Initial Combination versus Monotherapy for the Treatment of Type 2 DiabetesAuthors: Kacie Kuehn, PharmD: PGY-2 Ambulatory Care Resident
St. Louis College of Pharmacy/St. Louis County Department of Public Health – St. Louis, MO
Justinne Guyton, PharmD, BCACP: Assistant Professor, Pharmacy Practice
St. Louis College of Pharmacy
Program Number: 2017-12-11
Approval Dates: 2/7/2018 to 5/6/2018
Approved Contact Hours: One (1) CE(s) per LIVE session.
Submit Answers to CE Questions to Jim Andrews at: email@example.com
Objectives1) Describe the safety and efficacy outcomes of recent literature pertaining to initial combination therapy treatment of type 2 diabetes.
2) Create a patient-specific treatment plan for the management of type 2 diabetes.
IntroductionThe primary goals in the management of patients with type 2 diabetes are to reduce mortality and prevent microvascular and macrovascular complications. Although glycemic targets may be individualized, a targeted glycated hemoglobin (A1c) less than 7% set by the American Diabetes Association (ADA) is a glycemic goal of therapy to reduce the incidence of diabetes-related complications.1 However, only half of patients with diabetes are meeting this treatment goal, illustrating a need for improving diabetes management.2
In most patients, treatment begins with lifestyle modifications and the addition of one antihyperglycemic agent. If glycemic control is not met after titration, patients are managed with sequential add-on agents at subsequent visits. However, there are instances in which dual therapy is recommended initially. The ADA recommends considering initial combination therapy in patients with an A1c at or above 9%.1 In contrast, the American Association of Clinical Endocrinologists (AACE) indicates that combination therapy be initiated when patients present with an initial A1c above 7.5%.3 This contrast leaves practitioners with an important clinical question: why might initial combination therapy be beneficial and when should it be utilized? To help answer this question, this article will focus on four characteristics that may influence the decision: efficacy, hypoglycemia, side effects, and cost.
EfficacyThe concept of metabolic memory in type 2 diabetes has been discussed since the publication of the UKPDS 10-year follow-up in 2008. This trial established that a sustained period of early A1c control can have a long-term impact on subsequent risk of microvascular and macrovascular complications. In the UKPDS trial, a cohort of 3,867 patients newly diagnosed with type 2 diabetes was followed for 10 years. Patients were randomized to a standard A1c goal or an intensive A1c goal and then treated with a sulfonylurea alone or in combination with insulin. At 10 years, those in the standard A1c arm achieved a median A1c of 7.9% while the intensive A1c arm achieved a median A1c of 7.0% (P<0.001). Those treated with a sulfonylurea had a hypoglycemia rate of 17.7%, compared to 36.5% for those treated with insulin. Patients with diabetes managed with diet changes alone had a 1.2% rate of hypoglycemia. The patients in the intensive arm had a 25% risk reduction in microvascular complications (P<0.05), with no significant impact on cardiovascular outcomes.4 Interestingly, during post-trial monitoring, the A1c converged between arms within 1 year. At the end of the 10-year post-trial follow-up, both groups had a similar A1c at approximately 7.8% (P=0.71). Despite having a similar A1c upon completion of the follow-up period, those initially randomized to intensive A1c control still experienced long-term benefits. This intensive A1c arm had a 24% relative risk reduction in microvascular complications (P<0.05), a 15% relative risk reduction in myocardial infarctions (P<0.05), and a 13% relative risk reduction in all-cause mortality (P<0.01), compared to those with standard control at 10 years.5 These data support the concept of metabolic memory and begin to establish that a more aggressive early approach to glycemic control is essential to the treatment of type 2 diabetes.
Literature and guidelines have established metformin as first-line therapy for the treatment of type 2 diabetes, in the absence of contraindications, due to evidence of safety, efficacy, and a reduction in cardiovascular events.2,6 As new literature is published establishing the pleotropic benefits of other anti-hyperglycemic medications, thought must be given to when it is appropriate to initiate a second anti-hyperglycemic medication. In particular, focused research has been done to establish microvascular and macrovascular outcomes related to glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2-Is).7
The LEADER trial randomized patients with type 2 diabetes to receive liraglutide or placebo. At the end of the almost 4-year trial period, the 3-point major adverse cardiac events (MACE) primary outcome occurred in 13% of patients in the liraglutide group, compared to 14.9% in placebo (P=0.01).8 Another randomized controlled trial of patients with type 2 diabetes and risk of cardiovascular disease found that treatment with liraglutide compared to placebo reduced new-onset, persistent A3 albuminuria; at 15% and 19%, respectively (P=0.003)9. Similarly, empagliflozin was compared to placebo in the EMPA-REG OUTCOME trial, which included patients with type 2 diabetes. Treatment with empagliflozin significantly reduced the incidence of the 3-point MACE; 10.5% vs. 12.1% (P<0.01).10 The EMPA-REG ESRD trial found that empagliflozin reduced progression to A3 albuminuria when compared to placebo; 11.2% vs. 16.2%, respectively (P<0.001).11 This evidence supports the use of these medication classes, or certain medications within these classes, to prevent complications, particularly renal and cardiovascular complications. Delaying add-on treatment with one of these medications because a patient’s A1c is not above 9% at initial presentation (as the ADA guidelines recommend) may not be best practice because of the additional benefits of complication prevention.
Clinical inertia, the resistance to treatment initiation or intensification, despite a patient not reaching glycemic goals, also factors into the delay of add-on treatment.12 One study identified the prevalence of clinical inertia, with less than 50% of patients with type 2 diabetes and an A1c greater than 8% receiving treatment intensification.13 In 2014, Rajpathak and colleagues retrospectively analyzed the impact of timing of treatment intensification with oral add-on therapy on glycemic goal attainment among patients with type 2 diabetes failing metformin monotherapy. Almost 6,000 patients were evaluated and analyzed based on time to treatment intensification: no treatment intensification, early intensification at 3 months, intermediate intensification at 4 to 9 months, or late intensification within 10-15 months of first A1c above 7.5%. The majority of patients, 51%, stayed on metformin monotherapy during the study: 23% in the early group, 15% in the intermediate, and 11% in the late group. The baseline A1c was on average 8.01-8.5%. However, most patients never received therapy escalation, but if they did it was within 3 months. Patients with a baseline A1c of more than 8% and received early add-on of second agent, were more than 1.5 times more likely to reach their A1c goal of less than or equal to 7% at 2 years than those in the late add-on group.14 Use of dual initial therapy in patients with an A1c above 8% may help prevent clinical inertia and increase the chance of reaching an A1c goal of less than 7%, based on these results.
In addition to reaching an A1c goal, maintaining A1c at goal is another long-term target. The EDICT trial, published in 2015, aimed to determine the efficacy and durability of initiating a combination of agents to treat new-onset diabetes, compared to the sequential addition of agents. This randomized controlled trial included only drug-naïve patients with type 2 diabetes diagnosed within two years. Patients were randomized to receive conventional, sequential addition of therapy or initial combination therapy. Conventional therapy consisted of metformin combined with glipizide and then insulin glargine at one, two and three months. Initial combination therapy consisted of metformin, pioglitazone, and exenatide titrated at one and three months, if glycemic goals were not being met. On average, patients included in the trial were within six months of diagnosis and had a baseline A1c of 8.6%. At 24 months, patients who received conventional therapy reached an A1c of 6.5% and those with initial combination therapy reached an A1c of 5.95% (P<0.05). These results, although statistically significant, have less clinical significance because both groups reached the A1c goal. However, less than 75% of patients in the conventional group maintained an A1c less than 7%, compared to those in the initial combination group, in which over 90% maintained A1c at goal. In the conventional group, 46% of patient experienced mild hypoglycemic events compared to 14% in the initial combination group.15 This is an expected result considering the variability of insulin use between arms. Data from this study provides evidence that an effective and durable A1c reduction can be achieved using agents with a lower hypoglycemia risk. The EDICT trial utilized triple therapy in the combination group, which may not be practical for most clinical situations where the close monitoring of a randomized controlled trial cannot be duplicated. However, translating combination therapy to clinical practice may be achieved through dual therapy.
HypoglycemiaLimiting the risk of hypoglycemia is a major clinical consideration when choosing antihyperglycemic therapy. The EDICT trial illustrated that it is possible to achieve glycemic control without increasing the risk of hypoglycemia.15 The crux of this outcome is the choice of antihyperglycemic agents. Many agents confer a risk of hypoglycemia that increases with additional agents (Table 1). Excluding insulin, the highest rates of hypoglycemia occur with sulfonylureas, both as monotherapy and combination therapy. Therefore, if initiating dual initial combination therapy and hypoglycemia is a concern due to patient characteristics, it would be prudent to avoid sulfonylureas when possible. In addition, sulfonylureas have not demonstrated the same pleotropic benefits seen with SGLT2-Is or GLP1-RAs, further limiting their use in combination therapy.7
Hypoglycemia is often cited as a reason for not initiating more aggressive initial therapy. A 2016 systematic review found that physicians cited fear of hypoglycemia and other side effects as an influence on diabetes treatment.16 Conversely, in a 2014 systematic review, patients indicated they would prefer glucose control over avoiding minor hypoglycemic events.17 While hypoglycemia should remain at the forefront of clinical decision-making, this research may highlight the value of having patient-centered conversations of the risk versus benefits. Thus, the potential roadblock of hypoglycemia may be less of a concern in the decision to use monotherapy or combination therapy for initial treatment.
Side EffectsBesides hypoglycemia, other side effects influence clinical decisions for use in combination therapy as well. Interestingly, more research has begun to identify possible combinations of medication classes that would strategically reduce risk of side effects through their mechanisms of action. For example, when SGLT2-Is were added to pioglitazone, there was a reduction in hypervolemia typically seen secondary to thiazolidinediones18. Dipeptidyl peptidase 4 inhibitors (DPP4-Is), when added to SGLT2-Is, reduced the incidence of genital infections, although the mechanism of action of this benefit has not been established19.
This potential benefit of combination therapy comes with the caveat that any medication combination does: with each additional medication the side effect profile grows. If two medications started at the same time share a side effect, it may be difficult to discern which medication is the true cause. For example, GLP1-RAs and metformin can both cause gastrointestinal upset.20,21 If both medications were start concomitantly and the patient experienced nausea, it would be difficult to determine which medication to decrease to a lower dose or discontinue. This must be considered with dual initial therapy and patient education on side effects would be especially vital.
CostDepending on a given patient’s insurance status, cost may play a critical role in the choice of antihyperglycemic agents. As has been established, dual initial therapy provides efficacy and durability benefits in the treatment of type 2 diabetes. These benefits could make a higher initial cost of multiple medications worthwhile. In addition, combination pills are available for a variety of drug classes (Table 2), which may eliminate the increased cost incurred with multiple medications. This depends heavily on the route of administration for a given drug class, as GLP1-RAs clearly cannot be included in a combination with an oral medication and typically have higher co-pays associated with them.20,21 Monotherapy will usually be less expensive and therefore may be the only option for certain patients. Every avenue for assisting patients in this situation should be explored, including combination pills, discounted generic medications at certain pharmacies, and patient-assistance programs through medication manufacturers.
ConclusionThe ADA guidelines and AACE guidelines have established two different thresholds for when initial combination therapy should be considered; at or above 9% and above 7.5%, respectively.2,3 This establishes a “grey area” between an A1c of 7.5% and 9% -- should initial dual therapy be utilized in this range?
The early treatment of type 2 diabetes is integral to long-term prevention of complications. Metabolic memory resulting from early glycemic control establishes pleotropic benefits that are sustained, even if glycemic control is lost.22 ,Certain medication classes or medications within these classes have microvascular and macrovascular beyond the benefit established with glycemic control. This makes early initiation with classes, such as GLP1-RAs and SGLT2-Is, an integral component of patient-centered care. Clinical inertia may be a barrier to attaining these benefits. Therefore, it may not be prudent to rely on escalation of therapy over time to achieve glycemic control or to prevent complications. However, initial combination therapy may help prevent clinical inertia. If hypoglycemia is concern, care should be taken to appropriately titrate medications and the choice of medications is vital. Avoiding combinations with sulfonylureas will help reduce the risk of hypoglycemia. However, as evidenced in the EDICT trial, combination therapy can be utilized effectively to reach glycemic control, increase durability of control, and decrease risk of hypoglycemia.
In the evidence presented in this review, the majority of patients had a baseline A1c between 8-8.5%. Clearly, benefit is seen with initiating combination therapy in this population. Therefore, in treatment-naïve patients with an A1c greater than 8%, an initial dual oral antihyperglycemic regimen is favored.
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