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The Evolving Landscape of T2DM Management

The Evolving Landscape of T2DM Management

Type 2 diabetes mellitus (T2DM) is a disease characterized by hyperglycemia and insulin resistance and it affects approximately 28 million people in the United States (US).1 The prevalence of diabetes has almost doubled in the last two decades and it costs the US economy $245 billion annually; with most costs attributed to T2DM.1 Furthermore, about 7.2 million people with diabetes are not diagnosed, and an estimated 84.1 million people have prediabetes.2 Maintaining glycemic control is crucial in the long-term management of T2DM and to decrease the risk of major complications, and its importance is widely recognized in the clinical practice guidelines.3 However, even with the plethora of therapies currently approved for the management of T2DM, glycemic control remains suboptimal.4 Maintaining target HbA1c within the normal range remains elusive in many type 2 diabetics. Beyond HbA1c targets, patients with type 2 diabetes should also monitor glycemic variability, which has been associated with long-term T2DM complications such as cardiovascular disease.5 Now literature supports the view that while managing chronic hyperglycemia is important, closely monitoring glycemic variability (such as dangerous postprandial glucose spikes or hypoglycemia) is equally as relevant. Although many pharmacotherapies are available for treatment, spanning from the traditional (such as metformin, sulfonylureas, basal insulin, thiazolidinediones) to newer (newer insulins, DDP-4 inhibitors, SGLT-2 inhibitors, GLP-1 RAs) agents, there are still several major barriers in optimizing T2DM care:

  • Personalization of treatment remains a challenge for clinicians
  • Low patient adherence to treatment
  • Clinical inertia
  • Lack of clinician education about newer antidiabetic agents
Insulin therapy and clinical inertia
The main pathophysiology that has gotten the most attention in the treatment of T2DM is insulin resistance, or the decreased action of insulin in target tissues (primarily liver, skeletal muscle, and adipose tissue), leading to chronic hyperglycemia. In pre-diabetes and T2DM, initially there is an increased production of insulin from the pancreatic beta-cells to compensate for this insulin resistance. This “overproduction” ultimately leads to beta-cell death and decreased insulin secretion; meaning that most type 2 diabetics will need exogenous insulin administration at some point during their lifetime.6 Thus, defining T2DM as “non-insulin dependent diabetes mellitus” was not entirely accurate, and now is widely recognized and accepted that both insulin resistance and inadequate insulin secretion are major pathophysiologies of T2DM. The American Association of Clinical Endocrinologists and American Diabetes Association guidelines recommend early intensification of therapies targeting beta-cell preservation, initiating dual therapy with anti-hyperglycemic agents in untreated type 2 diabetes patients having A1Cs ranging from 7.6-9%. However, initiation of insulin is often delayed by at least 5 years, despite the patient’s need for glycemic control.7 Most clinicians and patients prefer to choose dual or even triple oral therapy before selecting injectable basal insulin to reach the patient’s individualized glycemic target, and its initiation in T2DM is often delayed.4,8,9 Physicians' barriers to initiation of insulin therapy include concerns about potential adverse effects (e.g., increased hypoglycemia and weight gain) and practical concerns (e.g., patient anxiety about insulin, perceived adherence issues, difficulties in training patients to administer insulin).4 In an international survey and a clinical practice review, PCPs and diabetes specialists reported that insulin initiation was prevented by lack of:4,10

  • time required to train patients
  • clear guidelines and definitions
  • support, as represented by Certified Diabetes Educators
  • experience in taking a proactive role in insulin initiation
  • coordination of care between PCPs and endocrinologists
  • motivation
Intensification has traditionally been achieved by adding short-acting insulin to cover post-prandial glucose (PPG) excursions that are not targeted by basal insulin. Intensive insulin regimens often result with a higher risk of hypoglycemia and weight gain, which can contribute to a greater cardiometabolic burden on patients.4Recently, newer ultra-fast-acting mealtime insulins have been approved, which allow for greater flexibility in managing PPG control.11 An alternative is to intensify therapy by adding a short-acting glucagon-like peptide 1 receptor agonist (GLP-1RA) rather than prandial insulin. This provides complementary actions, lowering both post-prandial glucose and fasting plasma glucose, and improves glycemic control with no increased hypoglycemia or weight gain.12 Recent studies have demonstrated that the combination of a GLP-1 RA with a basal insulin results in better glycemic control than adding multiple mealtime insulins.13Due to this evidence, the basal insulin/GLP-1 RA combination has been incorporated as a possible treatment option by both ADA/EASD and AACE/ACE.9,14 In addition, two agents that contain a fixed-ratio combination of basal insulin and GLP-1 RA delivered as a single daily injection are FDA approved (glargine U-100/lixisenatide and degludec/liraglutide).15,16 These fixed-ratio combinations combine the clinical advantages associated with basal insulin and GLP-1RA therapy while limiting the primary side effects of each individual agent.15,16 Given the benefits of a convenient once-daily schedule and improved glycemia and weight control with no increase in the incidence of hypoglycemia, early initiation of single dose GLP-1 RA/insulin combination therapy is an emerging treatment option for a spectrum of patients with type 2 diabetes, including those not controlled using metformin alone, metformin combined with another oral agent, or basal insulin.15,16
Navigating treatment algorithms

Current guidelines as put forth by the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) statement, and the consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) on the Comprehensive Type 2 Diabetes Management Algorithm, recommend an individualized approach that takes into account age, comorbidities, and hypoglycemia risk, as well as the patient’s access to resources and support systems.13,14 Because overly aggressive control in older patients with more advanced disease may not show significant benefits, current guidelines emphasize an individualized approach to treatment, taking into account the adverse effects of glucose-lowering medications, as well as the patient’s age and health status.
In certain patients, the goal of 7.0% may need upward adjustment, such as in those with longer diabetes duration, co-morbidities, shorter life expectancy, and advanced complications including nephropathy and severe hypoglycemia. Data from the National Health and Nutrition Examination Survey (NHANES) and the Veterans Administration found that diabetes is over-treated and over-intensified in those over 65 years, increasing the risk of severe hypoglycemia and hospitalization.17,18 Indeed, a large randomized trial of patients with an average age of 62 years showed that intensive treatment to target HBA1c levels < 6.0% resulted in increased mortality and no reduction in major cardiovascular events.19 Both the ADA and American Geriatric Society recommend that glycemic targets in the elderly need to be individualized based on their functional and cognitive status and life expectancy, with a focus on minimizing the complications of hypoglycemia as well as hyperglycemia and maximizing day-today functionality.20
While metformin is considered the first-line of pharmacotherapy, the rapid increase in the number of new therapies makes the choice of a second and third T2DM medication more difficult, and clinicians need to understand the comparative evidence of newer treatment choices to help guide clinical decision making.21 Metformin remains the initial drug of choice because of its antihyperglycemic efficacy, low risk of hypoglycemia, modest weight loss, low cost, and possible benefits on cardiovascular outcomes. In addition to reducing cardiovascular risk, patients should also be advised to stop smoking and adopt healthy lifestyle habits, and, if indicated, be prescribed antihypertensive therapy, statins, and antiplatelet therapy. If the initial HBA1c target is not reached after three months, one of six treatment options should be considered: a sulfonylurea, thiazolidinedione (TZD), dipeptidyl peptidase 4 (DPP-4) inhibitor, sodium glucose cotransporter 2 (SGLT-2) inhibitor, glucagon-like peptide-1 receptor agonist (GLP-1RA), or basal insulin. If, after another three months of dual therapy, HBA1c targets are still not reached, a third drug may be added. At that point, the addition of a third oral agent may enhance treatment efficacy, but the third drug will likely be less efficacious than if it were given as first-line or second-line therapy.14 Unfortunately, most clinicians and patients prefer to continue with oral agents before deciding to add an injectable basal insulin or GLP-1RA to reach the glycemic target.8Although sulfonylureas and TZDs have been routinely used in T2DM, they are associated with hypoglycemia and weight gain. DDP-4 inhibitors, on the other hand, are weight neutral and have a low risk of hypoglycemia.
A new class of medications, the gliflozins (SGLT-2 inhibitors), have shown efficacy in the treatment of type 2 diabetes with positive clinical outcomes of significant decrease in HbA1c and weight, without significant increases in hypoglycemia.22 This is an especially attractive profile since hypoglycemia and excessive weight gain are a major barrier to intensive glycemic control for many patients with T2DM. The mechanism of action for this class of agents is inhibition of the sodium-glucose transport protein (SGLT-1 or SGLT-2), located in the proximal convoluted tubule of the kidney, which increases glucose excretion and thereby improves glycemic control in those with diabetes.22 In 2013-2014, The US Food and Drug Administration (FDA) approved three oral SGLT-2 inhibitor agents as monotherapy for patients with T2DM: empagliflozin, canagliflozin, and dapagliflozin22; ertugliflozin was FDA approved in December of 2017 and sotagliflozin (a dual SGLT1 and SGLT2 inhibitor) is in phase 3 trials.22 Another new class of agents, the GLP-1 RAs, potentiate the effects of endogenous GLP-1, an incretin hormone that is secreted following a meal bolus. Effects of GLP-1 RA include stimulation of insulin secretion and inhibition of glucagon release when hyperglycemia is present, delay of gastric emptying, reduction of food intake with associated weight loss, and reduction of fasting and postprandial glucose.23 Five subcutaneous injectable formulations are available (lixisenatide, liraglutide, exenatide, dulaglutide, albiglutide) with variable dosing, efficacy, and tolerability.23 Three GLP-1 RAs formulations (exenatide, albiglutide, dulaglutide) are available for once-weekly dosing.23 Semaglutide as a once-weekly injection was approved at the end of 2017, and a novel oral formulation, is in the later stages of the FDA approval process.23 In addition to their glucose-lowering effects, results from recent cardiovascular outcome trials (CVOTs) have indicated that two SGLT-2 inhibitors (canagliflozin and empagliflozin) and two GLP-1 RAs (liraglutide and semaglutide) may be beneficial in decreasing cardiovascular risk in patients with T2DM and heart disease.24
Clinical practice guidelines and algorithms from ADA/EASD and AACE/ACE reflect the latest evidence-based data, incorporating the latest agents, results from CVOTs, emphasizing the need for individualizing treatment therapies, and focusing on patient-centered care.13,14 However, these guidelines have differences in their specific recommendations for monotherapy, step-wise therapy, as well as use different levels of HbA1c for recommendation of treatment initiation,13,14, which can add to the challenges clinicians face in optimizing care. Implementing the latest evidence-based therapies and guidelines is crucial in T2DM management, however clinicians should consider patient characteristics, co-morbidities, as well as efficacy and safety of anti-diabetic drugs.
An update on continuous glucose monitoring (CGM)

Measuring HbA1c has been the method of choice to assess glucose control; however, this method does not reflect potential glucose excursions leading to hypoglycemia or postprandial hyperglycemia, which increase the risk of long-term complications.5 Self-monitoring of blood glucose (SMBG), although beneficial in glycemic control, is associated with low patient adherence. The limitations of HbA1c measurement for glycemic control were recognized in the latest American Diabetes Association (ADA) standards of care for diabetes.13 Continuous glucose monitoring (CGM) technology can circumvent some of these issues in T2DM management by providing near real-time glucose concentrations derived from interstitial fluid (Danne 2017; Petrie 2017; Riddle 2017).5,25,26 Clinical trials have supported the role of CGM in improving HbA1c and decreasing potentially dangerous glycemic excursions in diabetic patients.27-30 The emergence of CGM has given clinicians more options in individualizing T2DM management; however, several factors have contributed to the relatively low implementation of such devices in clinical practice.5,25,26
The landscape for CGM technology is rapidly changing with the continual development of new devices, tools, and applications; thus, clinicians may have trouble navigating this evolving field. Education about existing guidelines and recommendations along with how clinicians can incorporate newest CGM technologies into their practice may help improve management of patients with T2DM. To date, a few position statements and guidelines have been put together by different professional societies to aid clinicians in incorporating CGM technologies in diabetes management.31-33 However, lack of consensus in use of available CGM remains a challenge. In 2017, a group of experts in CGM technologies, consisting of physicians, researchers, and patients, formulated new recommendations aimed to improve the utility of CGM, titled “International Consensus on Use of Continuous Glucose Monitoring”.5 The panel reviewed and made recommendations about the accuracy, data reporting, and utility of CGM systems. It called for usage of CGM technologies that have an acceptable level of accuracy and for standardization of key CGM metrics to assess glycemic control in order to optimize clinical decision-making.5 Furthermore, the panel reviewed different aspects of glycemic control that can be aided by CGM technologies, such as risk of hypoglycemia, glycemic variability, and HbA1c levels.5
Although the evidence regarding the use of CGM in T1DM patients is more robust, such evidence remains incomplete for T2DM. While it was initially believed that glucose measurements derived from interstitial fluid (measured by CGM sensors) were not as reliable as capillary blood glucose (using standard of care), recent studies have reported otherwise. A study evaluating the use of CGM in patients with T1DM reported that an increased time in target glucose range when insulin administration decisions were based on CGM as opposed to SMBG34; and CGM technologies have been demonstrated to be reliable when used with automated insulin delivery (AID) systems.25 CGM can be a more reliable tool in detecting glycemic variability, as demonstrated by a recent study comparing CGM to SBGM in patients with T1DM or T2DM (Mangrola 2017).35 Data from several studies support the use of CGM to determine glucose variability in T2DM patients.36-38
These studies have provided evidence about the utility of CGM technologies in managing T2DM, however, there is still a need for larger randomized clinical trials (RCTs) to evaluate CGM technologies in this setting.25 Furthermore, evaluating the utility of CGM devices is complicated by the different treatment regimens for T2DM patients, as well as the lack of standardization of outcome measures for glycemic control and glucose variability.25 CGM technologies have the potential to individualize treatment and care in T2DM, such as for patients at high risk for hypoglycemia, on insulin therapy, or with chronic kidney disease.5
Management of type 2 diabetes mellitus is constantly evolving, not only because there are new therapies and technologies available to clinicians, but also due to the ever-changing treatment goals and the re-definition of glycemic control. While it is important to recognize the new advancements in T2DM care, clinicians must take into account the efficacy and safety of each new approach and tailor treatment to accommodate the specific patient needs and characteristics.


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    October 2019 | Vol. 2 Q4