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Review

The Cardiovascular and Macrovascular Benefits of Achieving Early Type 2 Diabetes Remission

by
Lianna Khachikyan
1 and
Jay H. Shubrook
2,*
1
College of Osteopathic Medicine, Touro University California, Vallejo, CA 94592, USA
2
Department of Clinical Sciences and Community Health, College of Osteopathic Medicine, Touro University California, Vallejo, CA 94592, USA
*
Author to whom correspondence should be addressed.
Diabetology 2025, 6(10), 120; https://doi.org/10.3390/diabetology6100120
Submission received: 22 August 2025 / Revised: 24 September 2025 / Accepted: 11 October 2025 / Published: 17 October 2025
(This article belongs to the Special Issue Early Intervention and Treatment Strategies for Diabetes)
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Abstract

Type 2 diabetes is a chronic non-communicable disease that has reached epidemic levels. While there is ample evidence that type 2 diabetes can, for many, be prevented or at least well managed, this disease progresses in most people with type 2 diabetes who are not achieving glucose targets. Those who do not achieve glucose targets have higher rates of microvascular and macrovascular complications. Further, the economic burden of diabetes, its treatment and its complications is substantial. Diabetes management goals should include prevention in those at risk and early intensive control to induce benefits through the legacy effect. However, what is seen more often is therapeutic inertia with delays in the diagnosis and each step of care. This results in reactive diabetes management in which the disease progresses faster than the management. While the use of newer potent glucose-lowering agents continues to expand, the durability of these agents when treatment is stopped is unknown. In this narrative review, the authors explore the impact of achieving diabetes remission on the reduction in cardiovascular complications.

Graphical Abstract

1. Introduction

Type 2 diabetes mellitus (T2DM) prevalence is increasing worldwide. The International Diabetes Federation reported in 2024 that, worldwide, nearly 589 million adults aged 20–79 years had diabetes mellitus [1]. This is projected to rise to 643 million by 2030 and 853 million by 2050 [1]. While rates of T2DM are increasing worldwide, they are not increasing uniformly [1]. Traditionally, T2DM was considered a disease of the wealthy who had access to excessive amounts of food and were more sedentary. However, 80% of people with diabetes today live in lower to middle-income countries [1]. China and India currently have the highest number of residents with T2DM [1].
T2DM is a complex progressive multisystem disease that originates with insulin resistance leading to dysmetabolism of glucose and lipids, but is clinically seen to have at least eight abnormal physiologic pathways that have disruptive counterregulatory responses to hyperglycemia [2]. While there is a strong familial component to T2DM, modifiable risk factors also contribute to T2DM prevalence and progression. These include excessive adiposity, especially visceral adiposity, sedentary lifestyles, excessive intake of processed and ultra-processed foods, and sweetened beverages, leading to low-grade systemic inflammation and dysfunction [3].
Cardiovascular disease is a major cause of comorbidity and mortality in patients with T2DM [4]. The need to prevent and properly manage diabetes remains an ongoing hurdle. Traditional treatment guidelines follow a stepwise approach in managing T2DM, which includes diabetes education and subsequent medication intensification. However, most patients do not achieve adequate glycemic control with this approach [5,6].
We are also seeing increasing rates of T2DM in younger adults and even in children now. This is very concerning as it appears that the younger one is diagnosed with T2DM, the more virulent the disease is and the less responsive it is to treatment [7].
Management of T2DM requires a comprehensive multimodal approach. As this condition typically progresses sub-clinically for years in most people, the pathophysiologic abnormalities are well established at diagnosis. Most people with T2DM require lifelong therapeutic lifestyle change and an ever-increasing list of medications to manage their glucose. The average person in the US with T2DM takes 2–3 glucose-lowering medications, two blood pressure medications, and 1–2 lipid-lowering medications [8]. This is a challenge in the reactive approach, as people never feel like they can “control” their diabetes.
T2DM is a largely silent but progressive systemic disease that requires proactive and timely intervention. Unfortunately, because of its asymptomatic nature, more than two-thirds of people will already have complications from T2DM at the time they are diagnosed with T2DM [8]. Further, few people achieve glucose goals in a timely manner, allowing the disease to progress and reducing the likelihood of achieving sustained long-term glucose control.
T2DM has substantial comorbidities and complications. Despite an abundance of effective lifestyle and pharmacologic treatments, uncontrolled T2DM is still the leading cause of legal blindness, non-traumatic amputations, and end-stage kidney disease needing renal replacement therapies. (1) Cardiovascular disease is a major cause of comorbidity and mortality in patients with T2DM [4]. The primary cause of death for patients with T2DM is myocardial infarction [9]. In fact, many patients are diagnosed with T2DM after a myocardial infarction. A meta-analysis of newly discovered abnormal glucose tolerance in patients with acute myocardial infarction in 19 studies revealed a prevalence of 48.4% of newly discovered abnormal glucose tolerance with myocardial infarction [10]. There is enhanced cardiovascular risk even in those people with pre-diabetes (impaired glucose tolerance or impaired fasting glucose) [11]. The relative cardiovascular risk was 3.17 times higher in women before diabetes diagnosis, even after adjusting for smoking, BMI, and other CV risk factors. This further supports the need for early intervention to reduce cardiovascular risk.
While T2DM prevention is optimal, there is now ample evidence that people with early T2DM can achieve diabetes remission with a variety of interventions, including intensive lifestyle interventions, metabolic surgery, and early intensive insulin regimens [12].

2. Methodology

The authors searched the PubMed database in June 2024, December 2024, and August 2025. Keywords included diabetes remission. Filters included English language, original research, clinical trials, systematic reviews, and meta-analyses. The acceptable date range was 2000–2025. From these sources, the authors provide a narrative review based upon the results of these searches.

3. Diabetes Remission

Diabetes remission is defined accordingly, when a person diagnosed with T2DM sustains an HbA1c < 6.5% (48 mmol/mol) for 3 months or more without glucose-lowering medication [13]. Multiple health professional organizations have described and advocated for T2DM remission, including Diabetes Canada, Diabetes UK, The American College of Lifestyle Medicine, and the American Diabetes Association [13,14,15].
Many patients and clinicians see diabetes remission as the optimal goal of T2DM management. Sadly, spontaneous diabetes remission is highly unlikely (less than 2%) without targeted intervention [16]. The likelihood of achieving diabetes remission is greatest early in the disease and decreases over time. Therefore, the timing of the intervention is also important. Diabetes remission rates are doubled if achieved in the first two years after diagnosis [16].
Reduction in obesity is an important factor in achieving diabetes remission. Those patients who lost more than 10% of their body weight were more than 3.5 times more likely to achieve diabetes remission than those who lost less than 5% of their body weight [17]. Since T2DM is linked to obesity, newer treatment methods targeting weight loss, such as the incretin-based agents (GLP-1RA, GLP-1, and GIP RA) and SGLT-2 inhibitors, are essential to address the combined problem of obesity and T2DM. These agents have also shown cardiovascular and other extraglycemic benefits [18]. Diabetes organizations now recommend these agents as preferred treatment agents [18] This will be covered later in this article under diabetes remission under treatment. Recent studies have demonstrated an association between remission and decreased cardiovascular risk [19,20].

3.1. Lifestyle Approach

Therapeutic lifestyle interventions are paramount in treating diabetes. Recent studies have focused on intensive lifestyle interventions to achieve T2DM remission (Table 1). The main benefit of lifestyle interventions when inducing remission is achieved via weight loss. Sustained weight loss reduces visceral adiposity, which in turn improves insulin sensitivity [21,22].
The largest and longest trial achieving diabetes remission is the DiRECT trial. In this study, more than 300 primary care patients from 49 clinical sites in Great Britain were enrolled in an intensive lifestyle intervention treatment involving meal replacement shakes for a total of 800 kcals for 12–20 weeks. Nearly half (46%) of the intervention group achieved diabetes remission at one year, with higher rates of diabetes remission in those who lost at least 15 kgs of weight [23]. The remission rates in the treatment group were 36% at two years and 34% at 5 years [24,27].
This study was replicated in Australia with similar results. In this modified version of the DiRECT trial, the treatment group lost 8.1% body weight and experienced a 56% T2DM remission rate at 1 year [28].
There have been some recent trials looking at other dietary plans aimed at inducing type 2 diabetes remission. In the CARDIOPREV study, participants who increased their consumption of plant-based proteins while following either a Mediterranean diet or a low-fat diet were more likely to achieve diabetes remission than patients who decreased plant-based protein intake (HR = 1.71 (1.05–2.77)) [26].
Another trial of 23 newly diagnosed patients with type 2 diabetes compared the effects of the Mediterranean diet in a 2-week crossover dietary intervention [25]. In this study, the Mediterranean diet was compared with a personalized postprandial targeting (PPT) diet plan, implemented using a machine learning algorithm based on predictions of glycemic responses. Researchers found that 61% of the participants who continued the PPT plan for 6 months achieved HbA1c < 6.5% [25].

3.2. Surgical Approach

Metabolic surgery, including Roux-en-Y surgery, is an effective way to induce diabetes remission in people with type 2 diabetes (Table 1). The STAMPEDE trial was the first to demonstrate both immediate and lasting benefits (22%) [29]. In a 10-year follow-up in a randomized clinical trial, laparoscopic sleeve gastrectomy (LSG) versus Roux-en-Y Gastric Bypass (LRYGB), revealed that both procedures resulted in sustainable weight loss [32]. Diabetes remission was seen in 11 of 42 patients after LSG and 13 out of 39 patients after LRYGB. Preoperative T2DM duration was statistically significant with remission [32]. A second study reported three-year type 2 diabetes remission rates of 37.5% in those undergoing metabolic surgery versus 2.5% in those who received intensive medical treatment [33].
Finally, diabetes remission appears to be durable among these patients. A meta-analysis showed that those who had metabolic surgery experienced a six-fold increase in diabetes remission, and this lasted 5–15 years [30]. Another study showed that metabolic surgery achieved remission rates of 73% at 2 years, 62% at 6 years, and 51% at 12 years [31].
T2DM remission was more likely in younger patients, those with a shorter duration of diabetes, with lower HOMA-IR, and higher C-peptide levels [34]. While metabolic surgery currently shows the most significant duration of diabetes remission, it is also the intervention with the highest treatment risks and long-term treatment complications.

3.3. Pharmacologic Approach

Insulin has been used in type 2 diabetes most often in people with very high glucose levels (fasting glucose > 200 mg/dL (11.1 mmol/L) or a HbA1c > 10% with catabolic symptoms or when the type of diabetes mellitus is not clear at the time of diagnosis [40]. However, several studies have demonstrated the benefits of early intensive insulin regimens in inducing remission of T2DM (Table 1). There have been multiple clinical trials that demonstrate the benefit of early intensive insulin therapy on ongoing glucose control and diabetes remission. The studies appear to mitigate glucose toxicity, stabilize glucose control, enhance beta cell function through the redifferentiation of beta cells, and lead to improved insulin sensitivity [35,36,39,41,42].
In a mechanistic study, Weng et al. measured the effect of an intensive two-week insulin program on people newly diagnosed with T2DM. Patients were evaluated over two years. Using insulin clamp studies, they found that first-phase insulin secretion was quickly restored, insulin sensitivity improved, and glucose was normalized. Diabetes remission rates were 47.6% at 12 months and 30.7% at 24 months. Predictors of long-term remission included a younger age at diabetes diagnosis, higher baseline insulin levels, and rapidly resolving glucose levels on intensive insulin regimens [38].
A meta-analysis of the major intensive insulin trials found that among those trials, including diabetes remission as an outcome, remission was achieved 46.3% at 12 months and 42.1% at 24 months [37].

3.4. Diabetes Remission on Treatment

Recent clinical trials using potent glucose-lowering agents have demonstrated that participants can achieve dramatically improved HbA1c while on treatment. In the STEP 2 trial using semaglutide, 67.5% of participants taking 2.4 mg and 60.1% of those taking 1 mg achieved a HbA1c of <6.5% at 68 weeks [43]. In the SURPASS clinical trial series (1–5), over half (51.7%) of the participants who took tirzepatide 15 mg weekly achieved a HbA1c below 5.7% (SURPASS 1, 40 weeks), 50.9% (SURPASS 2, 40 weeks), 48.4% (SURPASS 3, 52 weeks), 43.1% (SURPASS 4, 52 weeks), and 62.4% (SURPASS 5, 40 weeks) respectively [44,45,46,47,48,49]. In the just-released SURPASS CVOT, tirzepatide reduced cardiovascular events in those with and without established ASCVD [50].
What is unresolved within these groups that achieved remission-level HbA1c while on treatment is the durability of this improvement once therapy is stopped.
It is important to note that several classes of agents have shown cardiovascular benefit in addition to improving glycemic control. For these patients, the benefit continues as long as the treatment is continued. For this reason, we have included the patients who can achieve an HbA1c below 6.5% while on treatment as part of the diabetes remission on treatment. We do not have evidence that this benefit is long-lasting once the treatment is stopped.

4. Diabetes Remission and Cardiovascular Benefit

Cardiovascular disease is the major cause of comorbidity and mortality in patients with T2DM [4]. The primary cause of death for patients with T2DM is myocardial infarction [51]. We now know that cardiovascular risk is elevated even in prediabetes states and increases further upon diagnosis. Interventions focused on normalization of the dysglycemic state provide an opportunity to control T2DM itself better, but also reduce complications.
While diabetes remission is an important goal, the question remains whether achieving early diabetes remission improves macrovascular outcomes and ultimately long-term improvement in cardiovascular outcomes. A survey of data from early intensive treatment cases, even in the absence of diabetes remission, may provide some initial insight.
In a Kaiser population-based study, those patients who did not achieve an HbA1c < 6.5% in the first year were more likely to experience microvascular and macrovascular events (HR 1.204 95% CI 10.63–1.365), and more likely to have increased mortality (HR 1.290 95% CI 1.104–1.507) at 10 years after the diagnosis [20]. This phenomenon has been termed the legacy effect of early glycemic control. Patients who did not have a repeat HbA1c three months after diagnosis had a higher risk of microvascular complications (HR 1.354 95% CI 1.218–1.505), macrovascular complications (HR 1.112 CI 1.050–1.177), and mortality at 10 years (HE 1.235 CI 1.094–1.394) [20]. This shows that close follow-up and monitoring progress is important not only for glycemic control but also for complication benefit.
Taking action in the first year of a diagnosis of T2DM is the most important time to achieve metabolic control. Even a one-year delay in treatment intensification has been found to increase rates of myocardial infarction, stroke, heart failure, and cardiovascular events (HR 1.62, 95% CI 1.46–1.8) [52]. Khunti et al. have referred to these treatment delays as the “dysglycemic gap”, a therapeutic inertia that leads to excess complications [53].
Another study of 251,339 newly diagnosed patients with T2DM and without cardiovascular disease at baseline found that poor glycemic control in the first three years after diagnosis is associated with increased risk of cardiovascular disease [54]. Khunti et al. have coined the delay in action or failure to act as “therapeutic inertia,” the cause of a dysglycemic gap that leads to excessive complications [53].

Remission and CV Events

In the Swedish Obese Subjects Study, 72.3% achieved diabetes remission at two years after surgery. This decreased to 38.1% at ten years and 30.4% at 15 years [55]. In this study, those who underwent metabolic surgery and achieved diabetes remission in the first two years showed a 46% reduction in cardiovascular mortality with 2.5 years longer life expectancy than those who did not achieve remission [56]. Even those without remission had a reduced myocardial infarction incidence [HR] 0.56 [95% CI 0.34–0.93]; p = 0.025) but no benefit of stroke incidence HR 0.73 [0.41–1.30]; p = 0.29) [57].
The Look AHEAD trial was a lifestyle program for people newly diagnosed with type 2 diabetes mellitus. Participants in the intensive lifestyle arm achieved 8.6% weight loss and saw a reduction in cardiovascular risk factors. In this study, the mean HbA1c dropped from 7.3 to 6.6% [58]. However, those who achieved diabetes remission (13%) during the study saw an even greater benefit. At four years, 7.3% of the participants had maintained diabetes remission [58]. Compared to participants who did not achieve remission, participants who experienced any diabetes remission had a 40% lower rate of the composite cardiovascular disease outcome (HR 0.60; 95% CI 0.47, 0.79) after adjusting for HbA1c, blood pressure, lipid levels, cardiovascular disease history, and diabetes duration. The longer the remission, the greater the benefit [59].
The DiRECT trial demonstrated significant diabetes remission even up to 5 years post-intervention. At 5 years, 26% of the original participants were still in diabetes remission. While the study was not powered for cardiovascular events, there were significant differences in cardiovascular risk factors and scores starting at 24 months [24]. There were reductions in systolic blood pressure (despite a decrease in blood pressure-lowering medications), lower triglycerides, and a reduction in the 10-year cardiovascular risk event score (Q-Risk score) [60].
Most early intensive insulin studies inducing remission focused solely on remission outcomes; however, some collective evidence has emerged regarding cardiovascular events. In an extensive real-world study in China, those people who received early intensive insulin at diagnosis had lower rates of reported stroke (31%) and hospitalization for heart failure (28%) than those who did not receive early intensive insulin [61]. Rates of reported coronary heart disease were similar between the two groups [61].
What is not well studied is what diabetes remission looks like long-term. The new potent incretin-based agents (semaglutide, tirzepatide) have shown the ability to prevent progression to T2DM in those at risk and induce remission and reduce cardiovascular risk in those with established disease. However, it is unclear whether these benefits persist when the medication is discontinued. These issues will need further study.
There have been multiple pathways to achieve diabetes remission, but one thing they all have in common is the need to act early in the disease [62]. Providing patients with early education about the timing and options for inducing diabetes remission is crucial. Further, as a progressive disease, further research is needed in maintaining diabetes remission long-term.

5. Limitations

While this narrative review provides a broad assessment of the current strategies for T2DM remission, this review has several limitations. First and most important, there are no head-to-head T2DM remission studies. This means that each study stands alone; however, we are unable to compare remission interventions directly due to the lack of homogeneity in patient populations, confounding variables, different outcome measurements, and inconsistent tracking of remission durations. This narrative review does not include other critical components of diabetes self-care, such as moderate physical activity, sleep hygiene, and the use of non-pharmacologic agents. These components of diabetes self-care were not identified as standalone interventions that can achieve diabetes remission. They, however, can be an effective part of any other treatment strategy.

6. Conclusions

Diabetes remission, defined as an HbA1c of <6.5% while not taking any diabetes medications for at least 6 months, has resurfaced as a treatment goal [11]. There have been multiple pathways to achieve diabetes remission, but one thing they all have in common is the need to act early in the disease [62]. The other key factor seen in most trials was weight loss, wherein a loss of 15 kg seemed to be highly predictive of diabetes remission [21].
The sooner clinicians can help patients establish control of their diabetes, assist with weight loss, and lower their HbA1c, the better the cardiovascular benefit the patients can expect over the next 10 years. Further studies should explore this relationship more deeply, including other benefits beyond those of CV disease and the health economics of diabetes remission.

Author Contributions

Conceptualization, J.H.S. and L.K.; methodology, J.H.S.; resources, L.K. and J.H.S.; data curation, L.K.; writing—original draft preparation, L.K.; writing—review and editing, J.H.S. and L.K.; supervision, J.H.S. All authors have read and agreed to the published version of the manuscript and revision.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

L.K. declares no conflicts of interest. J.H.S. has the following conflicts: He has served as a consultant for Abbott, Bayer, Corcept, Insulet, Idorsia, Madrigal, Novo Nordisk, and Sanofi.

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Table 1. References for achieving type 2 diabetes remission.
Table 1. References for achieving type 2 diabetes remission.
Method of Achieving RemissionReferencesRemission RateSample SizeFollow up Duration
LifestyleLean et al., 2018 [23]46%14912 months
Lean et al., 2019 [24]36%1492 years
Taylor et al., 2019 [21]46%, 36%14912, 24 months respectively
Zhyzhneuskaya et al., 2020 [22](n = 20) 51%392 years
Rein et al., 2022 [25]61%236 months
Gutierrez-Mariscal et al., 2023 [26]HR = 1.7117760 months
Lean et al., 2024 [27]13%855 years
Hocking et al., 2024 [28]56%15512 months
SurgicalSchauer et al., 2012 [29]42% gastric-bypass group, 37% sleeve-gastrectomy group50 gastric bypass group, 49 sleeve-gastrectomy group12 months
Sheng et al., 2017 [30]RR = 5.9032045 year follow up
Adams et al., 2017 [31]75%, 62%, 51%4182 years, 6 years, 12 years
Salminen et al., 2022 [32]26% LSG and 33% LRYBG121 to LSG and 119 to LRYGB10 years
Kirwan et al., 2022 [33]37.50%3163 years
Meira et al., 2025 [34]31%9510 years
MedicalWeng et al., 2008 [35]51.1%, 44.9%134 CSII, 124 MDI1 year
Chen et al., 2008 [36]47.10%13812 months
Kramer et al., 2013 [37]66.2%, 58.9%, 46.3%, 42.1%5593 months, 6 months, 12 months, 24 months
Wang H, Kuang J, Xu M, Gao Z, Li Q, Liu S, et al., 2019 [38]47.6%, 30.7%12412 months, 24 months
Zheng et al., 2020 [39]31%5612 months
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Khachikyan, L.; Shubrook, J.H. The Cardiovascular and Macrovascular Benefits of Achieving Early Type 2 Diabetes Remission. Diabetology 2025, 6, 120. https://doi.org/10.3390/diabetology6100120

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Khachikyan L, Shubrook JH. The Cardiovascular and Macrovascular Benefits of Achieving Early Type 2 Diabetes Remission. Diabetology. 2025; 6(10):120. https://doi.org/10.3390/diabetology6100120

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Khachikyan, Lianna, and Jay H. Shubrook. 2025. "The Cardiovascular and Macrovascular Benefits of Achieving Early Type 2 Diabetes Remission" Diabetology 6, no. 10: 120. https://doi.org/10.3390/diabetology6100120

APA Style

Khachikyan, L., & Shubrook, J. H. (2025). The Cardiovascular and Macrovascular Benefits of Achieving Early Type 2 Diabetes Remission. Diabetology, 6(10), 120. https://doi.org/10.3390/diabetology6100120

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