Clinical Epidemiology & Public Health

1. Introduction

Type 2 diabetes and heart disease are two major health problems in the U.S. Diabetes affects about 11.3% of Americans, and heart disease causes nearly one-third of all deaths each year (Heald, A. H., et al 2020 & Virani, S. S., et al 2023) Changing lifestyle habits is the main way to prevent and manage these diseases, but it’s often hard for people to stick with traditional diet plans. Due to its relative ease of long-term adherence IF which encompasses a variety of methods of  accomplish  total  energy  restriction  has  become  a  compelling. This results in periods of calorie deficiency and metabolic alteration which may have positive health effects such as weight loss increased insulin sensitivity and enhanced metabolic health in general. (Patterson, R. E., et al 2017) Alternative day fasting modified alternate day fasting periodic fasting and time restricted eating are some of the most popular IF techniques. ADF is a cyclic eating regimen that alternates a 24 hours period of normal eating with a 24-hour period of total fasting. Similar to the ADF and the mADF permits a calorie intake of 25% or less on days when fasting is observed. (Jaman, M. S., et al 2018) PF is a cyclic weekly pattern in which one or two of the day’s week are spent fasting (consuming a quarter or less of the daily caloric requirements or limiting daily caloric intake to 500-600 kcal) and the other five or six days are spent eating normally.  One common PF diet is the 5:2 diet. TRF entails eating normally the remainder of the day and fasting (no calories) for at least 12 hours.  With TRF the daily eating window is restricted to a certain time frame. For instance, a person may eat all of their meals inside an 8-hour window (for instance 12:00 pm to 8:00 pm) and fast for the remaining 16 hours of the day (16/8 method). The 16/8 and 14/10 TRF techniques are often the most often used. (Jaman, M. S., et al 2018) Intermittent fasting has showed modest promise in lowering cardiovascular disease risk variables in previous pairwise meta-analysis studies. But the outcomes are inconsistent. According to several meta-analysis intermittent fasting is a more efficient way to lose weight and reduce waist circumference than regular eating. Others however found no discernible difference between CER and IF for these metrics. It is unclear whether intermittent fasting an undesired decrease of muscle mass in terms of fat free mass. (Jaman, S., et al 2017 & Longo, V. D., et al 2016) while some studies revealed no effect, others revealed either an increase or a decrease in comparison to a typical diet. Additionally, blood pressure results are not always consistent while some meta-analysis found no significant difference others suggested that ID lowers both systolic blood pressure and diastolic blood pressure when compared to regular meals. Similarly, some research indicated that intermittent fasting decreased low density lipoprotein cholesterol and fasting blood sugar while other studies revealed in discernible difference in LDL reduction or fasting plasma glucose when compared to regular meals. (Jaman, M. S., et al 2018) Differences in the population the length of the intervention and the number of included studies may be the cause of the inconsistent outcomes throughout the earlier meta-analyses. Additionally, several people combined all intermittent fasting techniques in their analysis. (Woodruff, R. C., et al 2024) Intermittent fasting is a newer approach that’s showing promise. (Patterson, R. E., et al 2017) Unlike diets that focus only on cutting calories, IF focuses on when you eat instead of just what or how much you eat. (Jaman, M. S., et al 2018) This approach may be easier for some people to follow and may help the body become more flexible in how it uses energy, offering benefits beyond just weight loss. (Carter, S., et al 2018).

2. Methodology

2.1 Overview of the Review Process

This systematic review was conducted to provide a clear, evidence-based understanding of how intermittent fasting (IF) influences diabetes and cardiovascular disease (CVD) outcomes in the United States. To ensure reproducibility, each step of the review—from the initial literature search to the final organization of evidence—was performed with deliberate transparency and methodological consistency.

2.2 Search Strategy

A structured search strategy was used to identify relevant studies. We searched three major scientific databases—PubMed, Google Scholar, and Scopus—because they collectively offer broad coverage of biomedical, clinical, nutritional, and public health research. The search was carried out between January and April 2024, focusing on studies published within the past 10 years to capture the most current scientific understanding of IF. Keywords were combined using Boolean operators to refine results, including terms such as “intermittent fasting,” “time-restricted eating,” “alternate-day fasting,” “diabetes,” “type 2 diabetes,” “cardiovascular disease,” “blood glucose,” “LDL cholesterol,” “metabolic health,” and “United States population.” Search strings such as “intermittent fasting AND diabetes AND United States” and “time-restricted feeding AND cardiovascular outcomes” helped narrow the scope to studies directly relevant to this review.

2.3 Inclusion and Exclusion Criteria

To ensure scientific quality and relevance, we applied strict inclusion and exclusion criteria. We included peer-reviewed articles published in English, human studies involving U.S. populations or globally relevant metabolic outcomes, and research designs such as randomized controlled trials, observational studies, systematic reviews, and public health reports. Studies were excluded if they consisted of case reports, editorials, or non–peer reviewed material; focused solely on elderly or pediatric groups unless directly relevant; failed to address IF mechanisms or health markers; or lacked clear methodology or measurable outcomes.

2.4 Study Screening Process

Screening was performed in three steps. First, titles were reviewed to remove unrelated topics, including chemotherapy-related fasting or animal-only studies. Next, abstracts were screened to determine whether the research examined IF in relation to diabetes, metabolic outcomes, or cardiovascular health. Finally, full texts were assessed for eligibility based on the predefined criteria. When uncertainty arose, all reviewers discussed the article collectively to reach a consensus. This staged approach helped minimize bias and maintain uniform selection standards. 

2.5 Data Extraction and Organization

After selecting eligible studies, data were carefully extracted using a predefined table to ensure consistency. For each study, we documented its design, population characteristics, type of intermittent fasting evaluated (such as TRF, ADF, the 5:2 diet, or periodic fasting), duration of the intervention, primary outcomes—such as HbA1c, body weight, LDL cholesterol, blood pressure, or inflammatory markers—and key findings and limitations. The extracted information was then organized into thematic categories, including the epidemiology of diabetes and CVD in the U.S., biological mechanisms of IF, its metabolic and cardiovascular effects, associated risks and limitations, and broader policy or practical considerations. Throughout the process, priority was given to high-quality randomized trials, meta-analyses, and systematic reviews to ensure that the conclusions drawn were supported by robust and reliable evidence.

2.6 Definitions and Types of Intermittent Fasting

Here are the main types of intermittent fasting that researchers have studied (Table 1). All of these methods trigger a fasting state in the body, which activates certain biological processes that may improve heart and metabolic health. (Longo, V. D., et al 2016).

3. Epidemiology: Diabetes, CVD, and Diet in the U.S.

3.1 Diabetes and Obesity

Another element that could connect IF to worse cardiovascular outcomes is loss of body weight. A 12-week hypocaloric TRF regimen resulted in a higher reduction of Body weight than a traditional hypocaloric diet according to an RCT conducted on individuals who were overweight or obese. The loss of skeletal muscle mass was the main cause of the body weight drop which accounted for almost 65% of the total weight loss. This is significantly more than the usual 20-30% range seen with regular hypocaloric diets. Decreased events and cardiovascular death. These results emphasize the need for caution while evaluating IF for people who are susceptible to sarcopenia including cancer patients and the elderly. (Bhuiyan, M. R. H., et al 2022) How common it is: Over 37.3 million people in the U.S. have diabetes, and most of them (90–95%) have type 2 diabetes. (Heald, A. H., et al 2020) Connection to obesity: About 40% of U.S. adults are obese, which is the biggest risk factor for developing type 2 diabetes. (Virani, S. S., et al 2023).

3.2 Cardiovascular Disease Burden

One of the biggest gaps in nutrition research has been identified as the lack of observational studies examining the impact of long term IF use on cardiovascular health. Interestingly an eating widow longer than 11 hours is linked to a decrease cardiovascular disease (CVD) mortality rate in persons with heart failure according to a recently published observational analysis of data from the national health and nutrition examination survey. (Patterson, R. E., et al 2017) Similarly, scientist suggested that following an 8-hour TRF scheduled is linked to a 90 % higher risk of CVD death among a cohort of more than 20 000 adults in their independent preliminary analysis of NHANES data given at 2024 American heart association conference. People with preexisting heart issues were shown to have a notably higher mortality risk. These studies raise questions about the long-term effects of IF on cardiovascular health despite possible drawbacks such confounding variables and reliance on self-reported data that could introduce mistakes. (Woodruff, R. C., et al 2024) However, Heart disease causes around 695,000 deaths each year in the U.S. [9]. People with diabetes are twice as likely to develop heart disease, which leads to many early deaths. (Bhuiyan, M. R. H., et al 2022)

3.3 Dietary Patterns

According to an RCT conducted on obese patients who were metabolically fit the restricted window for eating during IF may cause them to consume more on fast days. By incorporating more gratifying rather than nutritionally balanced options this practice known as reward-based eating may lower the quality of the diet as a whole. In fact, several research have shown that those following IF regimens consume more sweets and meat, less fiber and less cognitive restraint than people following continuous calorie restriction. (Carter, S., et al 2018) We hypothesize that reward eating may be responsible for at least some of the cases of poor food quality. The higher levels of LDL cholesterol a risk factor for CVD observed in obese individuals undergoing a 12-month ADF but not in patients on a continuous hypocaloric diet may potentially be explained by poor dietary choices. People who follow IF also tend to consume more protein which may help them feel fuller for longer. Increased consumption of animal protein has been 

connected to cardiovascular disease and all-cause mortality despite the fact that plant-based protein sources are proven to improve cardiovascular health. It is anticipated that excessive consumption of animal-based foods such as red meat eggs and dairy will raise choline and carnitine intake which will then trigger the liver and gut microbiota to produce trimethylamine-N-oxide. (Woodruff, R. C., et al 2024) Significant adverse cardiovascular events and an increased risk of atherosclerotic CVD are linked to elevated levels of circulating TMAO. Elevated TMAO levels have been observed in obese individuals receiving 5:2 IF for 4 weeks despite the fact that a clear correlation between extended IF and TMAO has not been proven. However, the typical American diet is high in processed carbs, unhealthy fats, and sugary drinks. This kind of eating increases the risk of both diabetes and heart disease. (Mozaffarian, D., et al 2019) Intermittent fasting is being studied as a way to help reverse these effects.

4. How Intermittent Fasting Helps with Metabolism and Heart Health

Cells use glucose and fatty acids as their primary sources. Following meals fat stored as triglycerides in adipose tissue while glucose is used as fuel. Triglycerides are converted to glycerol and fatty acids during fasting which are then used as fuel. During fasting the liver transforms fatty acids into ketone bodies which serves as a significant source of energy for several tissues including the brain. Human blood levels of ketone bodies are low when eaten but they rise 8 to 12 hours after fasting begins and reach 0.2 to 0.5 mM. (Jaman, S., et al 2017) These levels are maintained for 24 hours and by 48 hours they have increased to 1 to 2 mM. within 4 to 8 hours of the start of fasting plasma ketone levels in rodents rise reaching millimolar levels in 24 hours. This responses timing provides some insight into when intermittent fasting regimens are optimal for fasting. The three intermittent fasting methods that have been examined the most in humans are daily restricted feeding, 5:2 intermittent fasting and alternate day fasting. Diet that drastically cut calories on one or more days of the week (for example cutting to 500-700 calories per day) cause ketone bodies to rise on those days. (Jaman, M. S., et al 2017) A lower respiratory exchange ratio is the result of the metabolic shift from using glucose as a fuel source to using fatty acids and ketone bodies. This suggests that energy from fatty acids and ketone bodies is more metabolically flexible and efficient. Ketone bodies are powerful signaling molecules that have a significant impact on organ and cell activities making them more than merely fuel for fasting periods. (Kahleova, H., et al 2019) Numerous proteins and compounds that are known to affect aging and health are regulated in their expression and function by ketones. These include ADP ribosyl cyclase sirtuins, PARP1, NAD+, PGC1 alpha. The ketone bodies generated during fasting have a significant impact on systemic metabolism by affecting these key physiological pathways. Additionally, ketone bodies promote the production of brain derived neurotrophic factor gene which may have consequences for mental health as well as neurodegenerative and psychiatric conditions. The clinical benefits of intermittent fasting on these metabolic processes are summarized in Table 2 and Table 3. However, Better Insulin Sensitivity: During fasting, the body produces less insulin, which helps cells respond to it more effectively. (Jaman, S., et al 2023) Weight Loss: IF naturally reduces calorie intake and helps the body burn fat, leading to weight loss and lower BMI. (Trepanowski, J. F., et al 2017) Improved Cholesterol: IF can lower harmful fats in the blood like triglycerides and LDL (bad cholesterol), while increasing HDL (good cholesterol) (Varady, K. A., et al 2019) Lower Blood Pressure: Some studies show that IF can slightly reduce both systolic and diastolic blood pressure. (Jaman, M. S., et al 2017) Less Inflammation: IF reduces inflammation markers like CRP, IL-6, and TNF-a, which are linked to chronic diseases. (Jamshed, H., et al 2019) Better Body Clock Alignment: Time-restricted eating (TRF) helps sync eating patterns with the body’s natural rhythms, improving how the body processes food. (Jaman, M. S., et al 2023).

5. Risks and Limitations

While IF has many benefits, it’s not suitable for everyone: Low Blood Sugar Risk: People with diabetes who take insulin or sulfonylureas may experience hypoglycemia. (Maniruzzaman, M., et al 2025) Hard to Stick With: Social habits and cultural food practices can make IF difficult to maintain. (Gabel, K., et al 2019). Eating Disorder Concerns: IF may not be safe for people with a history of disordered eating. (Levitsky, D. A., et al 2020) Lack of Long-Term Data: Most studies last less than a year, so we don’t yet know the long-term effects. (Lowe, D. A., et al 2020).

6. Policy, Equity, and Clinical Recommendations

To make IF more accessible and effective for everyone, the following steps are important: Educate Healthcare Providers: Doctors and dietitians need training to guide patients safely. (American Diabetes Association. 2022) Cultural Adaptation: IF plans should respect different cultural and religious eating habits. (Kumanyika, S. K. 2019) Insurance Support: Health insurance should cover nutrition counseling for IF. (Jaman, M. S., et al 2024) Public Awareness: Campaigns should promote not just healthy foods, but also healthy eating times. (Frieden, T. R., et al 2021).

7. Future Research Directions

Although there are some translational constraints from data that is now available and possible issues with the repetitive relocation of immune cells away from their prefasting location and potential influences of fasting induced immune cell redistribution on vascular function is intriguing. First the majority of the information that is currently available comes from research that looked at immune cell distribution in response to a single fasting refeeding cycle which might have immunologic consequences that are distinct from those of long term IF. (Jaman, M. S., et al 2017) Investing whether prolonged IF caused immune cell changes that lessen their propensity to migrate with repeated exposure is crucial. In contrast researcher demonstrated that when mice fasted for 24 hours every day for two weeks and the number of circulating monocytes decreased during each fasting window. This suggests that immune cells do not adjust to fasting response and continue to migrate to the bone marrow following each fasting episode. These finding further suggest that higher frequency IF regimens (5:2, ADF) may improve vascular outcomes through more regular redistribution of inflammatory vascular associated immune cells. (Patterson, R. E., et al 2017) Second more through research is needed to examine the connections between fasting immune cell redistribution and vascular health even if data indicates that humans experience this phenomenon. Using sophisticated in vivo and ex vivo labeling techniques to assess the immune cell subsets that vanish from circulation during fasting and resurface during refeeding an IF clinical study in patients with vascular dysfunction would be the most sensible next step. This would make it possible for scientists to clinically link alterations in vascular function to the redistribution of immune cells brought on by fasting. (Levitsky, D. A., et al 2020) Furthermore vascular associated immune cell redistribution may have cell specific advantages for vascular function. In order to control arterial stiffness. Scientist demonstrated that functionally distinct macrophages that are LYVE-1 positive and linked derived from bone marrow progenitors engages smooth muscle pericellular hyaluronic acid to decrease collage production by matrix metalloproteinase-9. (Longo, V. D., et al 2016) Additionally, researcher demonstrated that NK cells that were refed and returned to the spleen released more IFN-? mediated vascular dysfunction because NK cell IFN-? aggravates endothelial dysfunction. Therefore, even if the redistribution of certain immune cells may not have vascular benefits study is required to ascertain whether the redistribution of immune cells caused by fasting of several immune cell subsets supports a net benefit to vascular health. Then in order to optimize the cardioprotective advantage medications and other strategies could be created to take advantage of the redistribution of particular immune cells. However, more research is needed to fully understand and improve IF. Long-Term Studies: Trials lasting more than 2 years to see how IF affects heart health over time. (Bhuiyan, M. R. H., et al 2023) Diverse Populations: Studies should include people from different ethnic and income backgrounds. (Carnethon, M. R., et al 2019) Digital Tools: Apps and wearables can help people stick to IF and track progress (Direito, A., et al 2020) Biological Mechanisms: More research is needed on how IF affects gut bacteria and body clocks  (Zarrinpar, A., et al 2018).

8. Discussion

56 randomized controlled studies from 2013 to 2024 were used in this systematic review and network meta-analysis to synthesize the data on the impact of different IF techniques on cardiovascular disease risk variables. The results showed that various forms of intermittent fasting considerable decreased body weight, fat free mass, waist circumference, LDL levels, blood pressure and FPG in comparison to a typical diet. (Jaman, M. S., et al 2017) With high or moderate certainty of the evidence and the mADF was determined to be the most effective intervention for lowering cardiovascular risk variables such as weight, waist circumference, SBP and DBP. Time restricted eating was the most successful intermittent fasting regimen for lowering FPG and fat free mass when compared to a regular diet. (Jamshed, H., et al 2019) Moreover, PF was superior to a usual diet in reducing LDL levels. ADF did not show convincing evidence of superiority to a usual diet to reduce cardiovascular risks except for weight. When comparing each other mADF is more effective than ADF in reducing SBP and SBP. Similarly, TRE and PF are more effective than ADF in reducing DBP. Additionally, TRE is more effective in reducing FPG compared to PF and CER. (Levitsky, D. A., et al 2020) These findings are consistent with earlier studies. Demonstrating the intermittent fasting methods potential for weight management. These results support intermittent fasting potential as a successful weight loss or waist circumference reduction strategy. (Kumanyika, S. K. 2019) The possible negative impact of intermittent fasting on fat free mass loss which can harm physical function and cardiometabolic health is one of the issues surrounding this practice. The evidence for this effect was inconclusive though while some studies found no effect on fat free mass others showed that it increased and still others found that intermittent fasting drastically decreased fat free mass. Two intermittent fasting techniques TRE and PF showed a significant decreased in fat free mass while the others two techniques mADF and ADF showed no discernible decrease. However, most intermittent fasting techniques do not significantly vary in terms of fat free mass reduction when compared to CER. (Carnethon, M. R., et al 2019) It’s crucial to remember that different weight loss techniques all result in decreased in fat free mass. This emphasized how important it is to have a sophisticated grasp of the physiological alteration brought on by various intermittent fasting techniques. As a part of lipid profiles LDL cholesterol is another significant risk factor for cardiovascular disease. The impact of the various intermittent fasting techniques on LDL cholesterol varied according to our research. Notably LDL levels were significantly reduced by the PF regimen. This is consistent with a prior study. Other research however, has not consistently proven that intermittent fasting reduces LDL in comparison to a regular diet. (Levitsky, D. A., et al 2020) Significant drops in SBP and DBP were observed in our study using a variety of intermittent fasting techniques such as mADF, PF and TRE. These results show some agreement with earlier meta-analyses. IF was associated with a considerable drop in DBP in some people but not in others. Similarly, while some meta-analyses revealed no effect another meta-analyses. IF was associated with a considerable drop in DBP in some people but not in others. Similarly, while some meta-analyses revealed no effect another reported that intermittent fasting decreased DBP. These differences underline the need for more account each person’s unique risk factors and medical problems. The decrease of blood glucose levels or glycemic management is another possible advantage of intermittent fasting. According to our research the TRE technique dramatically lowered FPG levels. (Virani, S. S., et al 2023) These results do not however fully align with earlier studies. IF was found to significantly lower FPG in certain meta-analyses but not in others when compared to regular eating.  The disparity may be explained by variations in the number of studies (some having fewer studies) and the length of the intervention (some having shorter studies) as well as by certain analyses that combined several intermittent fasting techniques. It is believed that the metabolic shift that occurs during fasting from the use of carbohydrates to the oxidation of fat and ketones is at least partially responsible for the underlying processes of the effect of fasting on cardiovascular risk factors. Carbohydrates and fats are stored in the muscles adipose tissue and liver during regular meals. In contrast to continuous eating the body uses stored fat and glycogen for energy during fasting which leads to a more frequent cycle of storing and burning nutrients, metabolic flexibility and weight loss. (Direito, A., et al 2020) Better insulin sensitivity greater fat burning and weight loss are just a few of the health benefits that result from this since it makes the body more adaptable in how it uses energy. To precisely understand how particular intermittent fasting patterns impact fat turnover and breakdown as well as how they impact total caloric expenditure more research is necessary. (Zarrinpar, A., et al 2018).

9. Conclusion

CVDs and fasting are closely related. Fasting may help reduced a populations cardiovascular risk and according to available data. This is accomplished by lowering body weight and inflammatory biomarkers improving insulin resistance improving metabolic syndrome signs and enhancing the lipid profile. These findings are valid for all forms of fasting including protein restriction time restricted eating continuous fasting, CR and intermittent fasting. These findings are groundbreaking since no prescription during drug has such a profound impact on such a broad range of cardiometabolic risk factors. (Longo, V. D., et al 2016) When regular exercise is paired with fasting regimens and the effects is more noticeable, before drawing a final judgement more thorough data must be gathered through additional clinical trials and case control studies including larger sample sizes, we must carefully look at all possible negative effects of fasting on health. However, Intermittent fasting is a promising and science-backed way to improve blood sugar control and reduce the risk of heart disease in the U.S. While it’s not the right fit for everyone, it can be a powerful tool when used carefully. With proper medical guidance, cultural sensitivity, and supportive policies, IF could help address the growing problems of diabetes and cardiovascular disease. Researchers are requested to find its adherence, long term safety and popular diversity in future research.

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