Authors: Aadhitya Balaji, Maxence Lam, Nicholas Smemoe, and Ritvikka Sureshkumar
Mentor: Danish Malik. Danish is currently a medical student at the University of Oxford.
Abstract
Type 2 diabetes exerts a considerable global health burden and is the most expensive chronic condition in the USA. Its management is multifaceted, with a mixture of pharmacological, lifestyle, and surgical interventions being used worldwide. This review paper compares the pharmacological and lifestyle interventions for type 2 diabetes, and their relative roles in the treatment of the disease. It finds that lifestyle and pharmacological interventions can be useful in various areas of concern for type 2 diabetes, like mortality rates, morbidity rates, reversibility, side effects, and adherence. Lifestyle interventions are shown to be very effective in reducing mortality rates, as well as the rate of complications, however, these effects are greatly increased when combined with pharmacological interventions. On the other hand, we see that the treatment compliance for both intervention types have issues. Compliance is crucial for the efficacy of either intervention type so that patients can get the benefits of the treatment. Treatment cost and patient burden are factors that can have an influence on patient adherence. Overall, these findings showcase that the best approach for treating this condition is a joint approach, with a combination of pharmacological and lifestyle interventions.
Introduction
Type 2 diabetes (T2D) has a massive global health burden, with around £10 billion a year spent on it annually by the National Health Service alone (NHS England, 2022), making up 10% of the NHS’s budget. It is a condition of abnormal blood glucose regulation, leading to patients suffering from symptoms such as polydipsia, polyuria, fatigue, and weight loss. T2D makes up 90% of all diabetes mellitus cases, with 462 million cases in 2017 (Khan et al., 2020). There is a build of insulin resistance in the body, which means that organs and cells in the body do not respond to insulin properly. Insulin increases the rate of uptake of glucose out of the bloodstream and reduces the rate of glucose conversion or breakdown. The consequence of this trend is a build-up of glucose in the bloodstream and hence high blood glucose levels (CDC, 2022). This occurs mainly due to lack of exercise, obesity, a poor diet, as well as having an important genetic component. If not managed properly, the long-term complications of this disease can be devastating. It’s linked to an increased risk of cardiovascular disease, cerebrovascular disease, foot amputations, vision loss and nephropathy (National Health Service, 2020).
Management of T2D is multifaceted, with a mixture of pharmacological and lifestyle interventions being used worldwide. Some examples of lifestyle interventions include dieting and exercise, where it is not necessary for the patient to take medication. Pharmacological interventions are the opposite, where the patient does take medication, like Metformin, Gliclazide, Dapagliflozin, or Exenatide (National Health Service, 2020). Some of the major pharmacological interventions used in T2D management are outlined in the table below (table 1). It should be noted that while lifestyle and pharmacological interventions are the main groups of management for T2D, other treatment types exist, including natural remedies and surgery.
Table 1: Pharmacological options for T2D and their mechanism of action.
Pharmacological Intervention for T2D | Mechanism of Action | Side Effects | Sources |
Metformin | Not fully understood– changes the composition of gut microbiota and the AMP-activated protein kinase to decrease lipopolysaccharide levels in circulation and the liver in which it inhibits gluconeogenesis | Gastrointestinal (anorexia, nausea, abdominal discomfort), Lactic Acidosis | Marin-Penalver et al. (2016) Team (2023) |
Exanatide/ Exendin-4 | Binds to the intact human Glucagon-like peptide-1 receptor (GLP-1R) - facilitates glucose control and helps with weight loss by augmenting pancreas response, suppressing pancreatic release of glucagon, slowing down gastric emptying, reducing appetite and reducing liver fat content. | Gastrointestinal (acid or sour stomach, belching, diarrhoea, heartburn, indigestion, nausea, and vomiting.) Dizziness, headache, and feeling jittery. | Koole et al. (2017) Bunck et al. (2009) Shyangdan et al. (2011) Thornton (2023) Drugs.com (n.d.) Ezzo and Ambizas (2006) |
Sulfonylureas | Closes ATP-sensitive K-channels in the β-cell plasma membrane, initiating a chain of events leading to increased insulin release. | Hypoglycaemia Weight gain Nausea Erythema Multiforme Exfoliative dermatitis Photosensitivity | Sola et al. (2015) Ashcroft (1996) GoodRx (2023) |
Gliclazide | Binds to sulfonylurea receptors on the surface of pancreatic beta cells, decreasing K+ ion efflux, and increasing Ca2+ influx, leading to insulin release. | Hypoglycaemia in 12% of patients. Viral infection in 6-8% of patients. Hypertension in 3-4% of patients. | Megarbane et al. (2021) Schernthaner et al. (2004) |
This review will compare the success of pharmacological and lifestyle intervention treatments through the survey of various metrics, in order to identify the best treatment algorithm for this condition. To do so, many existing studies, systematic reviews, and meta-analyses will be examined and explained in detail. We aim to look at various different aspects of the treatments, including mortality rates and life expectancy; morbidity and complications; reversibility and glycaemic control; and adherence and side effects. By comparing these different parameters, we aim to elucidate the strengths and weaknesses of both types of intervention and define the best way of managing this condition.
Literature Review
Mortality Rates in Pharmacological and Lifestyle Interventions
A common factor used to determine the efficacy of a T2DM medication is mortality rates and life expectancy. One study by Australian researchers was an assessment, review, and comparison of data obtained from previously existing studies (Yuen et al., 2010). This paper reviewed 4 studies comparing the change of mortality rate among many other factors in lifestyle versus medicinal treatment, concerning 5196 participants. The study concluded that intensive lifestyle altercations were more effective in decreasing HbA1c levels and decreasing mortality rates than normal pharmacological treatment, but less intensive lifestyle changes weren’t as effective. Thus, we can recognise that lifestyle treatment is an effective mechanism to combat T2DM and reduce mortality rates as long as it is done intensively, however, the strength of this method otherwise falls. It’s also worth noting that the authors recognised a limitation of this study, as comparisons could not be made for lifestyle + pharmacological versus pharmacological alone as there were insufficient trials.
While the previous paper had some limitations, its conclusions were further corroborated by another study (Kianmehr et al., 2022). This study used the predictive microsimulation BRAVO model (Building, Relating, Assessing, and Validating Outcomes) to evaluate the potential lifespan increase of T2DM patients, comparing purely pharmacological treatment and lifestyle changes. The evaluation revealed that the most change was seen in obesity levels, metabolic syndrome components and values relating to physical activity, and in all of these components, lifestyle change was more effective than pharmacological medications such as metformin. The study additionally revealed that life expectancy changes also roughly doubled in lifestyle as compared to pharmacological interventions. Consequently, this study reinforces that mortality rate diminishes best in lifestyle-related changes. While this shows well-founded evidence, the backing of other studies or meta-analyses could further reinforce its results. Even though this study is quite equitable, there are some minor flaws. The most prominent detail is the fact that the researchers were unable to distinguish type 1 from T2D as the database record for type 1 was identical as the record for T2DM. Lastly, patients with a history of cardiovascular disease were excluded in the trials, which may limit the range of results obtained.
These studies' findings were further reinforced by a Japanese group, who showed that a more intensified lifestyle change leads to increased efficacy in preventing cerebrovascular events and reducing mortality rates. They conducted a randomised trial to determine whether intensive care was significantly more effective than standard therapies in reducing macrovascular complications and mortality rates (Ueki et al., 2017). Participants aged between 45-69, spread over 81 clinical sites in Japan, randomly undertook conventional or intensive lifestyle treatments to reduce HbA1c levels and lipid control. The primary measure of results was composites of T2DM-causing diseases, blood glucose levels, and mortality rate changes. In a post-hoc breakdown, frequencies of all-cause mortality and coronary events were found to be the same in both groups. However, the researchers also found that average HbA1c, systolic blood pressure, diastolic blood pressure, and LDL cholesterol concentrations were significantly lower in the intensive therapy group than in the conventional therapy group, as well as cerebrovascular events such as stroke and carotid endarterectomy which were significantly less frequent in the intensive therapy group. Hence, this study proves that an intensive lifestyle is more effective in lowering the HbA1c levels and cerebrovascular risk in T2DM individuals but leads to no significant change in mortality rate compared to standard lifestyle care.
Moreover, a long-term study conducted in Da Qing, China, aiming to assess the effects of lifestyle interventions on individuals with impaired glucose tolerance, also supported the efficacy of lifestyle interventions. The study involved 577 adults receiving medical care from 33 clinics. These clinics were randomly assigned to either provide standard care or one of three interventions: diet, exercise, or a combination of both. The participants were followed for up to 30 years to evaluate the impact of the interventions on various outcomes. After 30 years of follow-up, the combined intervention group experienced significant benefits compared to the control group, such as a higher median delay in the onset of T2DM, average increase in life expectancy, lower incidences of microvascular complications, and fewer cardiovascular disease events & deaths. Thus, these findings strongly support the implementation of lifestyle interventions to combat T2DM, and its associated consequences and raise life expectancy levels in individuals with T2DM. However, the long length of the study may mean that there could be a high chance of infrequent and inaccurate information. Adherence in patients also usually drops dramatically in long periods of time, meaning that some results may be erroneous.
Another study that aimed to evaluate the association between a healthy lifestyle and mortality among individuals with T2D also deemed that lifestyle interventions were quite effective in reducing mortality risk in individuals with T2DM (Han et al., 2022). A study conducted using data from the UK Biobank included 13,366 participants with baseline T2DM who were free of cardiovascular disease and cancer, and lifestyle information was collected through a baseline questionnaire, focusing on seven low-risk factors mentioned in diabetes management guidelines: no current smoking, moderate alcohol consumption, regular physical activity, healthy diet, less sedentary behaviour, adequate sleep duration, and appropriate social connection. During a median follow-up of 11.7 years, a total of 1,561 deaths were documented, including deaths from cancer, cardiovascular disease, respiratory disease, digestive disease, and neurodegenerative disease. The highest percentile of the people who died had a low or very low lifestyle score (1 or 2 out of 7). The study found that each lifestyle factor was significantly associated with all-cause mortality. Participants with a higher lifestyle score (scoring 6-7 out of 7) had a lower risk of all-cause mortality, as well as mortality specifically related to cancer, CVD, respiratory disease, and digestive disease. Hazard ratios associated with the lifestyle score indicated a reduced risk of mortality across these categories. Also, the association between a healthy lifestyle and mortality remained consistent regardless of factors reflecting diabetes severity, such as microvascular disease. In conclusion, this paper reinforces the above paper’s claim that lifestyle interventions are very effective and clears all doubts about both papers’ findings that non-pharmacological treatment is also effective in reducing mortality rates.
However, there is also some evidence showing the role of pharmacological interventions in reducing mortality risk. A meta-analysis study was conducted which aimed to evaluate the overall cardiovascular risk associated with metformin treatment in patients with T2DM (Zhang et al., 2020). The researchers conducted a comprehensive search of the PubMed, Embase, and CNKI databases to identify relevant studies, in which they analysed 16 studies encompassing 25 comparisons involving a total of 1,160,254 patients with T2DM and 701,843 patients following metformin treatment. The results of the meta-analysis demonstrated a statistically significant decrease in cardiovascular risk associated with metformin treatment in patients with T2DM. It also showed a decreased risk of mortality and incidence of cardiovascular events following metformin treatment. Consequently, we can see that pharmacological interventions such as metformin can also be very effective in raising life expectancy and reducing mortality rates, similar to the potency of lifestyle interventions, and therefore could also be quite a viable treatment option.
Morbidity Rates in Pharmacological and Lifestyle Interventions
In the context of T2D, morbidity refers to the negative health effects and conditions associated with the disease. Since diabetes is such a major health problem, it is important to analyse its pathophysiology to prevent the onset of microvascular or macrovascular complications. T2D, in particular, is highly correlated to obesity and is usually a result of impaired insulin secretion and/or resistance. Consequently, T2D is especially common in individuals with obesity and puts them at a higher risk for developing cardiovascular diseases. There are many available treatment options that are categorised under either lifestyle or pharmacological intervention. Lifestyle interventions like intensive weight loss therapies and DSE (diabetes support and education) as well as pharmacological interventions such as anti-diabetic drugs and insulin injections all work to help reduce diabetes symptoms and maintain optimal blood glucose levels. Nevertheless, it remains a matter of inquiry to see which of these techniques is more efficacious in tackling the consequential complications associated with Type 2 Diabetes (T2D).
As mentioned earlier in the context of mortality, the long-term effect of lifestyle interventions on morbidity was assessed in a randomised control trial across 33 clinics in Da Qing, China. The objective of this study was to test how efficiently implementing the suggested lifestyle changes would decrease complications for the participating subjects (Gong et al., 2019). Three experimental groups were created, and each was assigned to some form of a lifestyle intervention: diet, exercise, or diet and exercise. 30 years later, the findings were analyzed and they strongly indicate that the group with the combined intervention showed the most promising results. Following a strict diet and exercise plan is comparatively better than just one as it leads to a lower incidence rate of microvascular complications plus a decrease in the number of cardiovascular deaths. This conclusion is corroborated in The Look Ahead, one of the longest lifestyle-based weight loss intervention trials conducted to this day (Gregg et al., 2018). Its main purpose was to compare two methods: ILI (intensive lifestyle intervention) to DSE (diabetes support and education). Unlike the Da Qing trials, The Look Ahead focused on lowering physical disability because it inhibits healthy aging and leaves a patient more vulnerable to morbidity. The ILI group had a 0.8% lower incidence of physical disability than the DSE group per year which also suggests that lifestyle interventions are somewhat successful in lowering diabetes-related complications.
Some of the many complications that come with T2D include blindness, amputations, and kidney disease. All of which the anti-diabetic drugs and other forms of pharmacotherapy aim to resolve or at least manage. The United Kingdom Prospective Diabetes Study (UKPDS) was a randomised control study conducted to assess whether or not enhanced glycaemic control would reduce microvascular complications. Over the course of 10 years, the patients in the study were given either a diet-based treatment plan or a prescription of insulin or sulfonylurea. Analysis of the two different groups revealed that patients following the pharmaceutical treatment plan had 12% fewer diabetes-related endpoints and a 25% decrease in microvascular endpoints (Taylor et al., 2021). The data suggested that the implementation of medicine had more of a benefit for the patient, and the potential of chronic complications was better managed with the drugs rather than the lifestyle change. While the drug option did decrease the risk of complications, it was also associated with increased weight gain and hypoglycemia. This should be considered when comparing it to the lifestyle intervention treatment because a healthy, controlled diet actually helps with weight and glucose levels.
To further investigate the link between weight and antidiabetic drugs, a systematic analysis that compared 3 classes of groups of drugs was performed. Drugs were categorised into strong effect, moderate effect, and mild effect; and their effect on weight loss was recorded. Tackling obesity is a critical component of treating T2D because it will improve overall health and decrease the risk of cardiometabolic risk factors such as hypertension or raised fasting plasma glucose. The results of the study indicated that metformin, acarbose, empagliflozin, and exenatide resulted in a mild weight loss of less than 3.2% of initial weight (Lazzaroni et al., 2021). Evidently, pharmacological interventions aren’t as effective as intensive lifestyle interventions in terms of weight loss. This is an issue that’s currently subject to a lot of research, since drugs have been shown to me very effective in controlling glucose levels, but more needs to be done to show the efficacy of pharmacological measures in controlling weight. The newer non-insulin medications such as GLP1-RA and Tirzepatide have been shown to be more effective in maintaining body mass index, but metformin still tends to be the first choice of prescription.
A meta-analysis consisting of 16 studies with a total of 1,660,254 patients actually validates this notion, and its main result was that metformin significantly decreased cardiovascular risk in the studied patients (Zhang et al., 2020). Common cardiovascular risks associated with T2D such as diabetic cardiomyopathy will negatively impact a patient’s life expectancy. Metformin has been shown to play a role in reducing the risk of development of such cardiovascular diseases, both with mortality and incidence. This just goes to show that metformin is a beneficial drug because if it is implemented with proper lifestyle intervention, a patient will have reduced microvascular and cardiovascular complications. However, metformin isn’t as efficient in weight loss as other drugs. All things considered, lifestyle intervention combined with pharmaceutical intervention is the optimal option as the diabetes-related complications that comes with T2D are significantly decreased. Each intervention type on its own has its benefits and drawbacks, but together they help maintain optimal weight and glucose levels as well as reduce microvascular and cardiovascular complications.
Reversibility of the Disease
T2D is a reversible condition and there are a wide variety of recommendations and methodologies for this, and a primary option is Glycaemic control. Glycaemic control is the homeostasis of blood glucose levels in a certain range to prevent hypoglycaemia and hyperglycaemia (He et al., 2022). Hypoglycaemia is the condition of having too little sugar in the bloodstream, and hyperglycaemia is the condition of having too much sugar in the bloodstream, and both conditions are often found in comorbidity with Type 2 Diabetes (National Library of Medicine, 2020). If glycaemic control is maintained in diabetic patients, this can improve upon glucose utilisation, better physiologic insulin administration, as well as avoidance of fluctuations in the blood concentration of both insulin and glucose (Nissenson et al., 2023). Thus, glycaemic control is crucial in the reversibility of Type 2 Diabetes.
One lifestyle intervention that’s been shown to play a role in reversing the disease is exercise. The Cochrane collaboration performed a meta-analysis assessing the effects of exercise in the treatment of T2D, comparing various randomised control trials. It found that there was a significant improvement in glycaemic control in the groups that underwent exercise interventions, with there being marked, statistically significant decreases in their HbA1c levels (Thomas et al., 2006). Thus, we can see that exercise plays a role in glycaemic control and could be useful in reversibility of this disease. However, it is worth noting that it looked at trials with an intervention period of greater than 8 weeks, which isn’t a large scale of time in the context of diabetes treatment. On this note, the researchers did find that the effect on glycaemic control was greater in the shorter trials than the longer ones, suggesting that adherence could become a problem in longer-scale interventions.
The effect of exercise on glycaemic control in T2D was corroborated by a later systematic review (Rohling et al., 2016). They looked at fifteen randomised controlled trials and measured the changes in HbA1c seen in three different forms of exercise: resistance training, endurance training, and combined training. Their review found statistically significant HbA1c reductions in all three groups, further showcasing the role of exercise in glycaemic control and suggesting that lifestyle interventions can play a key part in an effective treatment algorithm for this condition. However, we should consider that this study looked at both type 1 and T2D. Therefore, the results should be reproduced in a review looking specifically at T2D to remove any differences in the data that could’ve come from intervention in the wrong condition.
Furthermore, a meta-analysis done by Sports Medicine looked at 12 trials across various databases to look at the effects of both resistance and aerobic exercise and its effectiveness and safety in patients with Type 2 Diabetes (Yang et al., 2013). The study found that while there was no significant difference between the two types of exercise, physical exercise of any kind will contribute to a reduction of HbA1c and in turn will contribute towards the reversibility of the disease. However, it is possible that further longitudinal studies will yield a more definitive result in terms of the difference between resistance and aerobic exercise, as the meta analysis done by Sports Medicine mostly included short-term trials from 8 weeks to 6 months. Additionally, most of the trials looked at had methodological limitations of some sort, but the conclusions that exercise can provide better glycaemic control and HbA1c reduction are still valid due to the statistical significance of the data.
Lifestyle intervention can improve glycaemic control but sometimes may struggle in long-term benefits, whereas some pharmacological solutions can provide similar benefits but on a long-term scale. The Regulatory Peptides journal found that Exenatide (a synthetic exendin-4), glucagon-like peptide-1 (GLP-1), and GLP-1 analogues could pharmacologically improve glycaemic control in diabetic patients (Nielsen et al., 2003). This journal looked at in vitro studies and in vivo studies on rats and large mammals, finding that all three types of drugs significantly helped with glycaemic control. Additionally, the study found that both exendin-4 and GLP-1 lead to long-term improvement in glucose control, something which may be lacking in a treatment consisting of purely lifestyle intervention. While this study is promising for long-term glycaemic control, these interventions needed to be studied in human systems to be wholly applicable. Ultimately, while lifestyle interventions can be effective for short-term glycaemic control, it seems that drugs like exendin-4 and GLP-1 can provide long-term solutions for glycaemic control.
Another common lifestyle intervention suggested for reversing T2D is weight loss. The International Journal of Clinical Practice shows that weight loss can help to improve glycaemic control, cardiovascular events, microvascular events, and other comorbidities (Wilding, 2014). Patients who lose weight will reach target HbA1 values more often than those who maintain or gain weight. Pharmacology & Therapeutics also found that “lifestyle interventions such as dietary modification and/or exercise training have been shown to improve glucose homeostasis but may not normalise the disease process unless weight loss is achieved and increased physical activity patterns are established” (Hays et al., 2008), While other lifestyle interventions can certainly aid with the reversibility of T2D, weight loss is essential to reversing the disease.
However, weight loss can be difficult for patients to keep up with sustainably. The JAMA Network performed a study assigning over 5,000 overweight US adults to an intensive lifestyle-based weight loss intervention (ILI), or a diabetes support and education intervention (DSE), in order to judge the benefits from a more hands-on approach towards patients in terms of weight loss – the ILI – or taking a laxer approach – the DSE (Gregg et al., 2012). The study ultimately found that participants assigned to the ILI group surpassed those assigned to the DSE participants in year 1 and year 4, the two years during which the participants were measured in terms of weight loss, activity levels, and partial or complete remission. Despite these promising findings, the study still found that complete remission/glucose normalisation through ILI is rare without drugs. However, partial remission without drugs is still an obtainable goal for some patients. A downfall of this study is that searching for remission was not a primary objective for the study, so the data and analysis on remission are exploratory, although the remission confidence intervals were extremely statistically significant, it is likely that the findings are still accurate.
A systematic analysis performed by Pharmacological Research found similar results that lifestyle-based weight loss strategies are not long-term effective (Lazzaroni et al., 2021). Instead, the analysis looked at non-insulin glucose-lowering drugs for weight loss in regards to their kilograms lost on average, their effect on body mass index and body composition. The analysis found that the GLP-1 RA class drugs are the most effective in inducing weight reduction in diabetic patients, but drugs like metformin, acarbose, and SGLT-2 I can all be effective for weight reduction. Since drugs can be taken continuously without much physical effort to the individual, drugs can provide the sustainability sometimes not achievable just through lifestyle interventions that are needed for a more reliable, long-term solution for weight loss.
While pharmacological treatment can be effective for long-term weight loss, some common pharmacological treatments can cause weight gain (Apovian et al., 2019). For example, drugs like thiazolidinediones, insulin secretagogues (sulfonylureas, meglitinides), and insulins are often associated with weight gain. The research looked at twelve different common types of medications, including metformin, GLP-1, and DPP-4i, along with the previously mentioned medications. It found that some medications like Metformin and GLP-1 lead to weight loss, medications like DPP-4i generally result in neutral weight loss/gain, and the previously mentioned medications can lead to weight gain. Ultimately, the research shows that antidiabetic medication needs to be tailored to the patient in order to not unintentionally slow the reversibility process due to weight gain caused by pharmacological treatment.
Adherence and Side Effects
When comparing pharmacological and lifestyle treatment for T2D, side effects, and adherence are crucial factors. One study analysed the patient’s perspective regarding lifestyle treatment and gathered qualitative data from patients to measure the level of adherence toward the treatment (Frandsen & Kristensen, 2002). Groups of diagnosed T2D patients above the age of forty were gathered, and the researchers led discussions across many different countries. The discussions led were based on the impact that T2D had on the patients and their compliance toward treatment. After discussions, patients filled out forms about eating habits and information sources. The study found that most patients had difficulty adhering to lifestyle-centred treatments, such as dieting. It mentions that the lack of comprehensive education and reasoning about lifestyle therapy for the patients could lead to a lack of participation and misconceptions, showing that patients can have a low level of adherence to lifestyle treatment. However, this study could be flawed as the data collected was self-reported patient information. In addition, the population of patients sampled were all over the age of 40, which doesn’t cover the younger population of T2D patients. Regardless of the limitations, other studies have drawn similar conclusions.
One study analysed the role of financial conditions in adherence to lifestyle intervention treatment for T2D patients (van Gils et al., 2011). Although it also used self-reported information from the patients, it used a conjoint analysis, requiring people to decide which aspects of the lifestyle treatment they found more important. However, it is noteworthy that this study has a small sample size of 174 observations. Patients were given a copayment (negative financial incentive) or a bonus (positive financial incentive) for the treatment and measured the willingness of the patients to participate in the lifestyle intervention between the two incentives. It found that copayments decreased the amount of adherence toward the lifestyle intervention programs and that bonuses did have a slight increase in adherence, but this wasn’t as impactful as the negative incentives. The study indicates that cost is a factor in the adherence of T2D patients for lifestyle interventions and that bonuses could be used to help increase the motivation of patients to adhere. This is in line with the previously mentioned study, in that patients have a hard time adhering to the lifestyle intervention treatments. However, it does indicate that there are solutions to fix the issue of lifestyle adherence in bringing up the bonuses.
There are a multitude of factors that could lead to decreased adherence in T2D patients for lifestyle treatment, including factors that only appear in certain populations. A review of the efficacy of lifestyle treatment for youth T2D patients found that while lifestyle treatment could be effective, there were some issues with younger patients that placed limits (McGavock et al., 2014). The study concluded that its research could not support the success of lifestyle treatment due to younger T2D patients facing substantial amounts of mental health issues and social adversity. The treatment adherence for younger patients could be decreased due to these matters. For instance, mental health issues can result in decreased motivation to take part in physical activity or diet. The study explains that the success of lifestyle treatment for younger patients wasn’t clear during their investigation due to these factors. This helps support that a factor of treatment efficacy is treatment adherence.
Low adherence isn’t only a problem for lifestyle interventions, as it can also have an effect on pharmacological interventions. A review of medication adherence for T2D found that medication adherence stayed low, despite the increasing education and intervention about the treatment (Polonsky & Henry, 2016). It explores the consequences and factors that contribute to poor medication adherence and highlights an issue in medication adherence for T2D patients. It mentions factors such as treatment burdens and patient beliefs that contribute to the decreased level of adherence. For example, the review explores the impact of dosage volume on adherence. It establishes a link between low medication adherence and high dosage volumes in many chronic diseases, including T2D. There are many other influences on medication adherence like there are for lifestyle adherence.
Another aspect of medication adherence is family support. A randomised control trial study on the impact that family support has on medication adherence for T2D patients found that providing families with support instructions and education yielded an increase in patients’ medication adherence (Khosravizade Tabasi et al., 2014). Ninety-one patients with families were selected and were tested on medication adherence, social support, and cognition. An intervention group of family members who would be educated on family support and medication adherence was set aside. These tests were conducted twice during the study, occurring once before the intervention group was educated and once after. The study showed that family support can lead to increased medication adherence. It also noted that this can indirectly help glycaemic control and cognition as patients take their medication. This study illustrates that increasing family support for patients could be a solution to low treatment adherence.
Similar to lifestyle adherence, the cost of treatment is a concern for medication adherence. One study found that the out-of-pocket pharmacy cost was negatively related to patient adherence (Bibeau et al., 2016). The study retrospectively observed a cohort in which patients were assigned to one of five cost levels. Each cost level would be measured on adherence through a sensitivity analysis. The findings of the study illustrate that the out-of-pocket pharmacy cost did have an impact on patient adherence. In the same vein as lifestyle treatment, patients do not want to have to spend large sums of money for treatment, leading to less adherence. The studies show that adherence is a problem in both lifestyle and pharmacological treatments. Treatment cost, burden, lack of education, and many other factors can contribute to this outcome. To compare the treatment types, exploring adherence is essential. However, exploring the side effects is equally crucial as it may impact adherence.
Side effects in pharmacological treatment are common. The National Library of Medicine published a review that highlights current treatment for T2D (Marin-Penalver et al., 2016). It includes both lifestyle treatments and pharmacological treatments. For each pharmacological treatment, the side effects of that treatment are summarised. For example, metformin, a widely used and accepted medication for T2D, has a chance to give gastrointestinal side effects. This includes conditions such as nausea, abdominal pain, and diarrhoea. Another commonly used treatment, sulfonylureas, has side effects such as weight gain and hypoglycaemia (low blood sugar). The review goes on to explore many other pharmacological treatments. It concludes that although many new treatment types are developing, metformin remains the primary choice of pharmacological treatment for patients. For alternative treatments, it is recommended that each patient be individualised based on complications, side effects, preference, and the properties of the treatment, among other factors. When choosing a treatment option for a patient, it is necessary to consider these factors so that patients’ adherence is not decreased. This demonstrates that side effects pose an issue in pharmacological treatment. In contrast to pharmacological treatment, the side effects of lifestyle treatment are less apparent.
Lifestyle treatment does not have any specific, widespread side effects. An important component of lifestyle treatment is dieting. It can have a positive effect on the body. However, if done wrong, it can have a negative effect. For example, a study done on people who take part in dieting and unhealthful weight control found that it can predict the outcome of eating disorders and obesity in some cases of adolescents (Golden et al., 2006). Using multiple linear and logistic regression models, it measured weight, weight control, binge eating, and self-reported eating disorders. The study demonstrates that if dieting is not done correctly, it can lead to future health issues. However, there are some limitations to this study. First, the adolescents self-reported eating disorders, which could lead to flawed data. The study only focuses on eating disorders for adolescents, meaning further research would have to be done on other populations. Also, this study does not explicitly examine people with T2D. The dieting done in lifestyle treatment for T2D could be much more organised than the dieting done by the adolescents in this study. Limitations aside, dieting can be harmful if misused. Lifestyle treatment generally has no common side effects, giving it an edge over pharmacological treatment in that regard.
Discussion
Lifestyle interventions can be very helpful in increasing weight loss, as obesity contributes to increased HbA1c levels due to increased insulin resistance. However, those who have rigidly scheduled lifestyles or are disabled in some way are unable to utilise the full potential of lifestyle changes. Meanwhile, pharmacological interventions are more dependable and less volatile than lifestyle changes and also provide overall stabler glycaemic control, but factors such as drug resistance may cause them to lose efficacy. Furthermore, many negative drug interactions such as hypotension could occur when using multiple pharmacological medications at once. Intensive interventions can be more effective than pharmacological counterparts, but the combination of result analyses has suggested that combined use of pharmacological and lifestyle would result in the best decrease in mortality rate in T2DM individuals.
Lifestyle interventions, such as dieting and exercise, play a key role in the reversibility of T2D, as they help with both weight loss and glycaemic control, which significantly increases the chances of reversibility and remission. However, while these interventions are very effective, they can sometimes be short-term, as long-term weight loss is not always sustainable without the aid of diabetic medication. In this regard, there are a wide variety of pharmacological interventions that can be used to aid in the reversibility of T2D, like metformin, GLP-1, and exendin-4. These pharmacological interventions often serve to pick up where lifestyle interventions no longer provide significant value to the patient, as they can provide more reliable and sustainable methods for weight loss and glycaemic control in a way that lifestyle interventions cannot always ensure. However, the pharmacological interventions need to be tailored to the patient, as some medications that may be helpful for the management of the disease, like insulin pumps, can lead to weight gain, resulting in more difficulty in the remission of T2D.
Looking at morbidity, lifestyle interventions such as intensive weight loss and exercise programs are helpful for lowering cardiometabolic risk and physical disability. They encourage patients to lead a healthy lifestyle and this lowers their chance of developing other related diseases. Studies have shown the efficacy of weight loss with proper lifestyle intervention, and this is useful because maintaining an optimal weight range will prevent obesity. Pharmacological interventions are better for enhanced glycaemic control and lowering the risk of microvascular complications such as retinopathy, neuropathy, and nephropathy. They are a more sustainable method and produce concrete results over a longer period of time; however, they do come with their own set of side effects and must be specialised to best fit the patient’s situation. When lifestyle intervention is combined with pharmacological intervention and implemented in an organised and balanced way, this will lead to the best results and reduction of complications.
Many studies show that both lifestyle and pharmacological interventions have trouble with patient adherence. Cost of treatment, patient motivation, and patient education and other factors can influence adherence in lifestyle interventions. Factors such as treatment burden, family support, cost, and dosage volume can influence adherence in pharmacological adherence. With an issue this complicated, conducting more research on solutions to the widespread dip in adherence is needed. Furthermore, pharmacological interventions include the risk of side effects for the patients, while lifestyle interventions don’t have major side effects. Varying from drug to drug, side effects can lead to health risks for patients. This could lead to less patient compliance.
Lifestyle interventions have been very effective in the treatment of T2D, with studies showing their role in reversibility. For example, Thomas, 2006 and Rohling, 2016 both found that exercise can be greatly helpful with glycaemic control, demonstrating that lifestyle interventions can be a useful treatment type for type two diabetes. On a different note, a study found that lifestyle interventions can delay the incidence of type two diabetes and reduce the number of cardiovascular deaths (Gong et al., 2019). This shows that lifestyle interventions are a solution for prevention and complications. In terms of mortality, a study found that the lifespan of patients increased with lifestyle changes (Kianmehr et al., 2022). The studies mentioned support lifestyle interventions as an effective treatment of type two diabetes in the areas of reversibility, morbidity and mortality. These areas are crucial for intervention methods as being able to treat the disease, reduce and/or prevent complications, and increasing lifespan are important aspects of the treatment. Therefore, lifestyle interventions are an efficacious treatment of type two diabetes.
At the same time, there are caveats of relying solely on lifestyle interventions. For example, lifestyle interventions have the limitation of generally being a short-term solution rather than a long-term solution (Nielsen et al., 2003; Lazzaroni et al., 2021; Gregg et al., 2018). Furthermore, in some cases lifestyle intervention simply cannot provide the same level of treatment that pharmacological intervention can, and in most cases complete remission cannot be achieved without pharmacological intervention (Gregg et al., 2012). Lastly, the level of lifestyle intervention has a significant effect on whether or not the treatment is successful (Hays et al., 2008; Gregg et al., 2012; Ueki et al., 2017). This can be an issue for patients if they are unable to spend the time or unable to physically complete the intensive lifestyle intervention, and in that case the lifestyle intervention recommendation would be far less effective.
When combined with pharmacological interventions, the effectiveness of the diabetic treatment is raised. For example, there is evidence that non-insulin diabetic drugs can help with weight loss (Nielsen et al., 2003; Lazzaroni et al., 2021), which can lower the risk of side effects and decrease HbA1c levels. Another study found that there was a significant decrease of cardiovascular risk and mortality rates after metformin treatment (Zhang et al., 2020), making it beneficial in preventing diseases which can be exacerbated by the presence of T2DM. Furthermore, a review paper expressed how drugs such as metformin have positive effects on cardiovascular diseases and have low risks of hypoglycaemia (Yakaryılmaz and Ozturk, 2017).
Furthermore, both intervention methods have problems with adherence, as shown by multiple studies. For example, it was found that adherence was an issue for lifestyle interventions due to a lack of comprehensive patient education (Frandsen & Kristensen, 2002). Another study found that pharmacological intervention adherence was an issue due to treatment burdens and patient beliefs (Polonsky & Henry, 2016). As mentioned before, both lifestyle and pharmacological interventions can be effective in the reversibility of the disease. However, adherence is necessary for the application of both interventions. Intensive lifestyle interventions which track patients’ progress and ensure that the treatment is being done could help increase adherence.
While adherence is an issue in both intervention methods, side effects do not have the same problem. While lifestyle interventions do not have any widespread side effects, a study on dieting found that if misused, dieting can lead to eating disorders (Golden et al., 2006). Even so, lifestyle interventions do not have the same level of side effects as pharmacological interventions. A review found that there are side effects for many drugs, such as metformin and sulfonylureas, which are used as common pharmacological interventions in the treatment of type two diabetes (Marin-Penalver et al., 2016). This reveals the contrast in the level of side effects between the two treatment types, in that pharmacological interventions have more side effects than lifestyle interventions.
Interestingly, we found that some pharmacological interventions cause weight gain, especially those that involve increasing insulin in the blood stream for the management of Type 2 Diabetes (Apovian et al., 2019). This emphasises the need for diabetic treatment to be catered and adapted to each individual patient. If a patient already struggles with weight loss, a medication with a neutral or weight loss side effect should be prescribed as opposed to one with a weight gain side effect in order to have a smoother remission process. It is essential that lifestyle and pharmacological interventions for a patient work with each other instead of against each other in order to provide a more holistic and effective treatment. On this note, we therefore see that a combinatory approach of both lifestyle and pharmacological interventions lead to the best outcomes in the treatment of this condition.
It’s worth noting that there are caveats to our findings. A recurring limitation, especially in studies on lifestyle intervention is that trials performed or surveyed have relatively short study spans (<1 year). (Yang et al., 2013) This could affect the data, as the conclusion that lifestyle interventions are only effective in the short-term could be in part due to the fact that a majority of studies on lifestyle interventions are short-term trials. Additionally, some of the studies, especially those looking at adherence, used self-reported information from the patients (Frandsen & Kristensen, 2002). A downside to using this type of data is that it could be inaccurate, leading to flawed results.
Therefore, further research needs to be done to clearly assess the direct comparison of lifestyle intervention to pharmaceutical intervention. The majority of studies that are available today focus on the efficacy of only one type of intervention. For instance, a study analysing lifestyle changes as a viable treatment option tends to compare one lifestyle change to another; the comparison of an intensive weight loss program to a strict diet plan. Likewise, a study focusing on pharmaceutical intervention would compare one class of a drug to another rather than comparing one drug to one lifestyle change. Another factor that should be given more importance in research studies is patient education and awareness. If patients are more knowledgeable on the complications and mortality of T2D, then they will be more likely to adhere to their prescribed treatment plans.
Conclusion
Type 2 Diabetes is a prevalent health issue that is characterised by high blood sugar and leads to a host of other chronic conditions such as nervous or cardiovascular damage. The prevention and management of this disease should be made a priority because it will improve quality of life for patients and prevent premature death rates. Lifestyle interventions and pharmacological interventions can both be effective in treating and managing Type 2 Diabetes depending on the circumstances of the individual patient, but generally, a combination of the two will garner the best results. Using both intervention methods in unison can help with prescribing treatment for type two diabetes patients that is more effective. Finding a common ground between treatment types is important so there can be a widespread treatment method for type two diabetes. It is worth noting that there are some limitations to our findings such as short study spans and self-reported information, so further research still needs to be done.
References
Apovian, C. M., Okemah, J., & O’Neil, P. M. (2018). Body weight considerations in the management of type 2 diabetes. Advances in Therapy, 36(1), 44–58. https://doi.org/10.1007/s12325-018-0824-8
Ashcroft, F. (1996). Mechanisms of the glycaemic effects of sulfonylureas. Hormone and Metabolic Research, 28(09), 456–463. https://doi.org/10.1055/s-2007-979837
Bibeau, W. S., Fu, H., Taylor, A. D., & Kwan, A. Y. M. (2016). Impact of out-of-pocket pharmacy costs on branded medication adherence among patients with type 2 diabetes. Journal of Managed Care & Specialty Pharmacy, 22(11), 1338–1347. https://doi.org/10.18553/jmcp.2016.22.11.1338
Bunck, M. C., Diamant, M., Cornér, A., Eliasson, B., Malloy, J. L., Shaginian, R. M., Deng, W., Kendall, D. M., Taskinen, M.-R., Smith, U., Yki-Järvinen, H., & Heine, R. J. (2009). One-year treatment with exenatide improves β-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients. Diabetes Care, 32(5), 762–768. https://doi.org/10.2337/dc08-1797
Centers for Disease Control and Prevention. (2022, June 20). Insulin Resistance and Diabetes. Centers for Disease Control and Prevention.
Drugs.com. (n.d.). Byetta prices, coupons, Copay & Patient Assistance. Drugs.com. https://www.drugs.com/price-guide/byetta#:~:text=Byetta%20Prices%2C%20Coupons%20and%20Patient,on%20the%20pharmacy%20you%20visit.
Ezzo, D. C., & Ambizas, E. M. (n.d.). Exenatide Injection (Byetta): Adjunctive Therapy for Glycemic Control. American Family Physician. 2006;73(12), 2213-2214
Frandsen, K. B., & Kristensen, J. S. (2002a). Diet and lifestyle in type 2 diabetes: The patient’s perspective. Practical Diabetes International, 19(3), 77–80. https://doi.org/10.1002/pdi.327
Golden, N. H., Irving, L. M., Klesges, R. C., Neumark-Sztainer, D., Nichter, M., Himes, J. H., Must, A., Lewinsohn, P. M., Kelley, A. E., Johnson, R. D., Hedley, A. A., Ogden, C. L., Mokdad, A. H., Grunbaum, J. A., Stice, E., Ackard, D. M., Patton, G. C., & Daee, A. (2006, March 28). Obesity, disordered eating, and eating disorders in a longitudinal study of adolescents: How do dieters fare 5 years later?. Journal of the American Dietetic Association. https://www.sciencedirect.com/science/article/abs/pii/S0002822306000046
Gregg, E. W., Chen, H., Wagenknecht, L. E., Clark, J. M., Delahanty, L. M., Bantle, J., Pownall, H. J., Johnson, K. C., Safford, M. M., Kitabchi, A. E., Pi-Sunyer, F. X., Wing, R. R., & Bertoni, A. G. (2012). Association of an intensive lifestyle intervention with remission of type 2 diabetes. Journal of the American Medical Association, 308(23), 2489. https://doi.org/10.1001/jama.2012.67929
Hays, N. P., Galassetti, P. R., & Coker, R. H. (2008). Prevention and treatment of type 2 diabetes: Current role of lifestyle, natural product, and pharmacological interventions. Pharmacology & Therapeutics, 118(2), 181–191.
He, I., Smart, G., Poirier, B. F., Sethi, S., & Jensen, E. D. (2022). An update on dental caries in children with type 1 diabetes mellitus. Pediatric Dental Journal, 32(2), 77–86. https://doi.org/10.1016/j.pdj.2022.05.001
Khan, M. A., Hashim, M. J., King, J. K., Govender, R. D., Mustafa, H., & Al Kaabi, J. (2020). Epidemiology of T2D – global burden of disease and forecasted trends. Journal of Epidemiology and Global Health, 10(1), 107. https://doi.org/10.2991/jegh.k.191028.001
Khosravizade Tabasi, H., Madarshahian, F., Khoshniat Nikoo, M., Hassanabadi, M., & Mahmoudirad, G. (2014). Impact of family support improvement behaviors on anti diabetic medication adherence and cognition in type 2 diabetic patients. Journal of Diabetes & Metabolic Disorders, 13(1). https://doi.org/10.1186/s40200-014-0113-2
Koole, C., Reynolds, C. A., Mobarec, J. C., Hick, C., Sexton, P. M., & Sakmar, T. P. (2017). Genetically encoded photocross-linkers determine the biological binding site of exendin-4 peptide in the N-terminal domain of the intact human glucagon-like peptide-1 receptor (GLP-1R). Journal of Biological Chemistry, 292(17), 7131–7144. https://doi.org/10.1074/jbc.m117.779496
Lazzaroni, E., Ben Nasr, M., Loretelli, C., Pastore, I., Plebani, L., Lunati, M. E., Vallone, L., Bolla, A. M., Rossi, A., Montefusco, L., Ippolito, E., Berra, C., D’Addio, F., Zuccotti, G. V., & Fiorina, P. (2021). Anti-diabetic drugs and weight loss in patients with type 2 diabetes. Pharmacological Research, 171, 105782. https://doi.org/10.1016/j.phrs.2021.105782
Marín-Peñalver, J. J., Martín-Timón, I., Sevillano-Collantes, C., & Del Cañizo-Gómez, F. J. (2016, September 15). Update on the treatment of tyoe 2 diabetes mellitus. World Journal of Diabetes. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027002/
McGavock, J., Dart, A., & Wicklow, B. (2014). Lifestyle therapy for the treatment of youth with T2D. Current Diabetes Reports, 15(1). https://doi.org/10.1007/s11892-014-0568-z
Mégarbane, B., Chevillard, L., Khoudour, N., & Declèves, X. (2021). Gliclazide disposition in overdose – a case report with pharmacokinetic modeling. Clinical Toxicology, 60(4), 541–542. https://doi.org/10.1080/15563650.2021.1993245
National Health Service. (2020, August 18). Health problems type 2 diabetes. NHS Choices. https://www.nhs.uk/conditions/type-2-diabetes/health-problems/
National Health Service. (2020, August 18). Understanding medicine type 2 diabetes. NHS Choices. https://www.nhs.uk/conditions/type-2-diabetes/understanding-medication/#:~:text=Metformin%20is%20the%20most%20common,or%20being%20sick%20and%20diarrhoea.
National Library of Medicine. (2020, October 22). Hyperglycemia and hypoglycemia in type 2 diabetes. https://www.ncbi.nlm.nih.gov/books/NBK279510/
NHS. (2022, March 28). NHS Prevention programme cuts chances of type 2 diabetes for thousands. NHS choices. https://www.england.nhs.uk/2022/03/nhs-prevention-programme-cuts-chances-of-type-2-diabetes-for-thousands/
Nielsen, L. L., Young, A. A., & Parkes, D. G. (2004). Pharmacology of exenatide (synthetic exendin-4): A potential therapeutic for improved glycemic control of type 2 diabetes. Regulatory Peptides, 117(2), 77–88. https://doi.org/10.1016/j.regpep.2003.10.028
Nissenson, A. R., Fine, R. N., Mehrotra, R., & Zaritsky, J. (2023). Handbook of dialysis therapy. Elsevier.
Polonsky, W., & Henry, R. (2016). Poor medication adherence in type 2 diabetes: Recognizing the scope of the problem and its key contributors. Patient Preference and Adherence, Volume 10, 1299–1307. https://doi.org/10.2147/ppa.s106821
Röhling, M., Herder, C., Roden, M., Stemper, T., & Müssig, K. (2016). Effects of long-term exercise interventions on glycaemic control in type 1 and type 2 diabetes mellitus: A systematic review. Experimental and Clinical Endocrinology & Diabetes, 124(08), 487–494. https://doi.org/10.1055/s-0042-106293
Schernthaner, G., Grimaldi, A., Di Mario, U., Drzewoski, J., Kempler, P., Kvapil, M., Novials, A., Rottiers, R., Rutten, G. E., & Shaw, K. M. (2004). Guide study: Double-blind comparison of once-daily gliclazide MR and Glimepiride in type 2 diabetic patients. European Journal of Clinical Investigation, 34(8), 535–542.
Shyangdan, D. S., Royle, P., Clar, C., Sharma, P., Waugh, N., & Snaith, A. (2011). Glucagon-like peptide analogues for T2D mellitus. Cochrane Database of Systematic Reviews. https://doi.org/10.1002/14651858.cd006423.pub2
Singh, K. (2022, November 9). Cost of Diabetes. Diabetes.co.uk.
Sola, D., Rossi, L., Schianca, G. P., Maffioli, P., Bigliocca, M., Mella, R., Corlianò, F., Fra, G. P., Bartoli, E., & Derosa, G. (2015). State of the art paper sulfonylureas and their use in clinical practice. Archives of Medical Science, 4, 840–848.
Team, S. (2023, June 13). How much is metformin without insurance?. The Checkup. https://www.singlecare.com/blog/metformin-without-insurance/
Thomas, D., Elliott, E. J., & Naughton, G. A. (2006). Exercise for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews, 2009(1).
Thornton, P. (2023, May 18). Byetta (injection pen) Usage & safety guide. Drugs.com. https://www.drugs.com/byetta.html
van Gils, P., Lambooij, M., Struijs, J., van den Berg, M., Flanderjin, M., de Wit, G. A., & Schuit, A. (2011). Willingness to participate in a lifestyle intervention program of patients with type 2 diabetes mellitus: A conjoint analysis. Patient Preference and Adherence, 537. https://doi.org/10.2147/ppa.s16854
Wilding, J. P. (2014). The importance of weight management in type 2 diabetes mellitus. International Journal of Clinical Practice, 68(6), 682–691.
Yang, Z., Scott, C. A., Mao, C., Tang, J., & Farmer, A. J. (2013). Resistance exercise versus aerobic exercise for type 2 diabetes: A systematic review and meta-analysis. Sports Medicine, 44(4), 487–499. https://doi.org/10.1007/s40279-013-0128-8