Cardiovascular Risk-Reducing Hyperglycemic Medications in Treating Adult Type 2 Diabetes
Purpose of the Review
Diabetes mellitus (DM) is associated with significant morbidity, mortality, and medical care costs. According to Yandrapalli and Aronow (2017), Type 2 DM (T2DM) represents the most common, affecting approximately 90 to 95 percent of those diagnosed with the disease among adults in the United States (US). The treatment of the condition has experienced a paradigm shift as the discovery becomes more common that T2DM is a major risk factor for cardiovascular (CV) disorder. Carbone et al. (2019) observe that while antihyperglycemic therapies typically target the glycemic control, there is now more focus on reducing the danger of CV events. Yandrapalli and Aronow (2017) claim that T2DM individuals are two to three times more at risk of CV compared with their non-diabetic counterparts, with CV mortality accounting for 80 percent of the deaths in T2DM. Hyperglycemia plays a little role in CV progression, compared with the metabolic risk factors that play a major role in the initiation and progression of the disease. For instance, the major culprits include hypertension, insulin resistance, dyslipidemia, and obesity (Yandrapalli & Aronow, 2017). Hence, the purpose of the literature review is to assess research concerning the perceived patient barriers to taking newly-indicated cardiovascular risk-reducing antihyperglycemic medications for 30 days in treating adult T2DM with established CV disease. The SGLT-2 inhibitors and GLP1-receptor agonists represent the new classes of therapeutics for diabetes treatment.
Literature Search
The literature search conducted used the databases, including Google Scholar, Medline, PMC, and a direct search on the Google search engine. The search entailed the use of keywords such as “hyperglycemic treatment, T2DM therapy, cardiovascular risk in T2DM, GLP-1 receptors, and SGLT-2 inhibitors.” Besides, the inclusion criteria constituted the selection of only the articles published from 2015 to 2020, original research studies, meta-analyses, systematic reviews, and researches establishing the link between CVD and T2DM. The exclusion criteria entailed leaving out anecdotal reports, summary articles, and general studies on the status of diabetes treatment. The review incorporated 15 articles that are relevant to the research problem. Furthermore, the major themes identified included the risk of CVD in patients with T2DM and its reduction. Besides, the important aspects of the Diabetes Care Guidelines 2020 entailed reducing CV in T2DM using SGLT-2 and GLP-1 treatments. The patient barriers to diabetes medication also identified include provider inertia and nonadherence to treatment.
CVD Risk in T2DM Patients
According to Abdul-Ghani et al. (2017), hyperglycemia represents a major risk factor for microvascular complications in T2DM patients. Since the principal cause of mortality is CVD, the lowering of hemoglobin A1C (HbA1C) produces modest effects in the reduction of CVD risk and death. Recently published trials demonstrate that the use of glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) lower the primary major adverse cardiac events endpoint. Since hyperglycemia is a weak CVD risk factor, the reduction of plasma glucose is not an effective therapy for lowering the CV risk and death (Abdul-Ghani et al., 2017). T2D individuals often show moderate to severe resistance to insulin, which is connected to multiple CV risk factors like obesity, procoagulant state, hypertension, dyslipidemia, and endothelial dysfunction. The insulin resistance syndrome is associated with increased risk for CV in T2D and requires a multifactorial intervention to improve the CV risk factors. Besides, the molecular mechanisms for insulin resistance directly contribute to atherosclerosis pathogenesis. Hence, individuals with obesity and insulin resistance syndrome but without diabetes are at a heightened danger for CVD compared with patients with T2D. The finding proves that hyperglycemia is not a major CVD risk factor, and the reduction of blood pressure and improvement of the lipid profile is preferred to manage CVD than plasma glucose reduction in diabetic patients (Abdul-Ghani et al., 2017). Hence, improving insulin sensitivity and the multiple insulin resistance syndrome components should be considered in treating T2D because of improved favorable effects on CVD risk.
Similarly, Gao et al. (2019) observe that evidence-based therapy targeting hypertension, hyperlipidemia, weight loss, and the cessation of smoking are significantly beneficial in the reduction of CVD risks. Hence, antidiabetic medications like GLP-1RAs and SGLT-2 inhibitors have indicated cardiovascular benefits on top of their antihyperglycemic effect. The macrovascular benefits are independent of the glycemic outcomes. Gao et al. (2019) report that the use of evidence-based therapy and management of cardiovascular risk in T2D and CVD is significantly suboptimal. For instance, between 199 and 2010, 78.7 percent of adults with T2D and CVD failed to attain one or more guideline-recommended goals for HbA1C, low-density lipoprotein cholesterol (LDL-C), and blood pressure (Gao et al., 2019). The failure to manage the CV risk factors is linked with significant barriers, some associated with the patient. Gao et al. (2019) list medication nonadherence and patient mistrust of providers as the challenges for treating CVD in T2DM. The evaluation of medication adherence utilizes the proportion of days covered (PDC), and medication possession ratio (MPR) measures for evaluation. Further, the nonadherence could be intentional or unintentional behavior, especially among patients with diabetes and cardiovascular risk factors compared with those with CV alone. Besides, the patient-physician mistrust hampers patients’ desire to share their viewpoints with providers and causes nonadherence.
Cardiovascular Risk-Reduction in Treating T2DM
CVD is among the most common comorbidities among people with diabetes type 2. Ali et al. (2019) report that global clinical records from over 4.5 million individuals indicate about a third have CVD, including coronary heart disease (CHD), myocardial infarction, heart failure (HF), angina, and stroke. Since a large proportion of diabetic individuals managed in routine practice have concomitant CVD, important questions have emerged regarding treatment. There is a question of whether to address each condition in isolation, or there is a need for a holistic, personalized approach that considers the shared risk factors and contributes to improved outcomes (Ali et al., 2019). Importantly, heart failure represents the most common and earliest presenting CV complications in people with T2DM, while previous considerations around CV outcomes have focused on the prevalence of MI, stroke, and CV mortality (Stones et al., 2018). Ali et al. (2019) establish a bidirectional relationship between T2DM and HF concerning the disease risks, with insulin resistance and hyperglycemia common factors in the development of both conditions. Therefore, there is a need for selection effective treatment approaches in routine practice recognizing both diseases. The providers must make considerations that exceed just elevated HbA1c in developing management strategies because of the independent determinant conditions for CVD in T2DM. Thus, a personalized approach that lowers glucose and reduces CV risk factors is appropriate and has been witnessed with the use of SGLT2 inhibition therapy.
Furthermore, Mohan et al. (2019) emphasize the need to reduce micro- and macrovascular outcomes in the treatment of T2DM. The major macrovascular events include death from CV causes, non-fatal MI, or non-fatal stroke, while microvascular events are new or aggravating nephropathy or retinopathy. Mohan et al. (2019) report that numerous studies have addressed concerns about sulfonylureas and cardiovascular complications. The researches show no difference in the risk of major adverse CV events or all-cause death between second-generation sulfonylureas and other categories of oral glucose-lowering agents. For example, the ADVANCE trial indicated that compared to standard control, intensifying gliclazide modified release (MR) treatment was related to long-term benefits on microvascular end points (Mohan et al., 2019). Besides, a network of meta-analysis showed later-generation sulfonylureas was associated with a lower risk of all-cause CV-related death. Similarly, the TOSCA.IT primary prevention trial provided proof for CV safety of second-generation sulfonylureas (Mohan et al., 2019). Besides, multiple CV outcomes trials (CVOTs) indicated that the newer agents like GLP-1RA and SGLT2i have an extended benefit in managing T2DM and CV outcomes. Hence, the goal of T2DM treatment is to use the agents that have demonstrated cardiovascular safety and benefits in macro- and microvascular outcomes. No wonder, the second-generation therapies are preferable over the older-generation agents because they show positive effect.
2020 Diabetes Care Guidelines
The American Diabetes Association (ADA) provides clinicians, researchers, patients, payers, and other interested parties with components of diabetes care, general treatment goals, and tools for evaluating the care quality. According to the ADA (2020), the Standards of Medical Care in Diabetes recognizes diabetes as a complex and chronic illness that requires continuous medical care applying multifactorial risk-reduction strategies exceeding glycemic control. The Standard of Care recommends measures such as screening, diagnostic, and therapeutic actions that favorably affect the patient health outcomes. ADA (2020) suggests that the pharmacologic agents for treating T2DM, including metformin, alpha-glucosidase inhibitors, GLP-1RAs, and thiazolidinediones, are approved for weight loss and reduce the rate of diabetes. Since individuals with prediabetes also have CV risk factors and susceptible to CVD, the therapeutic goals warrant increased vigilance to identify and treat the cardiovascular risk. Hence, ADA (2020) recommends the screening and treatment of the modifiable determinant conditions for CVD. Interaction between the care team and the patient is necessary for ensuring patient-centered collaborative care through close working relationships. The goals of intervention for diabetes are to prevent or delay complications and optimize life quality. Care teams must consider the patient’s choices, thereby requiring personalized intervention.
Reducing Cardiovascular Risk in T2DM with SGLT-2 and GLP-1
Inzucchi et al. (2015) argue that the multi-faceted pathogenesis of atherosclerosis in T2DM requires the mitigation intervention to address CV risk factors beyond glucose. Hence, SGLT-2 inhibitors represent a newer antihypoglycemic agent with multiple effects. For example, the treatment has the inherent ability to improve glycemic control by their mode of action to decrease the kidney glucose reabsorption. The agent works independent of insulin secretion with a low risk of hypoglycemia and increases the excretion of urinary glucose (Inzucchi et al., 2015). Furthermore, the goal of reducing CV risk in treating T2DM might incorporate glycemic control because it plays a crucial role in preventing and reducing CV complications. However, with existing multiple CV determinant factors beyond hyperglycemia, glucose-lowering treatment alone cannot be effective. There is the need for a multifactorial approach that incorporates blood pressure (BP) and lipid control, smoking cessation, weight management, and anti-platelet therapy when indicated (Inzucchi et al., 2015). Accordingly, SGLT-2 inhibitors are appropriate because they reduce renal glucose reabsorption, thereby increasing urinary glucose excretion (UGE). The US Food and Drug Administration (FDA) has approved SGLT-2 drug classes, which are canagliflozin, dapagliflozin, and empagliflozin (Inzucchi et al., 2015). Placebo-controlled phase III trials indicate that when the agents are used as monotherapy or combined with other glucose-lowering medications, they improve glycemic control with a low hypoglycemia risk. Besides, they reduce body weight and BP without increasing the heart rate as part of the compensatory mechanism. Zou et al. (2019) emphasize that SGLT-2 inhibitor treatment has a protective effect on the myocardium by enhancing epicardial adipose tissue (EAT) differentiation and reducing proinflammatory chemokine secretion. Arnott et al. (2020) draw a slightly different conclusion that highlights the effectiveness of SGLT-2 inhibitors in protecting against CVD and death among patients with T2DM, disregarding the history of CVD or kidney function. Among people with reduced kidney function, the treatment may protect against stroke. Therefore, the medication is beneficial for T2DM patients, even with absent established disease.
Meanwhile, the use of GLP-1 receptor agonists improves cardiovascular risk factors like dyslipidemia, glycemic control, weight, or arterial hypertension (Del Olmo-Garcia & Merion-Torres, 2018). The treatment also indicates benefits on endothelial function, heart failure, and coronary ischemia. GLP-1 RAs are both innocuous and beneficial in CVD. Del Olmo-Garcia and Merion-Torres (2018) argue that GLP-1 exerts action through GLP-1R, which are affected in numerous areas because of the wide GLP-1R distribution in the body. The actions include increasing glucose-dependent insulin synthesis and secretion, delay of gastric emptying and inhibiting pentagastrin and acid secretion that food ingestion stimulates, and CV benefits on BP. Additionally, GLP-1 acts as a neurotransmitter acting on the central nervous system (CNS) and peripheral nervous system (PNS). Del Olmo-Garcia and Merion-Torres (2018) note that the administration of short-acting GLP-1 RAs in relation to meals exhibit large plasma concentration fluctuations. Consequently, they cause intermittent GLP-1 RA activation that produces a modest effect on glucose levels between doses and fasting plasma glucose and HbA1c control. Besides, the long-acting agonists acting on the GLP-1R and administered daily or weekly prolong their pharmacodynamic action. They are more effective in fasting plasma glucose reduction and in controlling HbA1c compared with the short-acting medications. Besides, GLP-1 analogues used as treatment help reduce BP values, with the decrease independent of weight loss. The medication possibly acts by directly activating GLP-1 in arteries and the renal system (Del Olmo-Garcia & Merion-Torres, 2018). They may also improve endothelial function and inhibit the renin-angiotensin-aldosterone system (RAAS) in the vasodilator and natriuretic effect. Bashier et al. (2019) recommend that patients at a high risk for CVD or renal issues should choose the best treatment from SGLT2i and GLP1-RA. Additionally, in case the selected category does not work effectively, the individual should switch to the second class as a third line treatment.
Patient Barriers to taking T2DM medication
Provider Inertia
According to Okemah et al. (2018), there is a rising number of people with T2DM failing to achieve glycemic goals due to factors such as the delay in intensifying treatment, also known as clinical inertia. The problem prolongs the patient’s hyperglycemia and exposes them to the increased risk of diabetes-related complications and reduced life expectancy. Clinical inertia exists despite the increased availability of antihyperglycemic medications (Okemah et al., 2018). The patients fail to intensify their treatment despite not attaining their A1C goal, thus experiencing suboptimal glycemic control before therapeutic escalation. Significantly, clinical inertia hinders patients from escalating treatment from oral antidiabetes medications (OADs) to insulin therapy. Patients optimized on basal insulin without reaching their A1C targets fail to intensify therapy, even after achieving fasting plasma glucose (FPG) within target ranges (Okemah et al., 20108). Overcoming clinical inertia in T2DM is crucial in improving the long-term care for the patients and requires understanding the provider, patient, and healthcare system barriers and addressing them. Issues related to medication side effects contribute to the delayed treatment intensification for both healthcare providers and the patients. There are also weight gain concerns, the fear of hypoglycemia, and the increasing complexity of medication regimens that demand familiarization with new administration methods and dosing schedules (Okemah et al., 2018). The patient-related barriers can discourage the providers from initiating intensification therapy.
Patient Nonadherence with Medication Use
The adherence to T2DM treatment is important in the clinical care of the condition because it contributes to the effectiveness of therapy and the patient’s wellbeing. Brundisini et al. (2015) assert that poor compliance with medication regiments increases negative outcomes. The management of diabetes targets optimal levels of blood glucose to prevent the onset and progression of diabetes-related complications. Hence, effective therapy includes compliance with treatment regimens, whether insulin injections or hypoglycemic oral tablets. Nonadherence represents a challenge for both the patient and the healthcare systems because it increases morbidity and mortality, reducing the quality of life, and increasing the costs of medical care. The patient can refuse or fail to comply with the prescription medication instructions due to a lack of motivation or knowledge (Brundisini et al., 2015). Therefore, it is important to acknowledge the patient’s voices in making treatment decisions because their views on medications matter.
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