Therapeutic rationales for earlier combination therapy

by J. Seufert, Germany


Jochen SEUFERT, MD, PhD, FRCPE Division of Endocrinology and Diabetology, Department of Medicine II, University Hospital of Freiburg Medical Faculty University of Freiburg Freiburg, GERMANY

Type 2 diabetes is characterized by multiple pathophysiological defects in many organs that, in concert, contribute to the development of hyperglycemia. Moreover, type 2 diabetes is a progressive disease. Based on these observations, it is clear that the majority of patients require increasing levels of combination therapy to target multiple pathophysiological defects at once in order to achieve and maintain durable glycemic control. However, there is clinical inertia among physicians and patients to implement early combination therapies proactively, in part due to concerns about hypoglycemia and weight gain. While recommendations for early combination therapies, even at the time of diagnosis, are already integrated into international guidelines, evidence from real-world trials suggests that these recommendations are not broadly translated into clinical practice. However, there is equal evidence that delays in the implementation of early combination therapy can lead to higher rates of diabetes-associated complications. When looking at trials with newer antidiabetic drugs, early combination therapy using glucagon-like peptide-1 (GLP-1)–based drugs together with metformin and SGLT2 inhibitors and/or insulin may provide a multitude of additional benefits beyond durable glycemic control such as weight reduction, reduction in blood pressure, and a low rate of hypoglycemia. This approach bears the potential to affect the natural course of the disease with the hope of less progressive distortion of endogenous insulin production and, ultimately, lower rates of diabetes-associated complications. Therefore, early combination therapy should represent the mainstay of therapeutic strategies for most of the patients with type 2 diabetes.

The traditional approach to treating type 2 diabetes according to most international guidelines is characterized by a stepwise addition of diabetes drugs. However, when using this treatment algorithm, many patients do not achieve their individual treatment goals. More importantly, over time patients often fail to maintain adequate glycemic control, which is especially evident at the beginning of medical therapy when patients are treated with monotherapy.1,2 There are multiple reasons for this observation, including a neglect of the pathophysiology and the progressive nature of type 2 diabetes. Therefore, a gap exists between current treatment algorithms and optimal therapies that would provide adequate glycemic control to all patients. Currently, in Europe, only 62% of patients achieve an HbA1c target <7%.3

Figure 1.
drugs and
the possibilities
DPP-4, dipeptidyl
4; GLP-1
RA, glucagonlike
receptor agonist;

The stepwise addition of single drugs in patients failing to achieve glycemic control can, therefore, be looked at as a “treat to fail” strategy. In contrast, current evidence shows that an earlier combination therapy may perform better.4 Therefore, the objectives of this review are (i) to review the current management of diabetes and frequency of delays in treatment intensification; (ii) to highlight the importance of achieving early glycemic control; (iii) to discuss the potential benefits of an (early) combination therapy approach in overcoming treatment inertia and achieving improved glycemic control; and (iv) to discuss clinical data on (early) combination therapy with newer agents in type 2 diabetes.

Pathophysiology and time course of type 2 diabetes

Type 2 diabetes is a disease with multiple pathophysiological defects in many organs, some of which have not commonly been associated with glycemic control.5 Along with classic defects in insulin sensitivity in insulin target organs, such as the liver, muscle, and adipose tissue, and insulin secretory defects of the endocrine pancreas, other pathophysiological disturbances have been identified and characterized in recent years. These other disturbances involve inadequately elevated glucagon secretion from endocrine pancreatic α cells, an elevated hepatic glucose production due to insulin resistance of the liver, a reduced production of incretin hormones by the gut, increased lipolysis in adipose tissue, a reduced glucose uptake in muscles, increased glucose reabsorption in the kidneys, and, more recently, a dysfunction of neurotransmitters in the brain. These dysfunctions commonly contribute to the development of hyperglycemia and type 2 diabetes in concert. Given the variety of pathophysiological defects, it is already impudent at this point to expect that single individual drugs, which commonly target only one or two pathophysiological disturbances, could control glycemia adequately and continuously in patients with type 2 diabetes.5

Moreover, it is important to note that type 2 diabetes is a chronic progressive disease.6 This natural progression is mainly driven by a progressive deterioration of the function of the endocrine pancreas over time, which leads to the development of insulin deficiency along the history of diabetes progression.7 The underlying pathophysiology and nature of a constantly deteriorating endogenous insulin production are considered to represent the underlying cause of a progressively deteriorating glycemic control in patients with type 2 diabetes.5 Currently, there is insufficient evidence that commonly used diabetes drugs can slow down or prevent this progressive development of insulin deficiency in patients with type 2 diabetes, while evidence from diabetes prevention trials suggests that nonpharmacological treatments, such as diet and exercise, may potentially prevent a deterioration in glycemic control, at least in the beginning of the disease.8 Also, given the fact that newer antidiabetic drugs, such as glucagonlike peptide-1 (GLP-1)–based drugs or sodium-glucose cotransporter 2 (SGLT2) inhibitors, target multiple pathophysiological defects in type 2 diabetes, it may be envisioned that smart combinations of these drugs, also with insulin, could contribute to a deceleration of type 2 diabetes progression in individual patients.

These pathophysiological reasons by themselves call for a combination treatment approach that may provide a better option for targeting the multiple pathophysiological pathways in type 2 diabetes. Currently available options for combination therapies are depicted in Figure 1.

Recommendations for early combination therapy in treatment guidelines

While the common approach for treating type 2 diabetes is the sequential addition of single drugs along the course of the disease, recommendations for early combination therapy are also found in international position statements and treatment guidelines. The 2015 position statement update by the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD)9,10 states that: “…initial combination therapy with metformin and a second agent may achieve HbA1c targets more quickly than sequential therapy…”

In addition, several recommendations concerning combination therapies are included in the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) treatment guidelines.11 In patients with an entry HbA1c <7.5%, these guidelines recommend initiating combination therapy if HbA1c goals are not met within 3 months and suggest a quick addition of drugs up to triple therapy ± insulin. In patients with particularly high HbA1c values, initial combination therapies are recommended right from the beginning. In patients with an entry HbA1c >7.5%, dual therapy with a combination of two drugs is advised, and, in patients with an entry HbA1c >9%, combination therapy with three drugs and/ or insulin is recommended.11

Figure 2. Reasons
for clinical inertia and
barriers for treatment
intensification in
patients with type 2

However, despite guideline recommendations, delays in escalation to combination therapy are common. In a retrospective cohort study of 81 573 patients with type 2 diabetes in the UK, it was observed that the average time on therapy with HbA1c values >8% was 1.6 years for monotherapy and 6.9 years for dual therapy, despite the fact that treatment recommendations in the guidelines are advocating treatment intensification after 3 months if individual HbA1c targets are not met.12

Does it matter if therapy intensification is delayed in patients with type 2 diabetes?
There is growing evidence that delays in treatment intensification by combination therapy may very well put patients at a higher risk for the development of diabetic complications. In a retrospective analysis of the UK clinical practice research data link in 110 543 patients, the research tested whether a 6-month delay in therapy intensification will affect the cardiovascular risk of patients with type 2 diabetes.13 In the patient cohort with HbA1c values >7% 1 year after treatment initiation, one group received an immediate therapy intensification by adding a second oral antidiabetic drug or insulin, whereas, the second group had a 6-month delay in therapy intensification before a second oral antidiabetic drug or insulin was added. In an analysis that was done 5 years later, the overall risk for cardiovascular disease increased by 20% and the risk of myocardial infarction increased by 26% in the group with delayed intensification vs the group with immediate therapy escalation.13 These results provide a strong therapeutic rationale for early combination therapy in patients with type 2 diabetes to prevent macrovascular complications.

Evidence for early proactive treatment

The reasons for clinical inertia leading to delays in treatment intensification with combination therapy in patients with type 2 diabetes are manifold. Evidence suggests that multiple barriers for intensive treatment combinations are in place both at the patient and physician levels (Figure 2). Therefore, close collaboration between physicians and patients is critical to overcoming clinical inertia.

In an analysis of the health improvement network database, patients with newly diagnosed type 2 diabetes can achieve glycemic control within 6 months if appropriate treatment is initiated early.15 Further, a head-to-head study that compared the conventional treatment algorithm of the stepwise addition of single diabetes drugs to a strategy that used three drugs as an initial combination therapy (metformin, pioglitazone, and GLP-1 receptor agonist) demonstrated that initial triple combination therapy is more effective in continuously reducing HbA1c levels up to a 24-month treatment duration.16 While the HbA1c levels started to rise again (treatment failure) at 9 months in the conventional treatment group, the patients receiving an initial triple therapy displayed persistently low HbA1c values over time. These results suggest that initial combination therapy in patients with newly diagnosed type 2 diabetes may provide long-term durability of glycemic control and argue for a protective effect on endocrine pancreatic insulin production. In addition, UKPDS (UK Prospective Diabetes Study) demonstrated that early proactive combination therapy could improve the long-term outcomes with continued benefit even after intervention discontinuation.17

Figure 3. Requirements for novel antidiabetic drugs used for combination therapy.

Another study, which showed some beneficial effects of using oral add-on treatments early in the time course of the disease, investigated the attainment of glycemic targets in patients with metformin failure.18 In the group of patients who received early dual add-on therapy within 3 months, 47.23% achieved their glycemic target (HbA1c value <7%), whereas, only 43.33% of patients receiving intermediate dual therapy addition after 4 to 9 months achieved their HbA1c target. In the group of patients who received late dual therapy addition after 10 to 15 months, only 41.65% of patients achieved this HbA1c goal.18 These results provide evidence that aggressive early combination therapy prevents diabetic complications and delays disease progression and support the use of initial combination therapy in specific patients with type 2 diabetes.

Efficacy and safety benefits of combination therapy with newer glucose-lowering agents in type 2 diabetes

The development of antidiabetic therapies for type 2 diabetes has accelerated exponentially in the past 10 to 15 years.19 The advent of newer antidiabetic drugs, such as glitazones, dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, and newer insulins, has provided the basis for novel treatment combinations that target multiple pathophysiological defects with improved glycemic control, and, at the same time, provide multiple advantages that are not associated with glycemia. Apart from a profound and durable HbA1c-lowering effect, the expectations of novel antidiabetic drugs include a lower risk of hypoglycemia, beneficial effects on body weight, broad tolerability that may lead to lower discontinuation rates, the possibility for a wide range of combination therapy with other drugs, and, most importantly, data from cardiovascular outcome trials (Figure 3).

The rationale behind the use of antidiabetic drugs in double or triple combinations is the hope that combining treatments with complementary modes of action may provide clinical benefits in patients with type 2 diabetes beyond mere glycemic control. These additional benefits include improved target achievement, weight reduction, reduced risk of hypoglycemia, delayed disease progression, blood pressure reduction, improved long-term glucose control, and finally, reduced longterm diabetic complications (Figure 4, page 200).

In a trial that tested the initial combination of sitagliptin and metformin vs the single drugs in patients with newly diagnosed type 2 diabetes, initial combination therapy reduced HbA1c to a greater extent over the 2-year treatment period than each drug individually.20 A similar study, which investigated the combination therapy of the SGLT2 inhibitor dapagliflozin with metformin vs the single drugs, demonstrated that HbA1c levels could be lowered by up to 2% with this dual combination without increasing the risk of hypoglycemia, and with the additional benefit of a greater reduction in body weight.21 Moreover, triple therapy regimens have been shown to be superior to dual therapy regimens in patients with newly diagnosed type 2 diabetes and a particularly high baseline HbA1c level. In one such study, the triple combination therapy of metformin, dapagliflozin, and the DPP-4 inhibitor saxagliptin was compared with the dual therapy options of metformin and saxagliptin or metformin and dapagliflozin.22 In patients with a baseline HbA1c level around 9.5%, the triple combination therapy of metformin, dapagliflozin, and saxagliptin reduced the HbA1c levels by 1.47%, which was a greater reduction than either of the two other dual therapy treatments. Moreover, in this trial, 41% of patients receiving triple therapy achieved their target HbA1c (ie, <7%) vs the 18% and 22% of patients receiving either saxagliptin and metformin or dapagliflozin and metformin. An additional benefit has been observed in this study concerning bodyweight; the patients in the triple therapy group lost an average of 2.1 kg vs 0 kg in the metformin- and saxagliptin- treated group.

Combination therapy of insulin with GLP-1 receptor agonists

The combination of a GLP-1 receptor agonist and insulin can be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin, such as hy- combination of a GLP-1 receptor agonist and insulin has also been advocated as an effective option for patients requiring treatment intensification. Data from clinical studies support the therapeutic potential of this combination therapy, which has beneficial effects on glycemic control and bodyweight, results in a low incidence of hypoglycemia, and facilitates reductions in insulin dose for those on an established insulin therapy.

Figure 4. Rationale for combination of diabetes drugs with complementary modes of action and clinical benefits.
Abbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT-2, sodium-glucose cotransporter 2.

In a trial that investigated the treatment escalation in patients poorly controlled with insulin glargine by adding the GLP-1 receptor agonist exenatide, the combination therapy provided greater glycemic control than did uptitration of insulin glargine alone.24 The combination therapy led to a 1.74% decrease in HbA1c levels. Moreover, the combination therapy of insulin glargine and exenatide led to an average 1.78 kg reduction in body weight vs the 0.96 kg increase in body weight in the glargine uptitration group.24 In another trial that investigated a fixed-ratio combination of insulin and a GLP-1 receptor agonist (ie, insulin degludec and liraglutide [IDegLira]), vs degludec or liraglutide alone in combination with metformin showed that the combination therapy resulted in an impressive 1.84% decrease in HbA1c levels vs a 1.4% decrease with insulin degludec alone and a 1.21% decrease with liraglutide alone.25 The improvement in HbA1c levels with IDegLira was associated with a lower rate of hypoglycemia than was the combination of metformin and insulin degludec alone. Moreover, patients who were treated with IDegLira had a 2.8 kg reduction in bodyweight vs the patients who received an uptitration of insulin degludec alone.25

These results suggest that the addition of a GLP-1 receptor agonist to insulin early in the time course of the disease, as well as in later combination therapy, may be beneficial for patients regarding both the HbA1c-lowering capacity, the rate of hy hypoglycemia, and bodyweight. Therefore, this combination therapy may represent a favorable approach in current treatment algorithms.


The current approach of sequentially adding single antidiabetic drugs in patients with type 2 diabetes as it is recommended in several guidelines does not seem to represent the most beneficial treatment strategy for many patients. The pathophysiology of the disease with multiple defects in many organs together with the progressive nature of type 2 diabetes provides the rationale for advocating earlier combination therapy and for overcoming clinical inertia.

In addition, there is a multitude of evidence showing that, in patients newly diagnosed with type 2 diabetes or early during the time course of the disease, combination therapy may provide additional benefits beyond mere glucose lowering (ie, durability in glucose control) and effects on bodyweight, blood pressure, and the rate of hypoglycemia. These notions call for a change in the “treat to fail strategy” toward a strategy of proactive diabetes management with implementation of early combination therapy in type 2 diabetes.

In summary

• International treatment guidelines recommend a combination treatment approach, with the sequential addition of therapies at 3 months if treatment goals are not achieved.
• Delays in intensifying treatment despite poor glycemic control are common, which can increase the risk of diabetes-associated complications.
• Early, individualized combination therapy using newer drugs with complementary modes of action may provide additional clinical benefits beyond those currently achieved.
• Numerous combination treatment approaches have demonstrated efficacy and safety benefits in clinical trials. ■

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Keywords: combination; diabetes; GLP-1 receptor agonist; inertia, insulin; intensification; treatment goal; therapy