Sage Journals: Discover world-class research

Abstract

Chronic hyperglycemia is associated with poor cardiovascular surgical outcomes due to microvascular and macrovascular complications. This is a major concern as over one third of cardiovascular surgical patients have diabetes mellitus which greatly increases their risk of experiencing adverse cardiovascular events. A literature review was performed to identify articles discussing the effects of anti-diabetic medications (ADMs) on cardiovascular outcomes and surgical mortality and morbidity rates. Optimizing perioperative glucose levels remains a key factor in producing good surgical outcomes. In addition, recognizing gender differences, increasing patient satisfaction, and implementing dedicated diabetic teams all improve surgical mortality and morbidity rates in the diabetic population.

Keywords

antidiabetics diabetes multidisciplinary diabetic team coronary artery disease stroke cardiac surgery

Introduction

Over 400 million people suffer from diabetes mellitus and the World Health Organization (WHO) has declared it the 7th leading cause of death worldwide.¹ As cardiovascular complications are the most prevalent causes of diabetic morbidity and mortality, there is an urgent need to clarify the impact of anti-diabetic medications (ADMs) on diabetic patients’ cardiovascular health.² Specifically, diabetes has been shown to increase the risk of coronary vascular disease by 1.7 times compared to a healthy population.³ This mostly due to an increase in strokes and myocardial infarctions in the diabetic population.

In addition to the health risks, diabetic care poses enormous economic costs with worldwide care totaling over $1.3 trillion USD in 2015.⁴ The majority of these costs were associated with the cardiovascular complications of diabetes.⁵

The primary aim of this review is to discuss the role of anti-diabetic medications (ADMs) in patients with cardiovascular diseases, focusing specifically on the medications’ impact on mortality, morbidity and recovery time. Authority guidelines will be discussed and then our recommendations considering the review will be presented.

Pharmacology of Diabetic Control Medications

The pharmacology of diabetic control medications is diverse due to the different classes of drugs, which act on various receptors and endocrinological pathways. These are summarized in Table 1.^6

-13

Table 1.

Pharmacokinetics of Different Classes of Anti-Diabetic Medications.

Type of antidiabetic	Uses	Pharmacokinetics and interactions of drug in body
Insulin	All types of diabetes, mainly for type 1 diabetes mellitus Effective when combined with biguanides	Induces glycogenesis via the phosphorylation of insulin receptors, in turn storing glucose as glycogen
Biguanides	Mainly for type 2 diabetes mellitus Effective as single drug therapy as well as combination with another antidiabetic	Delays intestinal absorption of glucose and lactate synthesis. Promotes GLP-1 secretion
Sulfonylureas	All types of diabetes	Increases plasma insulin levels to lower glucose via receptors on beta-cells by blocking Potassium-ATPase channels (K+ efflux)
Thiazolidinediones	All types of diabetes	Reduces resistance in fat and muscle via peroxisome proliferator-activated receptor (PPAR) gamma and alpha
GLP-1 agonist	All types of diabetes	Activates GLP-1 receptor which leads to lowering glucose concentration, increasing insulin secretion, lowering glucagon levels—which leads satiety. This is known as incretin effect
DPP-4 inhibitors	All types of diabetes	Inhibits DPP-4, which its natural function is to inactivate incretin, thereby inducing incretin levels
SGLT-2 Inhibitors	All types of diabetes	Inhibits glucose reabsorption which leads to increase in glucose excretion thereby reducing plasma glucose levels

Mortality

The most common cause of death in T1DM and T2DM was identified as cardiovascular disease, contributing to around 44% and 52% respectively¹⁴. However, a study performed by Rawshani et al identified that there has been a significant reduction in both all-cause and cardiovascular mortality in the past 20 years. Their study has shown −26.0 (95% CI: −42.6 to −9.4) absolute change in the incidence rates of sentinel outcomes per 10,000 person-years. While the reduction in mortality has coincided with better antidiabetic treatment availability, multiple studies have shown that not all ADMs are effective at reducing mortality.¹⁵ A summary of different ADM classes’ outcomes from various studies is represented in Table 2.^{16

-32}

Table 2.

Potential Benefits and Adverse Outcomes of Anti-Diabetic Medications.

Insulin	– Increases risk of myocardial infarction over time – Improved glycemic control by continuous insulin infusion
Biguanides	– Increases risk of myocardial infarction – Reduction in morbidities postoperatively – No difference in postoperative atrial fibrillation rates
Sulfonylureas	– Increases risk of myocardial infarction, hospital mortality, and earlier onset of death
Thiazolidinediones	– Decreased risk of myocardial infarction, suggesting a protective effect
GLP-1 agonists	– Reduces risk of perioperative hyperglycemia, indicating a potentially protective factor – Did not show improvements in glycemic control
DPP-4 inhibitors	– Increases risk of organ dysfunction and heart failure
SGLT-2 inhibitors	– Increases risk of developing diabetic ketoacidosis
PPAR agonists	– Increases risk of heart failure

A systematic review compared the effects between ADMs on different cardiovascular outcomes, such as mortality, HDL/LDL cholesterol levels, systolic blood pressure, and triglyceride. Bolen et al compared oral agents—thiazolidinediones, biguanides, meglitinides, and alpha-glucosidase inhibitors in adults with type 2 diabetes. The review showed that treatment with Metformin was associated with decreased cardiovascular mortality compared to other oral anti-diabetic agents or placebo.²² Similarly, other meta-analysis has found strong association between metformin and risk of cardiovascular related mortality.²⁹ Contrastingly, there are studies that found Metformin’s effectiveness in reducing mortality, where one study compared the effects of perioperative metformin and unspecified non-metformin medications on in-hospital mortality and postoperative cardiac conditions.²⁰ While the results were similar for cardiovascular risks in both groups, patients treated with metformin had lower rates of infection and mortality.

Another ADM that has been shown to reduce mortality is insulin according to a study.¹⁸ A blood glucose of over 11 mmol/l, independent of diabetic status, was predictive of increased postoperative adverse outcomes. The investigators suggest that insulin may be given via both subcutaneous and intravenous delivery. Interestingly, they also identified that patients with diabetes had a higher rate of postoperative mortality compared to patients without diabetes (7.7% compared to 3.3%; P = .03), despite the multivariate analysis showing no significant differences, especially in CABG-only patients. However, a major limitation of this study is sampling bias since the single site study was at risk of author and selection bias. There was also no randomization or group control for comparison.¹⁸

Similarly, Higgs and Fernandez examined the evidence of insulin therapy algorithms following cardiac surgery. This systematic review analyzed 13 studies and found that the use of continuous intravenous insulin effectively improves blood glucose levels using the CII algorithm. However, a limitation of study was the inclusions of non-randomized trials which may have biased outcomes. This can be adopted into practice when insulin is used to control blood glucose levels.¹⁹

Sulfonylureas were identified to have a significantly higher hospital mortality of almost 3 times in a study that observed the outcomes of patients undergoing direct coronary angioplasty for acute MI.²³ In a multi-center trial, Pioglitazone as an add on to sulfonylureas was found to have no additional benefits of reducing major cardiac events.²⁴ While many studies indicate differences in mortality rates depending on the type of antidiabetic agent used, they also generally point toward the importance of perioperative glycemic control. A NICE-SUGAR study demonstrated a target glucose level of below 180mg/dl had reduced mortality in intensive care units in both surgical and non-surgical patients.³⁰

Morbidity

Vaidya et al stated that the cost of treating T2DM with cardiovascular complications was 58% higher than treating T2DM alone.³¹ The Steno-2 study indicates that aggressive intensified, target-driven therapy combined with medications and behavioral changes fared a better prognosis, which has led to a reduction in cardiovascular outcomes by as much as a half.¹⁵ While general interventions have indicated better CVS outcomes, the effects of separate ADMs need to be studied. As previously stated, Duncan et al identified that patients treated with metformin had lower rates of infection and overall morbidities.²⁰ With a similar comparison, Basnet et al compared the risk of postoperative atrial fibrillation (AF) between metformin treated and non-metformin treated patients.²¹ The study population received CABG and/or valve surgery. They found that approximately 20% of patients developed AF, however, there was no statistically significant effect on the risk of postoperative AF.

Vaccaro et al examined the effects of adding pioglitazone to sulfonylureas in type 2 diabetics.²⁴ It was found that thiazolidinedione (pioglitazone) was associated with fewer hypoglycemia but had no effect on the incidence of major adverse cardiac events.²⁴

Meier et al investigated on the effects of GLP-1 on blood glucose levels on patients with type 2 diabetes.²⁵ The study found that GLP-1 effectively normalizes blood glucose levels within 3 hours, whereas glucose levels remain to be raised in the placebo group. This is potentially a protective effect, reducing the risk of adverse cardiovascular outcomes.

Margolis et al compared risk of adverse cardiovascular outcomes with the use of ADMs. It was found that insulin use was associated with increased risk of MI, as well as for other ADMs including sulfonylureas and biguanides.¹⁶ Conversely, rosiglitazone and pioglitazone (thiazolidinediones) were associated with decreased risk, implying a protective effect.¹⁶ This is contrary to the common side effect of thiazolidinediones leading to fluid retention which can precipitate heart failure.⁷ Margolis et al’s study however used heart failure as the primary endpoint, meaning that there may be other confounding factors such as hypertension which were not measured. This therefore makes it difficult to establish a correlation between ADMs and cardiovascular complications.

A study compared the outcomes of the addition of DPP-4 inhibitor to standard sliding scale insulin, but they found that the addition of sitagliptin did not improve blood glucose control.²⁶ Further on the association of DPP-4 levels, another study found that lower DPP-4 activity was correlated with higher organ dysfunction, worse outcomes in patients admitted into intensive care unit postoperatively.²⁷ This may suggest a harmful effect of DPP-4 inhibitor due to the above association remains to be investigated through further research. A meta-analysis by Udell et al identified a moderate increase in the risk of heart failure with certain glucose lowering medications including PPAR agonists which was associated with the highest risk, followed by DPP-4 inhibitors. Their study results suggested that insulin glargine had a neutral effect on the risk of developing heart failure. Generally, the use of glucose lowering medications was associated with weight gain, which itself was associated with increased risk of heart failure.¹⁷

Studies examined the risk of developing diabetic ketoacidosis (DKA) with the use of SGLT-2 inhibitors following cardiac surgery. It was found that SGLT-2 inhibitor should be stopped 2 days before surgery to minimize the risk of DKA.²⁸ However, a main limitation of this study was that the case analysis only contained 3 patients with each having their own unique characteristics. This makes it difficult to generalize for the wider population.

Gender Perspectives

In the non-diabetic population, men have a much greater risk for developing coronary heart disease (CHD) than women.³³ However, multiple studies have found that in the diabetic population, women have a higher relative risk than men for developing adverse cardiovascular events.^33
-35 A 1997 Swedish study by Lungberg et al investigated diabetes as a risk factor for acute MI from a population of 2432 men and women aged 35-64 years in the Northern Sweden MONICA area that have a high cardiovascular risk. They found that while the prevalence of diabetes was higher in men when compared to women (5% vs 4.4%), the relative risk was higher in women (2.9 vs 5.0). When compared to a nondiabetic population, women with diabetes were 7 times more likely to die due to a myocardial infarction, whereas men were 4 times more likely. Independent of gender, diabetes increases the risk of acute MI attack rate, incidence, case fatality, recurrence and mortality for all diabetic patients. A similar study by Juutilainen et al also found that diabetic women had higher cardiovascular risks compared to diabetic males.³⁴ Interestingly, this study found that the diabetic women had higher HbA1c levels than the diabetic men. As previously mentioned, a raised HbA1c level has been associated with increased cardiovascular risk and therefore, may provide a possible explanation for the gender differences in diabetic cardiovascular risk. Another suggestion is that diabetes may have a greater effect on women’s blood pressure and atherogenic dyslipidemia than their male counterparts, leading to the increase in adverse cardiovascular events seen in women.³⁴

On the other hand, a meta-analysis performed in 2002 suggested that the perceived increase in diabetic women’s cardiovascular relative risk was merely due to the failure of studies to adjust for classic CHD risks including age, hypertension, smoking status, and total cholesterol levels.³⁶ Once the data was adjusted, the excess relative risk between diabetic women and men was abolished.

While there appears to be controversy over whether diabetic women have an increased relative risk compared to men for experiencing adverse cardiovascular events, the limited age range, geographical location and outdated time period in which these studies were performed warrants a more up to date comprehensive literature review over multiple populations to obtain a reliable result.³⁵

Patient Satisfaction

A 2010 study by Glickman et al looked at the relationship between patient satisfaction with clinical quality and inpatient mortality in the context of acute MI.³⁷ Examining data on 6467 patients at 25 US hospitals over 2005-2006, they found that patient satisfaction is positively correlated with 13 of 14 acute myocardial performance measures, showing that higher patient satisfaction is associated with improved guideline adherence and lower inpatient mortality rates. Therefore, patient satisfaction may be an accurate measure of the care they receive. However due to the fact that patient opinion is a subjective measure, and therefore highly variable depending on various social, cultural and time period factors, the results cannot be reliably generalized and applied to the general population.

A 2016 study by Bakar et al looked at the relationship between patient satisfaction and diabetes mellitus therapy adherence in a population of 165 patients across 3 hospitals in the state of Johor, Malaysia and found a significant (P < .01) positive fair correlation (r = 0.377) between satisfaction and adherence.³⁸ Limitations of the study, including a small sample size and cultural specificity of satisfaction measures in relation to hospital care means that the results cannot be readily applied to other populations with a different cultural outlook on medical care.

Guidelines

Antidiabetic Medicines and Cardiovascular Impact

Many regulatory bodies have provided guidance on the potential cardiovascular risks associated with the use of ADMs (see Table 3 for summary). The Food and Drug Administration (FDA) stated that regular human insulin has a higher risk of adverse events postoperatively than lispro (14% vs. 6.2%, respectively). The FDA also advises caution when using insulin in elderly patients due to a high incidence of cardiovascular events.³⁹ The European Medicines Agency (EMEA) described adverse cardiovascular events as a one of the most frequent serious events, however, they deemed it unlikely that these events were due to insulin.⁴⁰

Table 3.

Authority Guidance on Cardiovascular Risks Associated With Anti-Diabetic Medications.

Drug class	Authority (reference)	Guidance on cardiovascular risk
Biguanides	FDA (41)	Inconclusive evidence whether metformin reduces cardiovascular risk
Biguanides	European Medicines Agency (42)	Metformin reduces cardiovascular related risks
Sulfonylureas	FDA (43)	No significant adverse cardiac events
Sulfonylureas	European Medicines Agency (44)	No significant adverse cardiac events
SGLT-2 inhibitors	FDA (48)	May cause symptomatic hypotension, especially if combined with loop diuretics
SGLT-2 inhibitors	European Medicines Agency (49)	Did not report on cardiovascular outcomes but may increase the risk of post-op diabetic ketoacidosis
GLP-1 agonists	FDA (45)	Slight reduction in risk for major cardiovascular events
GLP-1 agonists	European Medicines Agency (46)	Slight increase in coronary artery disease compared to placebo
Insulin	FDA (39)	Use with caution in elderly patients due to increased risk of cardiovascular events
Insulin	European Medicines Agency (40)	Increased adverse cardiovascular events were recorded but deemed to be independent of insulin therapy
DPP-4 inhibitor	FDA (45)	Increased risk of hospitalization with heart failure
DPP-4 inhibitor	European Medicines Agency (47)	Slight risk for increasing blood pressure and heart rate

Regarding biguanides, the FDA states the evidence is inconclusive whether metformin reduced cardiovascular risks, however, the EMEA suggests that metformin causes a moderate reduction in cardiovascular risk.^41,42

The FDA states that there was no significant increase in adverse cardiac events in patients with severe heart failure (patients with New York Heart Association (NYHA) Class III or IV heart failure) using sulfonylureas.⁴³ Similarly, the EMEA advises that pioglitazone mono-treatment and combination treatment with thiazolidinediones are not associated with any significant adverse events.⁴⁴

In 2018, the FDA updated their guidance on the cardiovascular risks associated with DPP-4 inhibitors and liraglutide (GLP-1 agonist). The data was mainly obtained from Phase 3 trials with younger patients without cardiovascular disease and the study periods were up to 52 weeks. The broad search included most events related to MI and stroke, and custom queries included more clinically adverse events such as CAD, and acute MI. For GLP-1 agonists, the FDA reported 69 (1.62%) broad search events, with an odds ratio of 0.86 (95% CI: 0.59, 1.24); and 21 (0.49%) custom search events with an odds ratio of 0.71 (95% CI: 0.39, 1.3).⁴⁵ Contrastingly, the EMEA claims that the risk of CAD is higher in the GLP-1 group than those on placebo treatment (1% vs <1%).⁴⁶

For the DPP-4 inhibitor, sitagliptin, there were 100 (3.1%) broad search events, with an odds ratio of 0.96 (95% CI: 0.65, 1.42); and 23 (0.7%) custom search events, with an odds ratio of 0.52 (95% CI: 0.26, 1.04). For alogliptin, there were 24 (0.6%) broad search events, with an odds ratio of 0.9 (95% CI: 0.4, 1.9); and 14 (0.4%) custom search events, with an odds ratio of 0.8 (95% CI: 0.3, 2).⁴⁵ Overall, both DPP-4 inhibitors suggest a minor risk to adverse events. The EMEA suggests that except for minor effects on blood pressure and heart rate, major cardiovascular events are unlikely.⁴⁷

For SGLT-2 inhibitors, the FDA did not report any major adverse cardiovascular effects, but claims that it may cause symptomatic hypotension, and precautions should be taken if the patient is on loop diuretics.⁴⁸ The EMEA advise on the risk of diabetic ketoacidosis following surgery but does not report on any cardiovascular outcomes.⁴⁹

ADMs and Cardiovascular Surgical Outcomes

The European Association for Cardio-Thoracic Surgery (EACTS) guidelines in 2017 suggest having universal measurement of patient’s blood glucose levels throughout the whole perioperative and postoperative period regardless whether a diagnosis of diabetes mellitus has previously been made. The EACTS also advises that an HbA1c level should be taken if a patient has a fasting glucose level of greater than 6.6 mmol/l (or 120 mg/dl).⁵⁰

Preoperative blood glucose control has shown to reduce risk of death and adverse events during and after cardiac surgery.⁵¹ However, the EACTS has not specified how long prior to surgery glucose control should begin.⁵² Target levels of blood glucose level are controversial, but likely to be between 120 and 180 mg/dl.^53,54 For patients with insulin- dependent diabetes, some studies have suggested a similar target level of less than 180 mg/dl.^55,56

For post-op patients who require insulin therapy the EACTS suggests having a multidisciplinary diabetic team manage the transition to subcutaneous insulin upon discharge from intensive care. The team should also carefully manage the patient’s nutritional requirement and anti-diabetic regime. Prior to hospital discharge, the EACTS advise patients to have regular follow-up with a target HbA1c of less than 7%.⁵⁰

Limitations

Bias

When selection criteria are used to create a study population, there is always the risk of selection bias occurring. In Noels et al study, there was no mention of patient selection bias elimination methods such as randomization. The only methods mentioned were selection and exclusion criteria.²⁷

Another limitation encountered in the studies included in this literature review is the use of a single site registry which leads to selection bias. This was seen in Duncan et al study. They also did not mention randomization and had an unclear inclusion or exclusion criterion which can lead to measurement bias.²⁰ This may explain the contrasting absence of a statistically significant effect on postoperative AF in Basnet et al study while Duncan et al showed lower rates of overall morbidities.²¹ We would suggest conducting a randomized control trial as it will provide more evidence on the safety of biguanides usage prior to surgery.

Study Properties

Multiple studies mentioned in this literature review were clinical trials. However, there was a lack of large studies with a long study period and definitive endpoints such as MI at 12 months.⁵⁷

Another limitation encountered was the use of healthy controls, as seen in Noels et al’s study assessing the effect of DPP-4, where the diabetic patients’ comorbidities may have altered the results due to the absence of comorbidities in the control group.²⁷

Age Range

Most studies had an inclusion criterion of 18 years or above. Specifically, Udell et al restricted the study to 19 years or above, Margolis et al only considered patients aged 40 and over, and Basnet et al’s study was confined to those over 18 years.^{16
,
17
,
21} While these age restrictions help ensure fully informed consent is gained from all participants, it leads to a potential lack of understanding regarding the risks of cardiovascular complications in the pediatric diabetic population. Furthermore, the difference in study participants’ ages can pose a challenge when trying to compare clinical outcomes.

Future Directions and Our Recommendations

Medications

This review has identified the use of metformin as a feasible contestant for patients with cardiovascular disease as it has shown to reduce mortality. This is also generally agreed by the EMEA and FDA.^{41
,
42} We also identified the use of thiazolidinediones as it has shown to have no major adverse effects on the cardiovascular system and is also regarded as neutral by the EMEA.⁴⁴ We do not however recommend the use of sulfonylureas (which the FDA suggest is neutral), biguanides, DPP-4 inhibitors and SGLT-2 inhibitors during the perioperative period. Nearly all studies investigated monotherapy, whereas in practice, combination therapies including repaglinide, meglitinide, or metformin are common for the treatment of diabetes.⁴² We recommend that more RCTs be done to directly compare the outcomes between different AMDs.

Glycemic Control

Multiple studies have shown strong evidence for the tight glycemic control pre- and post-operatively. Therefore, we recommend maintaining glucose levels <180 mg/dl for diabetic patients. This has been shown to reduce mortality significantly.³⁰ While studies related to this have mentioned the use of constant insulin infusion for glycemic control pre- and post-operative, other studies have shown that this may increase the risk of MI and other adverse events.^{16
,
19} The EMEA states that insulin has a neutral effect and, in some cases, a beneficial effect but we recommend further research into the use of insulin as the FDA advises caution in certain patient populations.^39,40 There is also a lack of clarity in the guidance for intensive care unit glucose targets, which suggests a need for larger studies to better provide a gold standard reference range.

Multidisciplinary Diabetic Team Management

We also recommend the use of a postoperative dedicated multidisciplinary diabetic team to manage the transition from pre-operative to post-operative intensive care. This has been shown to reduce length of stay from a mean of 8.3 ± 0.18 days in 2002 to 7.7 ± 0.10 days in 2006. A much more significant fall was seen for emergency admissions from 9.7 ± 0.23 to 9.2 ± 0.20 (P < .001).⁵⁸ This shows that a team dedicated for diabetic patients following surgery can lead to a significant reduction in the length of stay. This is also supported by the EACT’s guidelines which supports regular follow-ups maintenance of HbA1c levels below 7%.⁵⁸

Another study by Warrington et al assembled a multidisciplinary team of pharmacists, physicians and other health care providers to provide optimum diabetic patient care for those undergoing CABG and other patients who have different causes of hyperglycemia.⁵⁹ Success was monitored by measuring postoperative serum blood glucose levels from January 2008 to December 2010. Analysis post-intervention identified an absolute risk reduction for serum blood glucose concentrations of >200 mg/dL on postoperative days 1 and 2 of 28.5% (95% CI: 0.20-0.36%).⁵⁹

Gender Perspectives

As discussed previously, diabetic women seem to be more greatly affected by the macrovascular complications of diabetes than their male counterparts. These findings challenge the assumptions of the cardioprotective nature of estrogen and demonstrate that the interactions between sex hormones and diabetes are complex and diverse. While the exact mechanism responsible for this difference between gender is still unknown, further research into the gender differences in diabetes may yield the answer. Future diabetic treatments may progress to involve tailored, sex-specific medications and risk factor modifiers to counteract the differences in diabetic CAD gender outcomes.

Patient Satisfaction

As discussed previously, patients that are satisfied with their treatments have better outcomes, therefore, targeting ways to improve satisfaction can lead to decreased cardiovascular complications.^37,38 A study by Gross et al indicates that being treated by a diabetic MDT does not only provide the clinical benefits previously mentioned but also increases patient satisfaction simultaneously which provides further incentive for their use.⁶⁰ Training programs can be designed for clinicians to improve their interpersonal skills and how to effectively provide diabetes education as these are both factors shown to improve satisfaction if performed correctly.^{60,
61} Encouraging clinicians to treat patients according to guidelines not only improves patient quality of care but have also been shown to improve patient satisfaction.⁶⁰ Guidelines can incorporate ways of assessing patient satisfaction such as the Diabetes Treatment Satisfaction Questionnaire (DTSQ) which can be used at patient reviews due to its simplicity, allowing clinicians to assess patients’ satisfaction with their current treatment regime or even use it to compare satisfaction to previous regimes, thereby assessing whether improvements are being made.⁶² The Diabetes Medication System Rating Questionnaire (DMSRQ) is more detailed than the DTSQ and allows for specific problems to be identified and can possibly be used on an annual basis.⁶³ The use of these questionnaires gives a more targeted approach to improving patient satisfaction and will hopefully lead to improved clinical outcomes.

Conclusion

There is significant evidence to suggest that diabetes is associated with adverse cardiovascular events. However, our study has found that the cardiovascular risks can be reduced by increasing patient satisfaction, integrating the dedicated diabetic team into hospital care, and identifying differences in diabetic gender outcomes. The use of different ADMs have been shown to cause either an increase or a decrease in a patient’s risk of developing cardiovascular complications. Therefore, clinicians should be aware of each class’ effect so that patients can be managed according to their individual needs and risks. To facilitate this, further research on the effects of ADMs on cardiovascular outcomes is required to enable the advisory bodies to produce unified guidelines to aid clinicians in the treatment of diabetic patients.

Footnotes

Authors' Note

Parker O'Neill and Marco Shiu Tsun Leung are co-first authors.

Author Contributions

P.O., M.S.T.L, and R.A.B.V. conducted literature research, designed tables, and wrote the manuscript. A.H. contributed to conception and design and supervised the work.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Marco Shiu Tsun Leung

Amer Harky

References

World Health Organization. DiabeteS. Published 2020. Accessed September 27, 2020. https://www.who.int/news-room/fact-sheets/detail/diabetes

Matheus

Tannus

Cobas

Palma

Negrato

Gomes

. Impact of diabetes on cardiovascular disease: an update. Int J Hypertens. 2013:653789.

Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States. Published 2014. Accessed September 27, 2020. https://www.cdc.gov/diabetes/data/statistics-report/index.html

Bommer

Sagalova

Heesemann

, et al. Global economic burden of diabetes in adults: projections from 2015 to 2030. Diabetes Care. 2018;41(5):963–970.

Bahia

Araujo

Schaan

, et al. The costs of type 2 diabetes mellitus outpatient care in the Brazilian public health system. Value Health. 2011;14(5):137–140.

Omar

Ahren

. Pleiotropic mechanisms for the glucose-lowering action of DPP-4 inhibitors. Diabetes. 2014;63(7):2196–2202.

Hauner

. The mode of action of thiazolidinediones. Diabetes Metab Res. 2002;18(suppl 2):S10–S15.

Collins

Costello

. Glucagon-like peptide-1 receptor agonist. Stat Pearls. Published 2020. Accessed September 27, 2020. https://pubmed.ncbi.nlm.nih.gov/31855395/#:∼:text=Excerpt,albiglutide%2C%20dulaglutide%2C%20and%20semaglutide

Kalra

. Sodium glucose co-transporter-2 (SGLT2) inhibitors: a review of their basic and clinical pharmacology. Diabetes Ther. 2014;5(2):355–366.

10.

Marín-Peñalver

Martín-Timón

Sevillano-Collantes

Del Cañizo-Gómez

. Update on the treatment of type 2 diabetes mellitus. World J Diabetes. 2016;7(17):354–395.

11.

Mauricio

Hramiak

. Second-generation insulin analogues—a review of recent real-world data and forthcoming head-to-head comparisons. Eur Endocrinol. 2018;14(suppl 1):2–9.

12.

Sola

Rossi

Schianca

, et al. Sulfonylureas and their use in clinical practice. Arch Med Sci. 2015;11(4):840–848.

13.

Bahne

Sun

EWL

Young

, et al. Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes. JCI insight. 2018;3(23):e93936.

14.

Morrish

Wang

Stevens

Fuller

Keen

. Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia. 2001;44(2):S14–S21.

15.

Rawshani

Franzén

, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med. 2017;376(15):1407–1418.

16.

Margolis

Hoffstad

Strom

. Association between serious ischemic cardiac outcomes and medications used to treat diabetes. Pharmacoepidemiol Drug Saf. 2008;17(8):753–759.

17.

Udell

Cavender

Bhatt

Chatterjee

Farkouh

Scirica

. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2015;3(5):356–366.

18.

Schmeltz

DeSantis

Thiyagarajan

, et al. Reduction of surgical mortality and morbidity in diabetic patients undergoing cardiac surgery with a combined intravenous and subcutaneous insulin glucose management strategy. Diabetes Care. 2007;30(4):823–828.

19.

Higgs

Fernandez

The effect of insulin therapy algorithms on blood glucose levels in patients following cardiac surgery: a systematic review. JBI Database Syst Rev Implement Rep. 2015;13(5):205–243.

20.

Duncan

Koch

, et al. Recent metformin ingestion does not increase in-hospital morbidity or mortality after cardiac surgery. Anesth Analg. 2007;104(1):42–50.

21.

Basnet

Kozikowski

Sun

Troup

Urrutia

Pekmezaris

. Metformin therapy and postoperative atrial fibrillation in diabetic patients after cardiac surgery. J Intensive Care. 2017;5:60.

22.

Bolen

Feldman

Vassy

, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007;147(6):386–399.

23.

Garratt

Brady

Hassinger

Grill

Terzic

Holmes

. Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol. 1999;33(1):119–124.

24.

Vaccaro

Masulli

Nicolucci

, et al. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial. Lancet Diabetes Endocrinol. 2017;5(11):887–897.

25.

Meier

Weyhe

Michaely

, et al. Intravenous glucagon-like peptide 1 normalizes blood glucose after major surgery in patients with type 2 diabetes. Crit Care Med. 2004;32(3):848–851.

26.

Brackbill

Rahman

Sandy

Stam

Harralson

. Adjunctive sitagliptin therapy in postoperative cardiac surgery patients: a pilot study. Int J Endocrinol. 2012;2012:810926.

27.

Noels

Theelen

Sternkopf

, et al. Reduced post-operative DPP4 activity associated with worse patient outcome after cardiac surgery. Sci Rep. 2018;8(1):11820.

28.

Lau

Bruce

Wang

Ree

Rondi

Chau

. Perioperative implications of sodium-glucose cotransporter-2 inhibitors: a case series of euglycemic diabetic ketoacidosis in three patients after cardiac surgery. Can J Anaesth. 2018;65(2):188–193.

29.

Griffin

Leaver

Irving

. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017;60(9):1620–1929.

30.

Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283–1297.

31.

Vaidya

Gangan

Sheehan

. Impact of cardiovascular complications among patients with type 2 diabetes mellitus: a systematic review. Expert Rev Pharmacoecon Outcomes Res. 2015;15(3):487–497.

32.

Azoulay

Suissa

. Sulfonylureas and the risks of cardiovascular events and death: a methodological meta-regression analysis of the observational studies. Diabetes Care. 2017;40(5):706–714.

33.

Maric-Bilkan

. Sex differences in micro- and macro-vascular complications of diabetes mellitus. Clin Sci. 2017;131(9):833–846.

34.

Juutilainen

Kortelainen

Lehto

Rönnemaa

Pyörälä

Laakso

. Gender difference in the impact of type 2 diabetes on coronary heart disease risk. Diabetes Care. 2004;27(12):2898–2904.

35.

Lungberg

Stegmayr

Asplund

Eliasson

Huhtasaari

. Diabetes as a risk factor for myocardial infarction: population and gender perspectives. J Int Med. 1997;241(6):485–492.

36.

Kanaya

Grady

Barrett-Connor

. Explaining the sex difference in coronary heart disease mortality among patients with type 2 diabetes mellitus: a meta-analysis. Arch Intern Med. 2002;162(15):1737–1745.

37.

Glickman

Boulding

Manary

, et al. Patient satisfaction and its relationship with clinical quality and inpatient mortality in acute myocardial infarction. Circ Cardiovascu Qual Outcomes. 2010;3(2):188–195.

38.

Bakar

Fahrni

Khan

. Patient satisfaction and medication adherence assessment amongst patients at the diabetes medication therapy adherence clinic. Diabetes Metab Syndr. 2016;10(2 suppl 1):S139–S143.

39.

Parks

. Highlights of Prescribing Information. Food and Drug Administration (FDA); 2009.

40.

Scientific Discussion for Approval of Actrapid: Clinical Safety. European Medicines Agency (EMEA); 2004:25.

41.

Glucophase(R) (Metformin hydrochloride) Tablets. Bristol-Myers Squibb Company. Food and Drug Administration (FDA); 2017:16.

42.

Scientific conclusions of metformin. European Medicines Agency (EMEA). 2016:3.

43.

ACTOS (Pioglitazone Hydrochloride) Tablets. Takeda America Research and Development Center, Inc. Food and Drug Administration (FDA); 1999:14.

44.

Scientific Discussion of Pioglitazone. European Medicines Agency (EMEA); 2003:17–18.

45.

Guidance for Industry: Diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Endocrinologic and Metabolic Drugs Advisory Committee Meeting; 2018: 9–11.

46.

Victoza. Procedural steps taken and scientific information after the authorisation. Eur Med Agen (EMEA). 2019:9.

47.

Scientific discussion of sitagliptin—overall conclusions, risk/benefit assessment and recommendation. European Medicine Agency (EMEA); 2007:37.

48.

Highlights of Prescribing Information: Farxiga, Warnings and Precautions. Food and Drug Administration (FDA); 2014:4–6.

49.

Assessment report: SGLT 2 inhibitors. European Medicine Agency (EMEA); 2016:5–7.

50.

Sousa-Uva

Head

Milojevic

, et al. 2017 EACTS Guidelines on perioperative medication in adult cardiac surgery. Eur J Cardio-Thorac Surg. 2017;53(1):5–33.

51.

Halkos

Lattouf

Puskas

, et al. Elevated preoperative hemoglobin A1C level is associated with reduced long-term survival after coronary artery bypass surgery. Ann Thorac Surg. 2008;86(5):1431–1437.

52.

Haga

McClymont

Clarke

, et al. The effect of tight glycaemic control, during and after cardiac surgery, on patient mortality and morbidity: a systematic review and meta-analysis. J Cardiothoracic Surg. 2011;6:3.

53.

Type 2 diabetes in adults: management: National Institute for Health and Care Excellence (NICE). Published 2015. Accessed August 30, 2020. www.nice.org.uk/guidance/ng28

54.

Dhatariya

. Management of adults with diabetes undergoing surgery and elective procedures: improving standards. Joint British Diabetes Societies Inpatient Care Group. 2011.

55.

Kotagal

Symons

Hirsch

, et al. Perioperative hyperglycemia and risk of adverse events among patients with and without diabetes. Ann Surg. 2015;261(1):97–103.

56.

Greco

Ferket

D’Alessandro

. Diabetes and the association of postoperative hyperglycemia with clinical and economic outcomes in cardiac surgery. Diabetes Care. 2016;39(3):408–417.

57.

Kumar

Kerins

Walther

. Cardiovascular safety of anti-diabetic drugs. Eur Heart J Cardiovasc Pharmacother. 2016;2(1):32–43.

58.

Flanagan

Moore

Baker

Wright

Lynch

. Diabetes care in hospital—the impact of a dedicated inpatient care team. Diabet Med. 2008;25(2):147–151.

59.

Warrington

Ayers

Baldwin

, et al. Implementation of a pharmacist-led, multidisciplinary diabetes management team. Am J Health-Syst Pharm. 2012;69(14):1240–1245.

60.

Gross

Tabenkin

Porath

, et al. The relationship between primary care physicians’ adherence to guidelines for the treatment of diabetes and patient satisfaction: findings from a pilot study. Family Practice. 2003;20(5):563–569.

61.

Boels

Vos

Hermans

TGT

, et al. What determines treatment satisfaction of patients with type 2 diabetes on insulin therapy? An observational study in eight European countries. BMJ Open. 2017;7(7):e016180.

62.

Saisho

. Use of diabetes treatment satisfaction questionnaire in diabetes care: importance of patient-reported outcomes. Int J Environ Res Public Health. 2018;15(5):947.

63.

Peyrot

Harshaw

Shillington

Rubin

. Validation of a tool to assess medication treatment satisfaction in patients with type 2 diabetes: The Diabetes Medication System Rating Questionnaire (DMSRQ). Diabet Med. 2012;29(8):1060–1066.

Diabetic Control Agents and Their Impact on Cardiac Surgery Patients: A Clinical Overview

Abstract

Keywords

Introduction

Pharmacology of Diabetic Control Medications

Mortality

Morbidity

Gender Perspectives

Patient Satisfaction

Guidelines

Antidiabetic Medicines and Cardiovascular Impact

ADMs and Cardiovascular Surgical Outcomes

Limitations

Bias

Study Properties

Age Range

Future Directions and Our Recommendations

Medications

Glycemic Control

Multidisciplinary Diabetic Team Management

Gender Perspectives

Patient Satisfaction

Conclusion

Footnotes

Authors' Note

Author Contributions

Declaration of Conflicting Interests

Funding

ORCID iDs

References