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Simultaneous combination therapy shows major potential in type 2 diabetes
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CHICAGO — When treating patients with type 2 diabetes, physicians may have more success if they use simultaneous combination therapy immediately rather than following the traditional stepped-up method of waiting to intensify treatment, according to a speaker at the Cardiometabolic Health Congress.
“I do believe that initial combination therapy with metformin plus a SGLT2 inhibitor or a GLP-1 receptor agonist may become the preferred standard therapy in newly diagnosed type 2 diabetes right from the outset,” Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City and clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas, said during a presentation.
Besides the standard metformin therapy, SGLT2 inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, insulin and sulfonylureas are among the types of medications that physicians can choose from when selecting treatment strategies for patients with type 2 diabetes, he said.
With a litany of cardiovascular outcome trials in the past decade alone showcasing the CV benefits of SGLT2 inhibitors and GLP-1 receptor agonists, the American Diabetes Association and European Association for the Study of Diabetes have created a “much improved” recommendation for treatment progression, according to Rosenstock, who noted that despite this improvement, the recommendation is still for sequential and not simultaneous combination therapies.
In addition, a large variance in the thresholds for when combination therapies should be used among organizations makes the process even less clear, Rosenstock said, noting this approach is like the classic definition of lunacy, as diabetes management has sometimes become “doing the same thing (stepped-up therapy) over and over again and expect[ing] different outcomes.”
“This is what we’ve been doing all along. Can we do it any different?” Rosenstock asked. “This is what happened with all the different tools that we have. We still have 45% to 50% of people getting to the target that we want despite the wonderful armamentarium that we have.”
SGLT2 inhibitors with metformin
There are several approaches that can be taken to confront the status quo that may be contributing to clinical inertia, according to Rosenstock. However, he argued that every one of these combination therapies must begin with metformin plus a SGLT2 inhibitor.
“If I develop type 2 diabetes, I would get started right away with metformin and an SGLT2 inhibitor. I see no reason whatsoever against this apporach, especially when you can actually do it in a fixed-dose combination,” Rosenstock said.
As has been made evident in numerous trials, including the EMPA-REG, CANVAS, DECLARE and CREDENCE trials, SGLT2 inhibitors “changed the face of the treatment of diabetes,” according to Rosenstock, particularly due to their cardiovascular benefits. Rosenstock also noted that results from the EMPA-REG trial of empagliflozin (Jardiance, Boehringer Ingelheim) were a real “game changer.”
“It is the only drug that has an indication for reduction of cardiovascular death. Very specifically,” Rosenstock said. “Nothing is more important than counting bodies.”
In addition, evidence has emerged indicating that combining SGLT2 inhibitors like canagliflozin (Invokana, Janssen) or empagliflozin with metformin creates “an additive effect” on HbA1c reduction that enhances the results of either medication by itself.
“It’s clearly more efficacious,” Rosenstock said. “It doesn’t take rocket science to say two tablets are going to do better than one tablet.”
Two tablets may not be enough, however, and that is where the possibility of triple therapy comes into play. Rosenstock recommends this approach if patients are unable to get their HbA1c below 7.5%, with four different paths that can be followed.
Incorporating DPP-IV inhibitors
The first path involves adding a DPP-IV inhibitor to the metformin and SGLT2 inhibitor. As evidenced in the VERIFY study, DPP-IVs like vildagliptin can produce enhanced and sustained glycemic control in the long term. In addition, evidence exists that DPP-IVs such as linagliptin (Tradjenta, Boehringer Ingelheim/Eli Lilly) can work effectively with SGLT2 inhibitors like empagliflozin along with metformin to consistently reduce HbA1c over longer periods, according to Rosenstock.
“In uncontrolled metformin monotherapy, if you have anybody with a HbA1c 8% to 8.5%, it just makes no sense to just add a single oral agent,” Rosenstock said. “That’s where you can use a simultaneous SGLT2 and DPP-IV because if you’re going to use one, it ain’t going to do it.”
GLP-1 receptor agonists and basal insulin
Rosenstock also recommended the use of oral semaglutide (Ozempic, Novo Nordisk) as initial therapy in combination with metformin and a SGLT2 inhibitor.
Starting with oral semaglutide “may be an even better option,” according to Rosenstock. As the PIONEER 3 randomized clinical trial illustrated, semaglutide in doses of 7 mg or 14 mg can be superior at reducing HbA1c in comparison with sitagliptin (Januvia, Merck). Oral semaglutide has been further tested across the PIONEER study series, with comparisons against numerous agents. What makes oral semaglutide stand out even more is that it can help achieve weight loss, according to Rosenstock.
“I’ve been doing this for 30 years. I’ve never seen a diabetes pill that gives you a 1.2% to 1.5% HbA1c reduction with a 4 kg to 5 kg weight loss,” Rosenstock said. “I think this is going to be a game changer. It all depends on how people are going to tolerate it and, of course, it all depends on access and cost.”
Injectables like weekly GLP-1 receptor agonists and basal insulin are also potential add-ons to the initial combination therapy of metformin and SGLT2 inhibitors,Rosenstock said, noting he largely recommends this as a treatment strategy if triple therapy with oral semaglutide or a DPP-IV inhibitor does not produce the desired HbA1c reduction. Rosenstock noted that GLP-1 receptor agonists are preferable to basal insulin since they do not carry hypoglycemic and weight-gain risks, but that cost can make them a less accessible option. In addition, when combined together, GLP-1 receptor agonists and basal insulin can be highly effective, but cost is once again a barrier to using two separate injectables.
For those who can afford such a treatment, the AWARD-9 and SUSTAIN 5 trials with weekly dulaglutide (Trulicity, Eli Lilly) and semaglutide, respectively, showed major benefits on HbA1c reduction when using any of these agents added to insulin glargine while counterbalancing basal insulin’s tendency to increase weight, according to Rosenstock. These benefits may be enhanced further if a fixed ratio co-formulation of basal insulin and a GLP-1 receptor agonist is used.
“I have always believed in the benefits basal insulin, and we know that eventually most of the people with type 2 diabetes are going to need basal insulin, so why not give a better basal insulin combined with a GLP-1 receptor agonist if it’s available and it’s affordable?” Rosenstock asked.
Rosenstock’s predictions for simple but highly effective simultaneous combination therapies are triple therapy with metformin, SGLT2 inhibitor and an oral GLP-1 receptor agonist or dual therapy with metformin and a SGLT2 inhibitor in a fixed-dose co-formulation plus a single injection of a fixed-ratio basal insulin and a GLP-1 receptor agonist co-formulation. According to Rosenstock, this would require a single pill and a single injectable.
“I think with this one pill, one shot, you can potentially control more than 90% of people with type 2 diabetes,” Rosenstock said. – by Phil Neuffer
Reference:
Rosenstock J. What to Choose? Initial Combination Therapy versus Sequential Therapy. Presented at: Cardiometabolic Health Congress; Oct. 10-13, 2019; Chicago.
Disclosure: Rosenstock reports he has received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Intarcia, Janssen, Lexicon, Merck, Novo Nordisk, Pfizer and Sanofi and served on the advisory board or received consultant honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Intarcia, Janssen, Novo Nordisk and Sanofi.
Perspective
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Kevin M. Pantalone, DO, ECNU, FACE
The management of type 2 diabetes has historically been referred to as a “treat-to-failure” approach. In this approach, diabetes therapies are added in a sequential manner to address persistent hyperglycemia. Given that approximately 50% of patients with type 2 diabetes do not have an HbA1c of less than 7%, this historical approach is clearly deficient and requires modification.
Research over the past decade has helped to accelerate a paradigm shift towards an alternative treatment approach, referred to as “treat-to-target.” The treat-to-target approach emphasizes the early and aggressive intensification of therapy, including the use of early combination therapy rather than the initiation of metformin alone. The earlier glycemic control is achieved, the risk for developing type 2 diabetes-related complications can be reduced. In addition, CV outcome trials conducted with newer type 2 diabetes therapies have identified additional benefits with these therapies beyond simply improving glycemic control.
The CV and renal benefits of GLP-1 receptor agonists and SGLT-2 inhibitors have been unequivocally established. Accordingly, maximizing the use of these therapies early in the course of management, particularly among those with established CVD and/or chronic kidney disease, appears warranted. Type 2 diabetes management guidelines set forth by the ADA/EASD and AACE have recently evolved to encourage the use of early combination therapy — particularly when patients present with a more prominent elevation of their HbA1c — and highlighted the need to prioritize CV and renal risk reduction when choosing diabetes therapies. However, this has yet to translate into routine clinical practice. The thresholds for when combination therapies should be used among the guidelines has made the process unclear. However, what is clear is that multiple diabetes medications used in combination will be required to obtain glycemic control in most patients with type 2 diabetes. The choice of treatments should prioritize CV and renal benefits, and not simply HbA1c.
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