonografia das artérias carótidas. Um exame de fundoscopia foi usado para rastrear retinopatia diabética. O escore de risco Framingham foi usado para estimar risco cardiovascular em 10 anos. O risco em 10 anos, em porcentagem, foi classificado como baixo risco (<10%), risco intermediário (10-20%), e alto risco (>20%).13 Todas as avaliações clínicas foram realizadas no basal e no seguimento. Durante o acompanhamento de dois anos, os participantes de ambos os grupos fizeram visitas regulares a cada três meses no ambulatório para revisão da planilha mensal da dieta e avaliação da adesão ao JI e DLC (grupo I). Os participantes que perderam uma visita ou não eram aderented ao JI ou à DLC prescrita foram excluídos do estudo.

Desfechos

Os desfechos deste estudo foram divididos em desfechos primários, que incluíram mortalidade e ocorrência de complicações macrovasculares como acidente vascular cerebral, angina instável, infarto do miocárdio, e progressão para DM. Os desfechos secundários foram ocorrência de complicações microvasculares: (1) retinopatia, definida como fraqueza progressiva dos vasos da retina, variando de retinopatia não proliferativa e pré-proliferativa à retinopatia proliferativa;14 (2) nefropatia, caracterizada por um declínio progressivo na TFGe abaixo de 90mL/min/1,73m2, albuminúria persistente, e pressão arterial elevada;15 e (3) neuropatia, diagnosticada clinicamente, com várias manifestações clínicas na forma de perda ou anormalidade da função motora, sensorial e/ou do sistema nervoso autônomo.14

 Análise estatística

A análise estatística foi realizada usando o programa SPSS versão 23 (Armonk, NY; IBM Corp.). Quanto à normalidade dos dados, usamos o teorema central do limite, que afirma que, quando o tamanho da amostra for maior ou igual a 100, a violação da normalidade não é uma questão importante.16 As variáveis quantitativas foram expressas em média ± desvio padrão. As variáveis qualitativas foram expressas em frequência e porcentagem. Usamos o teste t para amostras independentes para comparação das variáveis quantitativas entre os dois grupos. O teste do qui-quadrado (χ2) foi usado para comparar dois parâmetros qualitativos. Quando o valor esperado em uma célula foi inferior a cinco, o teste exato de Fisher foi usado. Um valor de p bicaudal <0,05 foi considerado estatisticamente significativo, e análise de regressão logística multivariada foi realizada para detectar preditores independentes de desfechos macrovasculares e microvasculares.

 Resultados

O presente estudo foi realizado com 485 pacientes pré-diabéticos sem evidência de doenças cardiovasculares. Não houve diferença estatisticamente significativa entre os dois grupos quanto à idade, sexo, fatores socioeconômicos, fatores de risco cardiovasculares, e nível educacional (Tabela 1). Não houve diferença significativa nas medidas antropométricas ou dados laboratoriais entre os dois grupos (Tabela 2).

Características basais, fatores de risco e fatores socioeconômicos dos pacientes submetidos ao jejum intermitente e à dieta restrita em carboidratos (grupo I) e ao consumo ad libitum (controle)
Grupo I (n=240) (JI e DLC) Grupo II (n=245) (controle ad libitum) Valor p
Idade, anos 48,11±7,58 48,64±8,46 0,470
Sexo masculino, n (%) 123 (51,3%) 122 (49,8%) 0,749
Tabagismo, n (%) 73 (30,4%) 68 (27,8%) 0,519
Hipertensão, n (%) 65 (27,1%) 77 (31,4%) 0,293
Dislipidemia, n (%) 80 (33,3%) 78 (31,8%) 0,725
História familiar de DCI, n (%) 61 (25,4%) 64 (26,1%) 0,859
Estresse psicossocial, n (%) 53 (22,1%) 51 (20,8%) 0,734
Sedentarismo, n (%) 86 (35,8%) 90 (36,7%) 0,836
Medicamento anti-hipertensivo hypertensive medication use, n (%) 43 (17,9%) 49 (20,0%) 0,558
Hipolipemiante, n (%) 66 (27,5%) 60 (24,5%) 0,450
Medicamento antiplaquetário, n (%) 22 (9,2%) 21 (8,6%) 0,818
Estado civil
Casado, n (%) 153 (63,8%) 158 (64,5%) 0,865
Separado/Divorciado/ Solteiro/Viúvo, n (%) 87 (36,3%) 87 (35,5%)
Renda
Alta, n (%) 139 (57,9%) 129 (52,7%) 0,244
Baixa, n (%) 101 (42,1%) 116 (47,3%)
Escolaridade
Superior, n (%) 124 (51,7%) 112 (45,7%) 0,190
Médio ou inferior, n (%) 116 (48,3%) 133 (54,3%)
Moradia,
Urbana, n (%) 133 (55,4%) 139 (56,7%) 0,770
Rural, n (%) 107 (44,6%) 106 (43,3%)
Status empregatício,
Empegado, n (%) 138 (57,5%) 147 (60,0%) 0,576
Desempregado, n (%) 102 (42,5%) 98 (40,0%)
Seguro saúde, n (%) 124 (51,7%) 128 (52,2%) 0,899
Escore de risco Framingham (%) 8,46 ± 6,98 8,71 ± 6,76 0,682

JI: jejum intermitente; DCI: doença cardíaca isquêmica; DLC: dieta restrita em carboidratos (dieta low-carb).

 Medidas antropométricas e dados laboratoriais basais dos pacientes submetidos ao jejum intermitente e à dieta restrita em carboidratos (grupo I) e ao consumo ad libitum (controle)
Grupo I (n=240) (JI e DLC) Grupo II (n=245) (controle ad libitum) Valor p
Peso (Kg) 73,52 ± 14,28 73,71 ± 11,94 0,869
Altura (cm) 1,67 ± 0,10 1,66 ± 0,08 0,563
IMC, (kg/m2) 26,44 ± 4,90 26,72 ± 3,45 0,470
Circunferência da cintura (cm) 98,72 ± 9,64 99,09 ± 7,04 0,626
Circunferência do quadril (cm) 103,5 ± 7,96 103,6 ± 7,09 0,905
Razão cintura-quadril 0,952 ± 0,04 0,955 ± 0,02 0,203
Gordura corporal (%) 27,11 ± 5,31 26,67 ± 4,41 0,318
Músculo esquelético (%) 28,28 ± 2,13 28,06 ± 1,42 0,166
Gordura visceral (%) 16,27 ± 0,46 16,32 ± 0,51 0,275
PA sistólica, mmHg 133,0 ± 13,1 131,8 ± 12,1 0,303
PA diastólica, mmHg 78,39 ± 10,5 77,71 ± 10,0 0,467
Frequência cardíaca (bpm) 75,3 ± 13,2 77,33 ± 11,8 0,091
FEVE, (%) 62,45 ± 3,36 62,88 ± 4,20 0,213
Glicemia de jejum (mg/dL) 114,9 ± 3,07 115,2 ± 2,78 0,208
Glicemia 2-h pós-prandial (mg/dL) (mmol/L) 164,4 ± 14,8 162,8 ± 17,7 0,288
HbA1c % 5,98 ± 0,24 6,01 ± 0,23 0,306
Hemoglobina, g/dL 12,39 ± 0,73 12,33 ± 0,74 0,429
Colesterol total (mg/dL) 216,9 ± 38,8 213,0 ± 37,3 0,262
TG (mg/dL) 156,8 ± 18,5 154,6 ± 11,1 0,109
LDL (mg/dL) 134,1 ± 24,5 136,6 ± 25,5 0,277
HDL (mg/dL) 44,7 ± 6,90 45,1 ± 7,32 0,502
Creatinina sérica (mg/dL) 1,03 ± 0,21 1,02 ± 0,14 0,980
TFGe (mL/min/1,73 m2) 94,1 ± 17,9 93,2 ± 10,6 0,515
Albuminúria (mg/g) 29,14 ± 4,82 28,88 ± 5,01 0,561
PCR (mg/L) 3,55 ± 1,66 3,67 ± 1,35 0,384
Ácido úrico (mg/dL) 5,78 ± 1,19 5,84 ± 0,57 0,494
Troponina I sérica (ng/mL) 0,031 ± 0,01 0,031 ± 0,02 0,740
Índice tornozelo-braquial 1,07 ± 0,15 1,04 ± 0,14 0,083
EIM carótida (mm) 0,97 ± 0,11 0,99 ± 0,10 0,103

JI: jejum intermitente; IMC: índice de massa corporal; PA: pressão arterial; FEVE: fração de ejeção do ventrículo esquerdo; TG: triglicerídeos, LDL: lipoproteína de baixa densidade; HDL: lipoproteína de alta densidade; TFGe: taxa de filtração glomerular estimada; PCR: proteína c reativa; HbA1c: hemoglobina glicada; EIM: espessura da camada íntima média da artéria carótida; DLC: dieta restrita em carboidratos (dieta low-carb).

Após dois anos de seguimento, os seguintes parâmetros foram significativamente mais baixos no grupo I que no grupo II: peso corporal, IMC, circunferência da cintura, e porcentagem de gordura corporal. A porcentagem de redução foi de 5,3% no peso corporal, 5,67 % no IMC, 1,12% na circunferência da cintura, e 6,6% na porcentagem de gordura. No entanto, no grupo II, houve aumento nesses parâmetros em 1,6%, 1,7%, 0.2%, e 1,8% respectivamente, sem diferença significativa entre os dois grupos quanto à gordura visceral ou porcentagem de músculo esquelético. As mudanças na pressão arterial sistólica, diastólica e frequência cardíaca não foram estatisticamente significativas. A glicemia de jejum e a HbA1c% foram estatisticamente mais altas no grupo II que no grupo I; contudo, não houve diferença estatisticamente significativa na glicemia de duas horas pós-prandial entre os grupos. Ainda, o número de pacientes que mostraram progressão de pré-diabetes para DM foi maior no grupo II que no grupo I.

Quanto ao perfil lipídico, a única alteração foi a redução significativa nos níveis de LDL no grupo I em comparação ao grupo II. A albuminúria foi significativamente maior no grupo II que no grupo I, enquanto a creatinina e a TFGe não foram significativamente diferentes entre os dois grupos. Ainda, não houve diferença em proteína C reativa, ácido úrico, ou troponina sérica I entre os dois grupos (Tabela 3). Desfechos microvasculares e macrovasculares ocorreram com menor frequência no grupo I, uma frequência significativamente maior de retinopatia, neuropatia, e angina instável foi observada no grupo II que no grupo I (Tabela 4 e Figura 1). Análise de regressão multivariada foi realizada para identificar fatores que afetassem desfechos microvasculares e macrovasculares, e revelou que peso corporal, glicemia de jejum, HbA1c% e LDL aumentados eram os preditores independentes de desfechos microvasculares e macrovasculares, como mostrado na Tabela 5.

Medidas antropométricas e dados laboratoriais basais dos pacientes submetidos ao jejum intermitente e à dieta restrita em carboidratos (grupo I) e ao consumo ad libitum (controle) após dois anos de acompanhamento
Grupo I (n=240) (JI e DLC) Grupo II (n=245) (controle ad libitum) Valor p
Peso (Kg) 69,60 ± 14,75 74,90 ± 12,80 0,001*
Altura (cm) 1,67 ± 0,10 1,66 ± 0,08 0,563
IMC, (kg/m2) 24,94 ± 4,76 27,17 ± 3,60 0,001*
Circunferência da cintura (cm) 97,61 ± 10,8 99,31 ± 7,77 0,047*
Circunferência do quadril (cm) 103,0± 8,20 104,2 ± 7,01 0,094
Razão cintura-quadril 0,949 ± 0,04 0,954 ± 0,02 0,087
Gordura corporal (%) 25,32 ± 4,20 27,15 ± 4,48 0,001*
Músculo esquelético (%) 27,93 ± 2,21 28,14 ± 1,39 0,209
Gordura visceral (%) 16,27 ± 0,47 16,35 ± 0,51 0,073
PA sistólica, mmHg 134,7 ± 12,2 133,5 ± 10,6 0,234
PA diastólica, mmHg 78,64 ± 10,2 77,15 ± 9,86 0,105
Frequência cardíaca (bpm) 75,68 ± 13,1 77,47 ± 13,1 0,136
FEVE, (%) 62,78 ± 3,65 63,24 ± 4,32 0,209
Glicemia de jejum (mg/dL) 113,4 ± 3,18 118,1 ± 5,04 0,001*
Glicemia 2-h pós-prandial (mg/dL) (mmol/L) 161,9 ± 15,3 164,8 ± 17,7 0,052
HbA1c % 5,89 ± 0,23 6,24 ± 0,24 0,001*
Progressão para diabetes mellitus 5 (2,1%) 17 (6,9%) 0,010*
Hemoglobina, g/dL 12,37 ± 0,73 12,30 ± 0,75 0,321
Colesterol total (mg/dL) 210,9 ± 39,2 216,9 ± 37,9 0,087
TG (mg/dL) 153,3 ± 31,6 155,1 ± 11,3 0,390
LDL (mg/dL) 132,1 ± 24,2 139,1 ± 25,7 0,002*
HDL (mg/dL) 44,07 ± 6,76 44,86 ± 7,36 0,219
Creatinina sérica (mg/dL) 1,04± 0,21 1,07 ± 0,16 0,165
TFGe (mL/min/1,73 m2) 93,01 ± 17,7 91,95 ± 10,0 0,415
Albuminúria (mg/g) 28,75 ± 4,69 30,33 ± 5,19 0,001*
PCR (mg/L) 3,59 ± 1,65 3,71 ± 1,37 0,388
Ácido úrico (mg/dL) 5,98 ± 0,78 5,87 ± 0,57 0,088
Troponina I sérica (ng/mL) 0,030 ± 0,01 0,032± 0,01 0,111
Índice tornozelo-braquial 1,05 ± 0,15 1,08 ± 0,14 0,073
EIM carótida (mm) 0,99 ± 0,11 1,01 ± 0,10 0,078

valor p significativo; JI: jejum intermitente; IMC: índice de massa corporal; PA: pressão arterial; FEVE: fração de ejeção do ventrículo esquerdo; TG: triglicerídeos; LDL: lipoproteína de baixa densidade; HDL: lipoproteína de alta densidade; TFGe: taxa de filtração glomerular estimada; PCR: proteína c reativa; HbA1c: hemoglobina glicada; EIM: espessura da camada íntima média da artéria carótida; DLC: dieta restrita em carboidratos (dieta low-carb).

 Desfechos macrovasculares e microvasculares em pacientes submetidos ao jejum intermitente e à dieta restrita em carboidratos (grupo I) e ao consumo ad libitum (controle) após dois anos de acompanhamento
Grupo I (n=240) (JI e DLC) Grupo II (n=245) (controle ad libitum) Valor p
Mortalidade, n (%) 0 (0%) 0 (0%)
Acidente vascular cerebral, n (%) 1 (0,4%) 2 (0,8%) 0,575
Angina instável, n (%) 2 (0,8%) 9 (3,7%) 0,036*
Infarto do miocárdio, n (%) 2 (0,8%) 3 (1,2%) 0,670
Doença arterial periférica, n (%) 5 (2,1%) 6 (2,4%) 0,787
Retinopatia, n (%) 5 (2,1%) 15 (6,1%) 0,025*
Nefropatia, n (%) 6 (2,9%) 9 (4,1%) 0,455
Neuropatia, n (%) 7 (2,9%) 17 (6,9%) 0,041*

valor p significativo. JI: jejum intermitente; DLC: dieta restrita em carboidratos (dieta low-carb).

 Desfechos macrovascular e microvascular de pacientes submetidos ao jejum intermitente (JI) e dieta restrita em carboidratos (low-carb) (Grupo I) ou consumo ad libitum (Grupo II, controle) após dois anos de seguimento. Análise de regressão multivariada mostrando os fatores de risco independentes dos desfechos microvasculares e macrovasculares
Análise multivariada Valor p
OR (IC95%)
Peso corporal 1,056 1,023– 1,090 0,001*
Índice de massa corporal 1,069 0,928– 1,230 0,356
Circunferência da cintura 1,024 0,975– 1,076 0,348
Gordura corporal % 1,068 0,983– 1,161 0,122
Glicemia de jejum 1,100 1,027– 1,178 0,006*
HbA1c % 9,575 2,175– 42,157 0,003*
LDL 1,078 1,039– 1,120 0,001*
Albuminúria 1,071 0,966– 1,187 0,190

LDL: lipoproteína de baixa densidade. HbA1c: hemoglobina glicada.

 Discussão

Os pacientes pré-diabéticos apresentam maior risco para DCVs e suas complicações macrovasculares e microvasculares. Mudanças no estilo de vida, incluindo dieta, atividade física, e cessação do tabagismo têm um papel crucial no manejo do pré-diabetes e do diabetes e redução de complicações. A dieta exerce um papel essencial no manejo em geral, incluindo nas complicações cardiovasculares.17 Assim, no presente estudo, investigamos o valor de se combinar duas estratégias dietéticas (JI e DLC) na prevenção de complicações microvasculares e macrovasculares em pacientes pré-diabéticos.

Neste estudo, encontramos uma redução significativamente maior no peso corporal, IMC, circunferência da cintura, e porcentagem de gordura no grupo I em comparação ao grupo II, mas não houve diferença significativa na gordura visceral ou porcentagem de músculo esquelético entre os grupos. Esses resultados estão de acordo com os apresentados por Kalam et al.,18 que estudaram 31 pacientes obesos submetidos a uma combinação de JI e DLC durante seis meses, e demonstraram reduções significativas no peso corporal (em 6,3±1,0%) e massa de gordura (p<0,01), e nenhuma alteração significativa na gordura visceral ou na massa magra. Ainda, O’Driscoll et al.,19 combinaram JI e DLC por 12 meses e relataram uma redução significativa no peso corporal em 9%, circunferência da cintura, e IMC em 8,6%. Moro et al.20 estudaram o efeito do JI em homens sadios treinados e encontraram uma diminuição na massa de gordura em 16,4% no grupo JI em comparação a uma diminuição em 2,8% no grupo controle, enquanto não houve alteração na massa livre de gordura e na massa muscular esquelética em ambos os grupos. Por outro lado, Zaki et al.21 mostraram que uma DLC pode reduzir o peso corporal, mas de modo menos eficaz que a dieta cetogênica.

Ainda, o grupo I apresentou melhora no perfil glicêmico por meio da redução significativa na glicemia de jejum e HbA1c. Wilkinson et al.22 e Wei et al.23 mostraram melhora semelhante na HbA1c e glicemia de jejum pelo JI, principalmente nos indivíduos que apresentavam uma glicemia de jejum basal mais alta. Ainda, Yamada et al.24 relataram uma redução significativa nos níveis de HgA1c (7,6 ± 0,4% vs. 7,0 ± 0,7%) nos indivíduos com DM2 submetidos à DLC em comparação àqueles submetidos à restrição calórica (7,7 ± 0,6% vs. 7,5 ± 1,0%). Contudo, não houve diferença significativa no peso corporal ou IMC. No estudo de Kalam et al.,18 embora não houve alteração na glicemia de jejum e na HbA1c após seis meses de DLC e JI, observou-se uma redução na insulina de jejum em 24%, o que pode ser explicado pelo curto período de intervenção com o JI.

Além disso, o presente estudo mostrou que a progressão de pré-diabetes para DM2 foi estatisticamente maior no grupo controle (6,9%) que no grupo JI-DLC. Esse dado está de acordo com o estudo de Wang et al.,25 que descreveram uma redução significativa na glicemia de jejum e na glicemia pós-prandial, acompanhada por uma redução na dose de insulina em 8,7% nos pacientes com DM2 submetidos à DLC por três meses. Em uma meta-análise comparando a DLC com a dieta hipolipídica em pacientes com DM2, os pacientes submetidos à DLC atingiram maiores taxas de remissão do DM em seis meses.26 Tal fato foi explicado por Sutton et al.,27 que avaliaram o efeito do JI em pacientes pré-diabéticos, e relataram um aumento na sensibilidade da insulina e função das células-beta, principalmente nos pacientes com sobrepeso. Furmli et al.28 também confirmaram uma redução na necessidade de insulina em pacientes com DM2 com o uso do JI.

Outro resultado importante do presente estudo foi a redução significativamente maior nos níveis de LDL no grupo I em comparação ao grupo II, sem alteração nos níveis de colesterol total, triglicerídeos ou HDL. Esse achado foi similar aos estudos de Kalam et al.18 e Jacobi et al.,29 que descreveram uma redução significativa no LDL e no colesterol total, e ausência de alteração nos níveis de triglicerídeos e HDL. Por outro lado, quatro artigos comparando JI e consumo ad libitum relataram uma redução no colesterol total, sem alteração no LDL, triglicerídeos ou HDL.30 Wilkinson et al.,22 contudo, relataram uma diminuição, do basal, no colesterol total, LDL, e colesterol não HDL com o JI, sem alteração nos níveis de triglicerídeos ou HDL. Ainda, o impacto da DLC foi investigado e comparado com uma dieta rica em carboidratos, sem mudanças significativas no perfil lipídico e uma leve redução nos níveis de triglicerídeos.31 O presente estudo mostrou uma mudança significativa na albuminúria, sem alteração na creatinina sérica, TFGe, e incidência de nefropatia. Sulaj et al.32 também mostraram que o JI foi mais efetivo em melhorar a albuminúria em comparação à dieta mediterrânea, sem diferença na TFGe ou creatinina sérica entre os dois grupos.

Assim, em relação aos desfechos primários, a incidência de angina instável foi significativamente maior no grupo I que nos controles. Esses resultados são reforçados pela elevação significativa na HbA1c no grupo II, bem como pela elevação no LDL, precursor de aterosclerose. De fato, Focardi et al.33 demonstraram uma melhora na função endotelial pela DLC. Vários estudos relataram o impacto do JI e da DLC sobre a morbidade e mortalidade por DCV pela melhora no perfil lipídico e glicêmico, além da mudança nos fatores de risco. Ainda, a incidência de retinopatia e neuropatia foi significativamente menor no grupo I (2,1% e 2.9 %, respectivamente) que no grupo II (6,1% e 6,9%, respectivamente).34–36 Esses desfechos comprovam o impacto do JI e da DLC na diminuição das complicações microvasculares. Nossos dados vão ao encontro dos descritos por Hammer et al.37 e Dannawi et al.,38 que revelaram uma redução na retinopatia e neuropatia pelo JI, e Hwang et al.39 que revelaram uma recuperação na função endotelial microvascular pela DLC somente após seis semanas. Uma baixa incidência de retinopatia e neuropatia está associada com uma redução na HbA1c e glicemia de jejum.40,41

 Conclusão

O JI, combinado com a DLC, pode exercer um importante papel na prevenção e no tratamento da DCV em pacientes pré-diabéticos. Este estudo mostrou melhora no status glicêmico, redução na progressão do diabetes e diminuição significativa na incidência de retinopatia, neuropatia, e angina instável no grupo JI-DLC. Ainda, a combinação do JI com a DLC associou-se com melhora nos desfechos primários e secundários em pacientes pré-diabéticos, com redução na morbidade cardiovascular. Aumento no peso corporal e níveis de glicemia de jejum, HbA1c, e LDL elevados foram fatores de risco independentes de desfechos microvasculares e macrovasculares.

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Aprovação ética e consentimento informado

Este estudo foi aprovado pelo Comitê de Ética da Faculdade de Medicina de Tanta University sob o número de protocolo 35721/9/22. Todos os procedimentos envolvidos nesse estudo estão de acordo com a Declaração de Helsinki de 1975, atualizada em 2013. O consentimento informado foi obtido de todos os participantes incluídos no estudo.

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Nutr Metab Cardiovasc Dis. 2011;21(2):144-9. doi: 10.1016/j.numecd.2009.08.001. Hammer SS Vieira CP McFarland D Sandler M Levitsky Y Dorweiler TF Fasting and Fasting-Mimicking Treatment Activate SIRT1/LXRα and Alleviate Diabetes-Induced Systemic and Microvascular Dysfunction Diabetologia 2021 64 7 1674 1689 10.1007/s00125-021-05431-5 37 Hammer SS, Vieira CP, McFarland D, Sandler M, Levitsky Y, Dorweiler TF, et al. Fasting and Fasting-Mimicking Treatment Activate SIRT1/LXRα and Alleviate Diabetes-Induced Systemic and Microvascular Dysfunction. Diabetologia. 2021;64(7):1674-89. doi: 10.1007/s00125-021-05431-5. Dannawi M Riachi ME Haddad AF El Massry M Haddad M Moukarzel P Influence of Intermittent Fasting on Prediabetes-Induced Neuropathy: Insights on a Novel Mechanistic Pathway Metabol Open 2022 14 100175 100175 10.1016/j.metop.2022.100175 38 Dannawi M, Riachi ME, Haddad AF, El Massry M, Haddad M, Moukarzel P, et al. Influence of Intermittent Fasting on Prediabetes-Induced Neuropathy: Insights on a Novel Mechanistic Pathway. Metabol Open. 2022;14:100175. doi: 10.1016/j.metop.2022.100175. Hwang CL Ranieri C Szczurek MR Ellythy AM Elokda A Mahmoud AM The Effect of Low-Carbohydrate Diet on Macrovascular and Microvascular Endothelial Function is Not Affected by the Provision of Caloric Restriction in Women with Obesity: A Randomized Study Nutrients 2020 12 6 1649 1649 10.3390/nu12061649 39 Hwang CL, Ranieri C, Szczurek MR, Ellythy AM, Elokda A, Mahmoud AM, et al. The Effect of Low-Carbohydrate Diet on Macrovascular and Microvascular Endothelial Function is Not Affected by the Provision of Caloric Restriction in Women with Obesity: A Randomized Study. Nutrients. 2020;12(6):1649. doi: 10.3390/nu12061649. Matsushita Y Takeda N Nakamura Y Yoshida-Hata N Yamamoto S Noda M A Comparison of the Association of Fasting Plasma Glucose and HbA1c Levels with Diabetic Retinopathy in Japanese Men J Diabetes Res 2020 2020 3214676 3214676 10.1155/2020/3214676 40 Matsushita Y, Takeda N, Nakamura Y, Yoshida-Hata N, Yamamoto S, Noda M, et al. A Comparison of the Association of Fasting Plasma Glucose and HbA1c Levels with Diabetic Retinopathy in Japanese Men. J Diabetes Res. 2020;2020:3214676. doi: 10.1155/2020/3214676. Casadei G Filippini M Brognara L Glycated Hemoglobin (HbA1c) as a Biomarker for Diabetic Foot Peripheral Neuropathy Diseases 2021 9 1 16 16 10.3390/diseases9010016 41 Casadei G, Filippini M, Brognara L. Glycated Hemoglobin (HbA1c) as a Biomarker for Diabetic Foot Peripheral Neuropathy. Diseases. 2021;9(1):16. doi: 10.3390/diseases9010016. Original Article The Value of Intermittent Fasting and Low Carbohydrate Diet in Prediabetic Patients for the Prevention of Cardiovascular Diseases 0000-0002-6105-9300 Khalfallah Mohamed 1 Conception and design of the research e Statistical analysis Analysis and interpretation of the data Critical revision of the manuscript for important intellectual content 0000-0002-5569-5781 Elnagar Basma 1 Acquisition of data Writing of the manuscript Soliman Shaimaa S. 2 Analysis and interpretation of the data Writing of the manuscript Eissa Ahmad 3 Acquisition of data Analysis and interpretation of the data Allaithy Amany 1 Writing of the manuscript Critical revision of the manuscript for important intellectual content Egypt Cardiovascular Department, Faculty of Medicine, Tanta University – Egypt Egypt Public Health and Community Medicine Department, Faculty of Medicine, Menoufia University – Egypt Egypt Endocrinology, Internal Medicine Department, Faculty of Medicine, Tanta University – Egypt Mailing Address: Mohamed Khalfallah Faculty of medicine, Tanta University – El-Geish Street, Tanta – Egypt. E-mail: khalfallah@yahoo.com

Potential conflict of interest

No potential conflict of interest relevant to this article was reported.

 Abstract Background:

Prediabetic patients are at increased risk for cardiovascular diseases and the development of microvascular and macrovascular complications. Intermittent fasting (IF) and low-carbohydrate diet (LCD) are promising dietary plans.

 Objectives:

Our aims to analyze the benefits of IF combined with LCD on microvascular and macrovascular outcomes in prediabetic patients.

 Methods:

The study included 485 prediabetic patients with no history of cardiovascular diseases divided into group I: (n = 240 patients) who underwent IF (16 h IF 3-4 days per week) combined with LCD (<130 g of carbohydrate per day), and group II: (n = 245 patients) with ad libitum calorie intake. The two groups were followed-up for two years for assessment of micro and macrovascular complications. A p-value < 0.05 was considered statistically significant.

 Result:

There was a significant reduction in body weight, body mass index, waist circumference, body fat percentage and glycated hemoglobin in group I. The incidence of progression from prediabetes to diabetes was significantly lower in group I (2.1% vs. 6.9% in group II, p = 0.010). In addition, a significant increase in the incidence of microvascular and macrovascular complications was observed in group II, including retinopathy, neuropathy and unstable angina. Multivariate regression analysis revealed that increased body weight, fasting glucose, glycated hemoglobin and low-density lipoprotein were independent risk factors impacting microvascular and macrovascular outcomes.

 Conclusions:

In prediabetic patients, IF, combined with LCD, was associated with lower progression to diabetes mellitus and lower incidence of microvascular and macrovascular complications.

 Keywords: Prediabetic State Fasting Diet Cardiovascular Diseases Central Illustration - Illustration of the main results of the article; IF: intermittent fasting Introduction

Cardiovascular diseases (CVD) are still a fundamental cause of death worldwide, accounting for approximately 20% of all deaths.1 Despite advances in CVD management, the morbidity and mortality due to CVD are significantly high which lead to an economic burden. Therefore, the early detection and treatment of the modifiable risk factors for CVD are of paramount importance. Major modifiable risk factors include overweight, dyslipidemia, hypertension and hyperglycemia.2 Prediabetes is characterized by a hyperglycemic state, below the level used to define diabetes mellitus (DM), with a high probability of progression to DM. Moreover, prediabetic patients are at high risk of endothelial dysfunction resulting in microvascular and macrovascular complications associated with higher cardiovascular morbidity and mortality.3 The incidence of prediabetes has increased and been associated with an increase in obesity worldwide.4

Several studies have validated lifestyle intervention as an effective method in preventing or delaying the progression to type 2 diabetes mellitus (T2DM) and decreasing the cardiovascular risk in prediabetic patients.5,6 Reduction of weight using lifestyle modification, diet plans, pharmacological and/or surgical interventions has a beneficial impact on hyperglycemic status.

Intermittent fasting (IF) is a dietary pattern characterized by a decreased caloric intake using a fasting period alternating with ad libitum food consumption. The most common type consists of hours of fasting followed by hours of free intake on the same day.7 Another dietary intervention especially in the hyperglycemic state is known as a low-carb diet (LCD), based on carbohydrate restriction. According to the carbohydrate consumption and its percent of total energy intake, LCD is classified into very LCD (20-50 g/day or <10% of energy intake), LCD (less than 130 g/day or < 26% of energy intake), and moderate carb (26- 44% energy intake).8

In recent years, the IF and LCD diets have been approved and become more and more popular and for weight reduction.9 However, their impact on human health, especially on cardiovascular outcomes in prediabetic and diabetic patients is still under investigation. This study aimed to investigate the impact of both IF and LCD on microvascular and macrovascular outcomes in prediabetic patients.

Patients and methods

This is a prospective cohort study, conducted with 485 participants attending the cardiovascular outpatient clinic in Tanta University Hospital, Egypt, from June 2019 to June 2020 with a follow-up period of two years. The study was approved by the research ethics committee of Tanta University Medical School and conducted in accordance with the principles of the Declaration of Helsinki II. All patients included in the study signed a written informed consent form and a code number was assigned to each patient. The included patients were randomized using a computerized random number generator to select randomly permuted blocks with a block size of two and an equal allocation ratio. Allocation concealment was performed using consecutively numbered opaque sealed envelopes which was opened after the patient signed the written consent and then enrolled into the respective group.

 Inclusion and exclusion criteria

All participants were above 30 years old and below 70 years old with a confirmed diagnosis of prediabetes either by glycated hemoglobin (HbA1c) 5.7–6.4% and /or fasting blood glucose of 100–125 mg/dl and/or two-hour post prandial blood glucose of 140–199 mg/dL.9 Patients with prior history of DM, CVD (stroke, ischemic heart disease, heart failure, and peripheral arterial disease), advanced liver or renal disease, and chronic inflammatory disease were excluded.

The participants were randomized into two groups according to their dietary plan; group I (IF–LCD): underwent IF (16/8: 16 hours of fasting followed by eight hours of unlimited eating for 3-4 days per week) in addition to low-carb intake (less than 130 g/day of carbohydrate and <26% of total energy intake, without increase in fat intake for seven days a week); group (II) (Control group): control group patients continued their usual daily dietary pattern with no calorie restriction. All participants were submitted to a detailed history taking, including cardiovascular risk factors – smoking, hypertension, dyslipidemia, family history of cardiovascular diseases – and manifestations of vascular complications of DM (e.g. chest pain, blurring of vision, and numbness). Psychosocial stress in all participants was estimated using the perceived stress scale scoring from 0-40 (scores <14 indicate absence or low stress condition, while scores ≥ 14 indicate status of considerable stress).10,11 Also, their physical activity was evaluated according to the duration and type of physical activity per week; participants who performed 150 minutes of moderate physical activity or 75 minutes of vigorous physical activity or more per week were considered physically active.12 Patients were also asked about health insurance, psychosocial stress, use and compliance to antihypertensive, cholesterol-lowering, and antiplatelet medications, and compliance to these medications. Furthermore, socioeconomic status including educational level, patients’ income, place of residence, marital and employment status, were assessed.

Anthropometric measurements and physical examinations were performed including measurements of height, waist circumference, hip circumference, and waist-hip ratio using a measuring tape. Body weight, body mass index (BMI), and body composition with bioelectrical impedance analysis were measured using the InBody230 device. Blood pressure and heart rate measurements and full neurological evaluation were also performed. Routine laboratory parameters including plasma glucose (fasting, 2 hours postprandial), HbA1c, serum total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), C-reactive protein, serum creatinine and estimated glomerular filtration rate (e-GFR) were also analyzed. A urine sample was taken in the early morning for albuminuria and the albumin/creatinine ratio, and an electrocardiogram and echocardiography were performed in all patients. Furthermore, the ankle-brachial index was calculated by dividing the highest ankle systolic pressure by the highest brachial systolic pressure. Carotid intima-media thickness was obtained by carotid ultrasound. A fundoscopic examination was performed for diabetic retinopathy screening. Framingham risk score was used to estimate 10 years of cardiovascular risk. The ten-year risk in percentage was classified as low risk (< 10%), intermediate risk (10–20%), and high risk (> 20%).13 All clinical assessments were performed at baseline and follow-up. During the two years of follow-up, participants of both groups made regular visits every three months at the outpatient clinic for revision of their monthly diet sheet and assessment of the adherence to IF and LCD (group I). The participants who missed a visit or was not adherent to the IF or to the LCD prescribed were excluded from the study.

Outcomes

The outcomes of this study were divided into primary endpoints which included mortality and the occurrence of macrovascular complications, such as stroke, unstable angina, and myocardial infarction, and progression to overt DM. Secondary endpoints were the occurrence of microvascular complications: (1) retinopathy, defined as progressive weakness of retinal vessels varying from non-proliferative and pre-proliferative to proliferative retinopathy;14 (2) nephropathy, characterized by a progressive decline in e-GFR below 90 mL/min/1.73 m2, persistent albuminuria, and elevated arterial blood pressure;15 and (3) neuropathy which has many clinical manifestations in the form of abnormal or loss of motor, sensory, and/or autonomic nervous system function, diagnosed clinically.14

 Statistical analysis

Statistical analysis was done using SPSS 23, (Armonk, NY; IBM Corp.). As regarding the normality of the data, we used the central limit theorem which states that when the sample size has 100 or more observations, violation of the normality is not a major issue.16 Quantitative variables were expressed as mean ± standard deviation. Qualitative variables were expressed as frequency and percentage. Independent samples t-test was used for comparison of quantitative variables between the two groups. The chi-square test (χ2) was used to compare two qualitative parameters. When the expected value in a cell was less than five, the Fisher’s exact test was used. A two-sided p-value <0.05 was considered statistically significant. Multivariate logistic regression analysis was performed to detect the independent predictors of macrovascular and microvascular outcomes.

 Results

The present study was conducted with 485 prediabetic patients with no evidence of cardiovascular diseases. There was no statistically significant difference between the two groups regarding their age, sex distribution, socioeconomic factors, cardiovascular risk factors and level of education, as shown in Table 1. There was no significant difference in baseline anthropometric measurements or laboratory data between the two groups (Table 2).

Baseline characteristics, risk factors and socioeconomic factors of patients undergoing intermittent fasting (IF) and lowcarbohydrate (low-carb) diet (group I) and ad libitum food intake (control, group II)
Group I (n=240) (IF and low-carb diet) Group II (n=245) (Ad libitum control) p value
Age, years 48.11±7.58 48.64±8.46 0.470
Male gender, n (%) 123 (51.3%) 122 (49.8%) 0.749
Smoking, n (%) 73 (30.4%) 68 (27.8%) 0.519
Hypertension, n (%) 65 (27.1%) 77 (31.4%) 0.293
Dyslipidemia, n (%) 80 (33.3%) 78 (31.8%) 0.725
Family history of IHD, n (%) 61 (25.4%) 64 (26.1%) 0.859
Psychosocial stress, n (%) 53 (22.1%) 51 (20.8%) 0.734
Physical inactivity, n (%) 86 (35.8%) 90 (36.7%) 0.836
Anti-hypertensive medication, n (%) 43 (17.9%) 49 (20.0%) 0.558
Cholesterol-lowering medication, n (%) 66 (27.5%) 60 (24.5%) 0.450
Anti-platelets medication use, n (%) 22 (9.2%) 21 (8.6%) 0.818
Marital status
Married, n (%) 153 (63.8%) 158 (64.5%) 0.865
Separated/Divorced/ Single/ Widow/Widower, n (%) 87 (36.3%) 87 (35.5%)
Income category
High income, n (%) 139 (57.9%) 129 (52.7%) 0.244
Low income, n (%) 101 (42.1%) 116 (47.3%)
Level of education
Bachelor’s degree or higher, n (%) 124 (51.7%) 112 (45.7%) 0.190
High school or less, n (%) 116 (48.3%) 133 (54.3%)
Residence,
Urban, n (%) 133 (55.4%) 139 (56.7%) 0.770
Rural, n (%) 107 (44.6%) 106 (43.3%)
Occupational status,
Employed, n (%) 138 (57.5%) 147 (60.0%) 0.576
Unemployed, n (%) 102 (42.5%) 98 (40.0%)
Health insurance, n (%) 124 (51.7%) 128 (52.2%) 0.899
Framingham risk score (%) 8.46 ± 6.98 8.71 ± 6.76 0.682

IHD: ischemic heart disease.

 Baseline anthropometric measurements and laboratory data of patients undergoing intermittent fasting (IF) and low-carbohydrate (low-carb) diet (group I) and ad libitum food intake (control, group II)
Group I (n=240) (IF and low-carb diet) Group II (n=245) (Ad libitum control) p value
Weight (Kg) 73.52 ± 14.28 73.71 ± 11.94 0.869
Height (cm) 1.67 ± 0.10 1.66 ± 0.08 0.563
BMI, (Kg/m2) 26.44 ± 4.90 26.72 ± 3.45 0.470
Waist circumference(cm) 98.72 ± 9.64 99.09 ± 7.04 0.626
Hip circumference (cm) 103.5 ± 7.96 103.6 ± 7.09 0.905
Waist-hip ratio 0.952 ± 0.04 0.955 ± 0.02 0.203
Body fat (%) 27.11 ± 5.31 26.67 ± 4.41 0.318
Skeletal muscle (%) 28.28 ± 2.13 28.06 ± 1.42 0.166
Visceral fat (%) 16.27 ± 0.46 16.32 ± 0.51 0.275
Systolic BP, mmHg 133.0 ± 13.1 131.8 ± 12.1 0.303
Diastolic BP, mmHg 78.39 ± 10.5 77.71 ± 10.0 0.467
Heart rate, (bpm) 75.3 ± 13.2 77.33 ± 11.8 0.091
LVEF, (%) 62.45 ± 3.36 62.88 ± 4.20 0.213
Fasting plasma glucose (mg/dL) 114.9 ± 3.07 115.2 ± 2.78 0.208
2-h post prandial plasma glucose (mg/dl) (mmol/L) 164.4 ± 14.8 162.8 ± 17.7 0.288
HbA1c % 5.98 ± 0.24 6.01 ± 0.23 0.306
Hemoglobin, g/dL 12.39 ± 0.73 12.33 ± 0.74 0.429
Total cholesterol (mg/dl) 216.9 ± 38.8 213.0 ± 37.3 0.262
TG (mg/dL) 156.8 ± 18.5 154.6 ± 11.1 0.109
LDL (mg/dL) 134.1 ± 24.5 136.6 ± 25.5 0.277
HDL (mg/dL) 44.7 ± 6.90 45.1 ± 7.32 0.502
Serum creatinine (mg/dL) 1.03 ± 0.21 1.02 ± 0.14 0.980
e-GFR (mL/min/1.73 m2) 94.1 ± 17.9 93.2 ± 10.6 0.515
Albuminuria (mg/g) 29.14 ± 4.82 28.88 ± 5.01 0.561
CRP (mg/L) 3.55 ± 1.66 3.67 ± 1.35 0.384
Uric acid (mg/dL) 5.78 ± 1.19 5.84 ± 0.57 0.494
Serum troponin I (ng/mL) 0.031 ± 0.01 0.031 ± 0.02 0.740
Ankle brachial index 1.07 ± 0.15 1.04 ± 0.14 0.083
Carotid IMT (mm) 0.97 ± 0.11 0.99 ± 0.10 0.103

BMI: body mass index; BP: blood pressure; LVEF: left ventricle ejection fraction; HbA1c: glycated hemoglobin; TG: triglyceride; LDL: low density lipoprotein; HDL: high density lipoprotein; e-GFR: estimated glomerular filtration rate; CRP: C - reactive protein; IMT: intima media thickness; BP: blood pressure.

After two years of follow-up, the following parameters were significantly lower in group I than group II: body weight, BMI, waist circumference, and body fat percentage. The percentage of reduction was -5.3% in body weight, -5.67 % in BMI, -1.12% in waist circumference, and -6.6% in body fat percentage, however in group II, there was an increase in these parameters by +1.6%, +1.68%, +0.22%, and +1.79% respectively with no significant difference between the two groups in visceral fat or skeletal muscle percentage. The changes in systolic and diastolic blood pressure and heart rate were not statistically significant. Fasting plasma glucose and HbA1c % were statistically higher in group II than group I; however, there was no statistically significant difference in 2-h postprandial plasma glucose between the two groups. Moreover, the number of patients who showed a progression from prediabetes to DM was higher in group II than group I.

As regarding lipid profile, the only change was the significant reduction in LDL level in group I than group II. Albuminuria was significantly higher in group II than group I, whereas creatinine and e-GFR showed no significant difference between the two groups. Also, C-reactive protein, uric acid, and serum troponin I were not different between the two groups (Table 3). Microvascular and macrovascular outcomes occurred less frequently in group I, and significantly higher frequency of retinopathy, neuropathy, and unstable angina was found in group II than group I (Table 4 and Figure 1). Multivariate regression analysis was performed to identify factors affecting microvascular and macrovascular outcomes, which revealed that the increase in body weight, fasting plasma glucose, HbA1c % and LDL were independent predictors of microvascular and macrovascular outcomes as shown in Table 5.

Anthropometric measurements and laboratory data of patients undergoing intermittent fasting (IF) and low-carbohydrate (low-carb) diet (group I) and ad libitum food intake (control, group II) after two years follow-up
Group I (n=240) (IF and low-carb diet) Group II (n=245) (ad libitum control) p value
Weight (kg) 69.60 ± 14.75 74.90 ± 12.80 0.001*
Height (cm) 1.67 ± 0.10 1.66 ± 0.08 0.563
BMI, (kg/m2) 24.94 ± 4.76 27.17 ± 3.60 0.001*
Waist circumference(cm) 97.61 ± 10.8 99.31 ± 7.77 0.047*
Hip circumference(cm) 103.0± 8.20 104.2 ± 7.01 0.094
Waist-hip ratio 0.949 ± 0.04 0.954 ± 0.02 0.087
Body fat (%) 25.32 ± 4.20 27.15 ± 4.48 0.001*
Skeletal muscle (%) 27.93 ± 2.21 28.14 ± 1.39 0.209
Visceral fat (%) 16.27 ± 0.47 16.35 ± 0.51 0.073
Systolic BP, mmHg 134.7 ± 12.2 133.5 ± 10.6 0.234
Diastolic BP, mmHg 78.64 ± 10.2 77.15 ± 9.86 0.105
Heart rate, (bpm) 75.68 ± 13.1 77.47 ± 13.1 0.136
LVEF, (%) 62.78 ± 3.65 63.24 ± 4.32 0.209
Fasting plasma glucose (mg/dl) 113.4 ± 3.18 118.1 ± 5.04 0.001*
2-h post prandial plasma glucose (mg/dl) (mmol/L) 161.9 ± 15.3 164.8 ± 17.7 0.052
HbA1c % 5.89 ± 0.23 6.24 ± 0.24 0.001*
Progression to diabetes mellitus, n (%) 5 (2.1%) 17 (6.9%) 0.010*
Hemoglobin, g/dL 12.37 ± 0.73 12.30 ± 0.75 0.321
Total cholesterol (mg/dl) 210.9 ± 39.2 216.9 ± 37.9 0.087
TG (mg/dL) 153.3 ± 31.6 155.1 ± 11.3 0.390
LDL (mg/dL) 132.1 ± 24.2 139.1 ± 25.7 0.002*
HDL (mg/dL) 44.07 ± 6.76 44.86 ± 7.36 0.219
Serum creatinine (mg/dL) 1.04± 0.21 1.07 ± 0.16 0.165
e-GFR (mL/min/1.73 m2) 93.01 ± 17.7 91.95 ± 10.0 0.415
Albuminuria (mg/g) 28.75 ± 4.69 30.33 ± 5.19 0.001*
CRP (mg/L) 3.59 ± 1.65 3.71 ± 1.37 0.388
Uric acid (mg/dL) 5.98 ± 0.78 5.87 ± 0.57 0.088
Serum troponin I (ng/mL) 0.030 ± 0.01 0.032± 0.01 0.111
Ankle brachial index 1.05 ± 0.15 1.08 ± 0.14 0.073
Carotid IMT (mm) 0.99 ± 0.11 1.01 ± 0.10 0.078

Significant P value; BMI: body mass index; BP: blood pressure; LVEF: left ventricle ejection fraction; HbA1c: glycated hemoglobin; TG: triglyceride; LDL: low density lipoprotein; HDL: high density lipoprotein; e-GFR: estimated glomerular filtration rate; CRP: C - reactive protein; IMT: intima media thickness.

 Macrovascular and microvascular outcomes in patients undergoing intermittent fasting (IF) and low-carbohydrate (low-carb) diet (group I) and <italic>ad libitum</italic> food intake (control, group II) after two years of follow-up
Group I (n=240) (IF and low-carb diet) Group II (n=245) (Ad libitum control) p value
Mortality, n (%) 0 (0%) 0 (0%)
Cerebral stroke, n (%) 1 (0.4%) 2 (0.8%) 0.575
Unstable angina, n (%) 2 (0.8%) 9 (3.7%) 0.036*
Myocardial infarction, n (%) 2 (0.8%) 3 (1.2%) 0.670
Peripheral arterial disease, n (%) 5 (2.1%) 6 (2.4%) 0.787
Retinopathy, n (%) 5 (2.1%) 15 (6.1%) 0.025*
Nephropathy, n (%) 6 (2.9%) 9 (4.1%) 0.455
Neuropathy, n (%) 7 (2.9%) 17 (6.9%) 0.041*

significant P value.

 Macrovascular and microvascular outcomes of patients undergoing intermittent fasting (IF) and low-carbohydrat (low-carb) diet (Group I) or ad libitum food consumption (Group II, controls) after two years of follow-up. Multivariate regression analysis showing the independent risk factors of microvascular and macrovascular outcomes
Multivariate analysis p value
OR (95% CI)
Body weight 1.056 1.023– 1.090 0.001*
Body mass index 1.069 0.928– 1.230 0.356
Waist circumference 1.024 0.975– 1.076 0.348
Body fat % 1.068 0.983– 1.161 0.122
Fasting plasma glucose 1.100 1.027– 1.178 0.006*
HbA1c % 9.575 2.175– 42.157 0.003*
LDL 1.078 1.039– 1.120 0.001*
Albuminuria 1.071 0.966– 1.187 0.190

LDL: low density lipoprotein.

 Discussion

Prediabetic patients are at high risk of CVD and its microvascular and macrovascular complications. Lifestyle modifications including diet, physical activity, and smoking cessation, play a crucial role in the management of prediabetes and diabetes and reduction of complications. The diet plays an essential role in overall management including cardiovascular complications.17 Therefore, in the current study, we investigated the adding value of the combination of two dietary methods (IF and LCD) in preventing microvascular and macrovascular complications in prediabetic patients.

In this study, we found that there was a significantly greater reduction in body weight, BMI, waist circumference, and fat percentage in group I than in group II, but no significant difference in visceral fat or skeletal muscle percentage between the two groups. In agreement with our results, Kalam et al.18 studied 31 obese patients who underwent a combination of IF with low-carb intervention for six months and demonstrated significant reductions in body weight (by 6.3 ± 1.0%) and fat mass (p < 0.01), while visceral fat and skeletal mass remained unchanged. Also, O’Driscoll et al.19 combined IF and LCD for 12 months and reported a significant reduction in body weight by 9%, waist circumference, and BMI by 8.6%. Moro et al.20 studied the effect of IF in healthy-trained males and found a decrease in fat mass by 16.4 % in the IF group compared to the normal diet group (2.8%), while the fat-free mass and the skeletal mass remained unchanged in both groups. On the other hand, Zaki et al.21 showed that a LCD can reduce body weight but not as effectively as ketogenic diet.

Furthermore, the group I showed improvement in glycemic profile by a significant reduction in fasting glucose and HbA1c. Similarly, Wilkinson et al.22 and Wei et al.23 showed an improvement in HbA1c and fasting glucose by IF, mainly in the subjects with higher glycemia at baseline. Also, Yamada et al.24 reported a significant decrease in HbA1c levels (7.6 ± 0.4% vs. 7.0 ± 0.7%) in T2DM individuals submitted to the LCD compared to those submitted to caloric restriction (7.7 ± 0.6% vs. 7.5 ± 1.0%); however, there was no significant change in body weight or BMI. In the study by Kalam et al.,18 although fasting glucose and HbA1c remained unchanged after six months of LCD and IF, there was a reduction in fasting insulin by 24%, which was explained by the short interventional period of IF.

In addition, the present study showed that the progression from prediabetes to T2DM was statistically higher in the control group (6.9 %) than in the IF- LCD group (2.1%). This is in accordance with the study by Wang et al.,25 who found a significant reduction in fasting and postprandial glucose accompanied by a reduction in the insulin dose by 8.7% in T2DM patients who underwent LCD for three months. In a meta-analysis comparing LCD with a low-fat diet in patients with T2DM, patients on LCD achieved higher diabetes remission rates at six months.26 This was explained by Sutton et al.,27 who applied IF to prediabetes and reported an increase in insulin sensitivity and beta-cell function, especially in overweight patients. Furmli et al., 28 also confirmed a decrease in insulin need in T2DM with IF.

Another important finding in the present study was the significantly greater reduction in LDL in group I than in group II with no change in total cholesterol, triglycerides or HDL. This was quite similar to the studies by Kalam et al.18 and Jacobi et al.29 who reported a significant reduction in LDL and total cholesterol while triglyceride and HDL levels did not change. On the other hand, four trials comparing IF to ad libitum food consumption found a reduction in total cholesterol with no change in LDL, triglycerides or HDL.30 Wilkinson et al.,22 however, reported a decrease from baseline in total cholesterol, LDL, and non-HDL with IF, and no change in triglycerides or HDL. Additionally, the impact of LCD was investigated and compared with a high-carb diet, with no significant changes in lipid profile and a slight reduction in triglycerides.31 The present study reported a significant change in albuminuria despite no change in serum creatinine, e-GFR, and incidence of nephropathy. Sulaj et al.32 also reported greater improvement in albuminuria with IF as compared with the Mediterranean diet and no difference in e-GFR or serum creatinine between the two groups.

Thus, regarding the primary outcomes, the incidence of unstable angina was significantly lower in group I than in controls. These results were supported by the significant elevation in Hb1Ac in group II, as well as by the significant elevation in LDL, which is the precursor of atherosclerosis. Moreover, Focardi et al.33 demonstrated the improvement of coronary endothelial function by LCD. Numerous studies reported the impact of IF and LCD on CVD morbidity and mortality by the enhancement of lipid and glycaemic profiles in addition to risk factor modification.34–36 Furthermore, the incidence of retinopathy and neuropathy was significantly lower in group I (2.1% and 2.9 %, respectively) vs. group II (6.1% and 6.9%, respectively). These outcomes proved the impact of IF and LCD on decreasing microvascular complications. In agreement with our results, Hammer et al.37 and Dannawi et al.38 revealed a reduction in retinopathy and neuropathy by IF, and Hwang et al., 39 revealed a recovery in microvascular endothelial function by LCD only after six weeks. A low incidence of retinopathy and neuropathy is associated with the reduction of HbA1c and fasting plasma glucose values.40,41

 Conclusion

IF, in combination with LCD, can play a main role in the prevention and treatment of CVD in prediabetic patients. This study showed improvement in the glycemic status and reduction in diabetes progression and a significant reduction in the incidence of retinopathy, neuropathy, and unstable angina in the IF-LCD group. In addition, the combination of IF with LCD was associated with improved primary and secondary outcomes in prediabetic patients with a decrease in cardiovascular morbidity. Increased body weight, fasting plasma glucose, HbA1c, and LDL were the independent risk factors of microvascular and macrovascular outcomes.

Sources of funding

There were no external funding sources for this study.

Study association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Faculty of medicine, Tanta University under the protocol number 35721/9/22. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013. Informed consent was obtained from all participants included in the study.