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Future challenges and therapeutic opportunities in type 2 diabetes: Changing the paradigm of current therapy

Most algorithms for type 2 diabetes mellitus (T2DM) do not recommend treatment escalation until glycated haemoglobin (HbA1c) fails to reach the recommended target of 7% (53 mmol/mol) within approximately 3 months on any treatment regimen (“treat to failure”). Clinical inertia and/or poor adherence to therapy contribute to patients not reaching glycaemic targets when managed according to this paradigm. Clinical inertia exists across the entire spectrum of anti‐diabetes therapies, although it is most pronounced when initiating and optimizing insulin therapy. Possible reasons include needle aversion, fear of hypoglycaemia, excessive weight gain and/or the need for increased self‐monitoring of blood glucose. Studies have suggested, however, that early intensive insulin therapy in newly diagnosed, symptomatic patients with T2DM with HbA1c >9% (75 mmol/mol) can preserve beta‐cell function, thereby modulating the disease process. Furthermore, postprandial plasma glucose is a key component of residual dysglycaemia, evident especially when HbA1c remains above target despite fasting normoglycaemia. Therefore, to achieve near normoglycaemia, additional treatment with prandial insulin or a glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) is often required. Long‐ or short‐acting GLP‐1 RAs offer effective alternatives to basal or prandial insulin in patients inadequately controlled with other therapies or basal insulin alone, respectively. This review highlights the limitations of current algorithms, and proposes an alternative based on the early introduction of insulin therapy and the rationale for the sequential or fixed combination of GLP‐1 RAs with insulin (“treat‐to‐success” paradigm).

Most algorithms for type 2 diabetes mellitus (T2DM) do not recommend treatment escalation until glycated haemoglobin (HbA1c) fails to reach the recommended target of 7% (53 mmol/mol) within approximately 3 months on any treatment regimen ("treat to failure"). Clinical inertia and/or poor adherence to therapy contribute to patients not reaching glycaemic targets when managed according to this paradigm. Clinical inertia exists across the entire spectrum of anti-diabetes therapies, although it is most pronounced when initiating and optimizing insulin therapy. Possible reasons include needle aversion, fear of hypoglycaemia, excessive weight gain and/or the need for increased self-monitoring of blood glucose. Studies have suggested, however, that early intensive insulin therapy in newly diagnosed, symptomatic patients with T2DM with HbA1c >9% (75 mmol/mol) can preserve beta-cell function, thereby modulating the disease process. Furthermore, postprandial plasma glucose is a key component of residual dysglycaemia, evident especially when HbA1c remains above target despite fasting normoglycaemia. Therefore, to achieve near normoglycaemia, additional treatment with prandial insulin or a glucagon-like peptide-1 receptor agonist (GLP-1 RA) is often required. Long-or short-acting GLP-1 RAs offer effective alternatives to basal or prandial insulin in patients inadequately controlled with other therapies or basal insulin alone, respectively. This review highlights the limitations of current algorithms, and proposes an alternative based on the early introduction of insulin therapy and the rationale for the sequential or fixed combination of GLP-1 RAs with insulin ("treat-to-success" paradigm).

K E Y W O R D S
GLP-1, insulin therapy, treatment algorithm, type 2 diabetes mellitus 1 | INTRODUCTION Type 2 diabetes mellitus (T2DM) is a complex, metabolic and progressive disease commonly associated with diverse pathophysiology, which is characterized by relative insulin insufficiency and insulin resistance leading to excessive hepatic glucose production, and fasting and postprandial hyperglycaemia. 1,2 In clinical practice, this manifests as a broad phenotypic expression due to patients presenting at different stages in the natural history of the disease. Pancreatic beta-cell dysfunction is critical to disease development, 2 and insulin resistance in the liver and peripheral target tissues also has a central role in the development of cardiometabolic changes. 3 Genetic susceptibility to T2DM is also an important factor as many genes interact with environmental factors, which, in turn, affect downstream pathways, resulting in the heterogeneous nature of the disease. 4 The currently available glucose-lowering agents are reviewed, and guidance for clinicians on treatment choices based on an individual patient-centred approach is provided in guidelines published by the European Association for the Study of Diabetes (EASD), American Diabetes Association (ADA), American Association of Clinical Endocrinology (AACE), American College of Endocrinology (ACE), and International Diabetes Federation. [5][6][7] The advised treatment target is generally glycated haemoglobin (HbA1c) ≤7% (53 mmol/mol), seen as indicative of good control. Among patients in the USA diagnosed with T2DM, only 52% have HbA1c <7% (53 mmol/mol), while 13% have values >9% (75 mmol/mol). Indeed, only 14% of individuals achieve recognized targets for glucose, blood pressure and lipids (alongside non-smoking status). 8 Of considerable concern, in Eastern Europe, Latin America and Asia, 36% of patients with T2DM have never had their HbA1c measured; among those with measurements, 36% achieved HbA1c <7% (53 mmol/mol), and only 3.6% achieved all three recommended targets for glucose, blood pressure and lowdensity lipoprotein cholesterol. 9 Possible reasons for these poor results include poor understanding of the disease and its potential consequences, as well as the necessary lifestyle changes and available treatment options, all of which contribute to non-compliance. In addition, the lack of agreement among healthcare providers regarding the value, and hence the proper application, of self-monitoring of blood glucose (SMBG) can be a compounding factor. Initial pharmacotherapy is generally metformin introduced at, or soon after, diagnosis in conjunction with diet and lifestyle changes.
Alternative therapies are recommended if the patient is intolerant to metformin or its use is contraindicated. 7,10 Where monotherapy does not achieve or sustain the mutually agreed HbA1c target after approximately 3 months, treatment will need to be advanced, with a number of options advocated as second-line therapies. These include agents within the following categories: sulphonylurea, thiazolidinedione, alpha-glucosidase inhibitor, dipeptidyl peptidase-4 (DPP-4) inhibitor, glucagon-like peptide-1 receptor agonist (GLP-1 RA), sodium-glucose co-transporter-2 (SGLT-2) inhibitor and basal insulin. 7 These options can be tailored according to a patient's treatment needs and disease characteristics. In patient populations with elevated cardiovascular (CV) risk, the CV outcome trials LEADER (liraglutide), EMPA-REG (empagliflozin) and SUSTAIN 6 (semaglutide) all showed a reduction in CV events (according to the primary 3-point MACE). [11][12][13] In contrast to the GLP-1 RAs, treatment with empagliflozin was associated with a reduction in CV death from early in the trial, suggesting a haemodynamic mechanism. This is supported by the significant reduction in hospitalization due to heart failure in this study. 13 The National Institute for Health and Care Excellence advocates continuation of current therapy until the patient no longer meets the desired target [HbA1c 7.5% (58 mmol/mol)], and only then should further options be considered, i.e. a "treat-to-failure" approach. 10 For patients who do not reach target HbA1c after 3 months, clinicians are encouraged to discuss the aforementioned second-line treatment classes, usually in combination with metformin, with the choice of treatment being dependent on patient preference and disease status. 7 Basal insulin or premixed insulin formulations are often not considered until advanced disease when patients do not achieve target HbA1c despite intensive treatment with a single or a combination of anti-diabetes therapy. There is, however, evidence demonstrating that the early introduction of intensive insulin therapy (firstline), especially in those with an HbA1c >9% (75 mmol/mol; usually symptomatic with a short disease history), positively influences glycaemic control, maintenance of beta-cell function and rates of remission (many patients maintaining optimum glycaemic control for at least 12 months). 2 Basal insulin alone has also obtained similar responses to continuous insulin infusion (CSII) in an equivalent setting. 14 In cases where basal insulin has been up-titrated to achieve a near-normal fasting plasma glucose (FPG) yet HbA1c remains above target, a short-acting GLP-1 RA or prandial insulin can be added to reduce postprandial plasma glucose (PPG) excursions. 7 In patients with HbA1c >9% (75 mmol/mol; with/without symptoms), EASD/ ADA and AACE/ACE guidelines advocate first-line combination therapy over sequential treatment. 5,7 However, there remains a considerable delay in progressing treatment in clinical practice. 15 Most patients with T2DM require multiple treatments to maintain adequate glycaemic control. For example, in the UK Prospective Diabetes Study, about 50% of patients with newly diagnosed T2DM maintained HbA1c <7% (53 mmol/mol) with monotherapy for 3 years, although only about 25% achieved this glycaemic target with monotherapy after 9 years. 16 Even with basal insulin treatment, a significant proportion of patients continue to have an HbA1c above target. 17 This review considers the limitations of the current treatment algorithms and proposes an alternative paradigm based around the early introduction of insulin therapy (especially, based on available evidence, in those with high HbA1c) and combination therapy with a GLP-1 RA.

| CURRENT TREATMENT LANDSCAPE
Type 2 diabetes mellitus is often inadequately controlled despite the availability of numerous injectable and oral anti-diabetic drugs (OADs) supported by a variety of treatment guidelines. Between 24% and 54% of patients treated with basal insulin do not achieve HbA1c ≤7% (53 mmol/mol), despite meeting target FPG levels. 18 Clinical inactivity, "inertia," among healthcare professionals, and poor patient adherence to therapy are among the major reasons why many patients do not reach their glycaemic target when adopting current treatment paradigms, i.e. therapy is not intensified despite poor glycaemic control on an existing regimen. 19,20 Furthermore, numerous studies (in the USA and Europe) suggest that clinical inertia is unacceptably common in the management of T2DM. [20][21][22] Brown and colleagues reported that, on average, patients accumulated approximately 10 years of excess glycaemic burden with HbA1c >7% (53 mmol/mol) from diagnosis until beginning insulin treatment. 15 This may have a significant impact on disease severity and risk of micro-and macrovascular complications. 23 Several factors can potentially contribute to clinical inertia and poor patient adherence to therapy: the introduction of newer, more complicated and expensive therapies compounded by inadequate educational support, which will undoubtedly influence the time taken for clinicians to become acquainted with these treatments. To date, there are few head-to-head cost-benefit comparisons between the ever-increasing number of newer treatments available to assist clinicians in making informed decisions. Tolerability is also a major factor, for example, insulin and sulphonylureas are associated with hypoglycaemia and weight gain; thiazolidinediones with increased risk of weight gain, oedema, heart failure and bone fractures; SGLT-2 inhibitors with genito-urinary infections, polyuria, volume depletion, hypotension, dizziness, increased low-density lipoprotein cholesterol, transient increases in creatinine, increased risk of bone fractures 24 and non-hyperglycaemic ketoacidosis. 25 GLP-1 RAs induce transient gastrointestinal (GI) intolerance in the majority of patients, although <10% of individuals discontinue treatment due to any adverse event. 26 It is also becoming increasingly recognized that there is considerable variation in patients' response to anti-diabetes therapy, which can be explained by genetic differences (e.g. for metformin, sulphonylureas and incretin-based therapies). 27,28 Despite a growing number of treatments, 5 to 10 years after diagnosis, most patients will eventually require insulin therapy to achieve their glycaemic target. 29 Clinical inertia is most pronounced when introducing insulin, 30 and may relate to a number of factors, including fear of hypoglycaemia and excessive weight gain, 31,32 together with the need for structured education including SMBG. 33 In the START study of patients with stable but poorly controlled T2DM, a 1 unit/d self-titration bolus insulin algorithm to reach a target 2-hour PPG of 5.0 to 8.0 mmol/L was seen to be as effective as a physician-managed algorithm. 34 Similar results were reported in a study of 4961 patients with poorly controlled T2DM who initiated and titrated insulin according to either an investigator-or self-led algorithm. 35 In this study, patients using the self-led algorithm experienced greater decreases in HbA1c vs patients whose insulin treatment was investigator led (P < .001), and there was no significant difference in the occurrence of severe hypoglycaemia between the 2 groups. 35 Of note, even though there is some unity and agreement between the current treatment algorithms, 36 algorithm-driven insulin use in advanced T2DM is often associated with a greater incidence of hypoglycaemia and weight gain than when initiated earlier in the course of disease. 30 In a pooled analysis of 11 prospective trials, early use of insulin in combination with metformin resulted in less weight gain and symptomatic hypoglycaemia compared with insulin added to 2 OADs (reflective of treatment later in the disease course). 37 The issues discussed above highlight the need to re-consider the current treatment algorithms for the management of patients with T2DM. Alternative approaches include the early initiation of insulin therapy with the addition of a GLP-1 RA when appropriate. This option raises the prospect of improved success in achieving glycaemic targets sooner and maintaining them for longer than with the conventional approach, while reducing the risk of hypoglycaemia and mitigating weight gain due to lower doses of the individual components.

| THE CASE FOR THE EARLY INTRODUCTION OF INSULIN THERAPY
Studies have suggested that the introduction of intensive insulin treatment in patients presenting with even moderately high HbA1c (median of 7.2%) can alter the progressive nature of T2DM by reversing the adverse impact of glucotoxicity and lipotoxicity on beta-cell function and insulin sensitivity. 38 In patients with newly diagnosed T2DM [mean baseline HbA1c ≥9.5% (80 mmol/mol)], both CSII and multiple daily insulin (MDI) injections increased target glycaemia attainment in less time than with OADs. 2 Markers of beta-cell secretion also improved more dramatically following early and intensive insulin therapy. 2 Furthermore, rates of remission were increased with CSII and MDI injections vs OADs. In a separate study, 39 a greater proportion of patients newly diagnosed with T2DM [HbA1c ≥9% (75 mmol/mol)] achieved glycaemic targets with a combination of an OAD plus insulin in less time than with OADs alone. Following 1 year of treatment, more patients maintained target glycaemia with an OAD plus insulin than with OADs alone, and maintained beta-cell function more effectively than when OADs were employed solely. 39 A recent 21-year update to a study that treated patients with T2DM and microalbuminuria (mean disease duration~6 years) over 7.8 years with an intensive, multifactorial step-wise approach (including dietary changes followed by OADs stepping up to Neutral Protamine Hagedorn insulin and multiple insulin injections in patients failing to achieve stringent blood pressure, HbA1c and cholesterol targets as well as behavioural approaches) vs a conventional treatment approach reported a marked legacy effect on CV outcomes with intensive early treatment of these risk factors. 40 Significantly fewer patients receiving the early intensive intervention died during the follow-up period compared with those treated conventionally (P = .005); the former group also had 8.1 years longer before experiencing a CV event (P = .001) and lived 7.9 years longer than the conventional cohort. 40 A post hoc analysis of the LIBRA (LIraglutide and Beta cell RepAir) trial identified that the most important factor in improving outcomes is the duration of disease at the initiation of intensive treatment. 41 In LIBRA, 25 patients with T2DM for ≤7 years received 4 weeks of intensive insulin therapy to achieve fasting glucose <6.94 mmol/L followed by placebo for 48 weeks. Rates of remission [HbA1c <6.5% (48 mmol/mol) and no medication during the 48-week placebo period] were 78%, 71% and 58% in patients with T2DM of <1, 2 and 3 years duration, respectively, and loss of remission was slower in patients with disease duration of <2 years vs those with a more established disease. 41 In a population-based study, the best HbA1c reductions were observed when basal insulin was introduced directly after failure of metformin monotherapy, 37 while the improvement of HbA1c was less marked when basal insulin was added only after combinations of OADs had failed. This demonstrates that a better response to basal insulin can be expected in the earlier stages of T2DM. 37 Aside from glycaemic control, the additional anti-inflammatory and anti-oxidant properties of insulin may also help to protect against endothelial dysfunction and consequent vascular disease. 23,42 Nevertheless, even in cases where early insulin treatment has been shown to be beneficial (symptomatic, markedly hyperglycaemic, newly diagnosed T2DM), such treatment may not be applied due to the perceived increased work load for the patient as well as healthcare professionals. However, studies show that the improvements in glycaemic control, betacell function and plasma lipid profiles associated with basal insulin monotherapy are comparable with those seen with CSII. Therefore, there is the option of a less complex basal insulin regimen in patients newly diagnosed with T2DM. 14 When OADs fail to control glycaemia, adding basal insulin predominantly targets FPG, which reflects the reduction of overnight hepatic glucose production and suppression of free fatty acid release by adipose tissue. 29 Several randomized studies have shown that the decrements in HbA1c are linearly related to insulin dose (approximately 0.5% decrease in percentage HbA1c for each increase in insulin dose equivalent to 0.1 U/kg/d up to 0.5 U/kg). 43 Above this dosing threshold, the improvement in HbA1c is halved (0.5% decrease in percentage HbA1c for each increase in insulin dose of 0.2 U/kg/d). Weight gain, however, increases linearly throughout the dose range. 44 Patients with T2DM typically exhibit substantial PPG excursions early in the evolution of the disease, which is why basal insulin monotherapy, despite achieving near-normal FPG levels, fails to normalize HbA1c in approximately 30% of patients 45 ; as T2DM progresses, defects in PPG are quickly followed by fasting hyperglycaemia due to the dawn phenomenon. 46,47 Therefore, as PPG can be a significant contributor to overall hyperglycaemia at lower levels of HbA1c, 46 reducing postprandial excursions is particularly important in patients with relatively modest HbA1c elevations or when no further improvement in FPG is feasible with basal insulin. Despite adequate basal insulin dose titration, a substantial proportion of patients on basal insulin therapy will require additional treatment with either a prandial insulin or a GLP-1 RA to address PPG and further improve HbA1c. 7 While prandial insulin is routinely added to basal insulin in a threetimes-daily basal-bolus approach, it has been found that a once-or twice-daily regimen can achieve similar HbA1c reductions, with a lower risk of hypoglycaemia. 48 The hypoglycaemia risk associated with increments in insulin doses highlights the need for treatments that augment glycaemic control, but which carry limited additional risk of hypoglycaemia.

| Rationale for GLP-1 RA therapy
Native GLP-1 is secreted to augment insulin secretion and suppress glucagon release primarily in response to a nutrient challenge. In the circulation, it is quickly degraded (within 2-3 minutes). 49  The currently available GLP-1 RAs allow different patterns of administration, ranging from twice daily to once weekly, providing a flexibility in patient treatment options around their differing pharmacological properties (Table 1). For example, short-acting/prandial GLP-1 RAs might be used once or twice daily 58 before the main meal(s) in addition to insulin therapy. In addition to their effects on glycaemic control, hypoglycaemia and weight, it is important to consider the effects of the GLP-1 RAs on the CV and other systems. The GLP-1 receptor is widely expressed throughout the body, including the heart (predominantly in the sino-atrial node), 73 and GLP-1 has been demonstrated to have neuroprotective properties, for example, crosses the blood-brain barrier, enhances neurogenesis and reduces the chronic inflammatory responses in the brain. 74 Incretin-based therapies, i.e. GLP-1 RAs and DPP-4 inhibitors, reportedly exert cardio-protective effects, including positively influencing cardiac function (in vitro and animal data), and improving endothelial function (human data). 75

| GLP-1 RA therapy in combination with insulin therapy
Combining basal insulin with a short-acting GLP-1 RA that predominantly lowers PPG is a logical management approach when the former fails to achieve adequate glycaemic control even when optimally titrated. 49  weight gain when compared with once-or thrice-daily prandial insulin (glulisine). 91 Furthermore, PPG was significantly reduced with lixisenatide compared with both glulisine regimens, although, as expected, transient nausea, vomiting and diarrhoea events were more common with lixisenatide. 91 These findings suggest that a short-acting GLP-1 RA, such as lixisenatide, could be a preferred intensification treatment option compared with prandial insulin when a basal insulin regimen is found to be insufficient.

| Fixed-ratio combinations (FRCs) of basal insulin and GLP-1 RAs
Combining insulin and incretin therapy is suggested as a treatment option in the EASD/ADA guidelines. 7 (HbA1c); B, fasting plasma glucose (FPG) and C, body weight changes with liraglutide in combination with basal insulin. 84,85 Modified intent-to-treat populations: *26-week study; † 16-week study; ‡ study conducted in Japanese patients with low body mass index at enrolment. CI, confidence interval. Standard errors/standard deviations were not reported in the text of these studies, but were reported in corresponding line graphs  Failure to attain glycaemic control has implications for patients, healthcare professionals and healthcare systems due to the increased risk of micro-and macrovascular complications associated with diabetes. Currently, only a third of people with T2DM achieve and maintain their target HbA1c level, and it is expected that the number of T2DM cases will dramatically increase over the coming decades, with the potential for a substantial negative impact on medical costs and healthcare resources. 101 Achieving good glycaemic control in an attempt to avoid complications is, therefore, paramount but the hur- tively. 102 Liraglutide has been shown to be cost effective compared with the DPP-4 inhibitor, sitagliptin, added to metformin, with an incremental cost-effectiveness ratio below $50 000 per QALY gained. 103 Using a medical economic model, lixisenatide was also considered a cost-efficient therapy when compared with bolus insulin, with benefits in terms of QALYs gained and a reduction in lifetime healthcare costs. 104 The rationale for developing FRCs of basal insulin and GLP-1 RAs is scientifically valid, allowing the introduction of complementary therapies for improved outcomes with a lower risk of adverse events at any stage in the treatment algorithm. 51 Importantly, the FRCs offer a real opportunity of introducing these therapies at an earlier stage in the disease process when, arguably, the greatest benefit will accrue. 37 To be successful, this proposed change to the current treatment paradigm will require adequate education in order to realize the full benefits of the early introduction of insulin therapy and GLP-1 RAs in the form of FRCs. [30][31][32]100,105 The ability to self-titrate FRCs in a similar manner to basal insulin, but with no additional risk of hypoglycaemia and/or weight gain, is a clear benefit. Also, FRCs could offer the potential to reduce the time taken to achieve good glycaemic control and modulate the disease process, which may reduce the burden on associated healthcare resources and result in cost benefits.

| CONCLUSIONS
Poor glycaemic control underscores the limitations of current treatment options and algorithms advocated in management guidelines.
An unacceptably high proportion of people with T2DM, despite the many therapeutic options available, fail to reach their glycaemic tar-