Combining treatments 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 combination therapy immediately rather than following the traditional method of waiting to intensify treatment, according to a speaker at the Cardiometabolic Health Congress.

rosenstock julio 2019 - Combining treatments shows major potential in type 2 diabetes

Julio Rosenstock

“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 trials in the past decade alone showcasing the positive effects of these medications, 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 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 repeats the same procedures and expects different outcomes.

pills shutterstock - Combining treatments shows major potential in type 2 diabetes 

When treating patients with type 2 diabetes, physicians may have more success if they use combination therapy immediately rather than following the traditional method of waiting to intensify treatment.

Source: Shutterstock

“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 an SGLT2 inhibitor.

“If I develop type 2 diabetes, I get started right away with metformin and an SGLT2 inhibitor. I see no reason [not to] whatsoever, 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 a DPP-IV inhibitor in addition to the metformin and SGLT2 inhibitor. As evidenced in the VERIFY study, DPP-IVs like vildagliptin can produce enhanced glycemic management 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 during larger 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

DPP-IV inhibitors are not the only medications that may work in the triple-therapy approach. Rosenstock also recommended the use of oral semaglutide (Ozempic, Novo Nordisk), a weekly GLP-1 receptor agonist or fixed-ratio basal insulin with a GLP-1 receptor agonist in addition to the initial combination therapy of metformin and an SGLT2 inhibitor.

Starting with oral semaglutide, this “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). Semaglutide has been further tested across the PIONEER study series, with comparisons against numerous agents. What makes 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 GLP-1 receptor agonists and basal insulin are also potential add-ons to the initial combination therapy of metformin and SGLT2 inhibitors and are what Rosenstock said he largely recommends 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 effective, but cost is once again a barrier.

For those who can afford such a treatment, the AWARD-9 and SUSTAIN 5 trials showed benefits for HbA1c reduction when using these two types of agents together while the GLP-1 receptor agonist essentially counterbalances basal insulin’s tendency to increase weight, according to Rosenstock. These benefits may be enhanced further if a fixed ratio is incorporated when combining these agents.

“I believe in basal insulin, that eventually most of the people with type 2 diabetes are going to need basal insulin, but why not give a better basal insulin if it’s available and it’s affordable?” Rosenstock asked, while noting that this would require a single pill and a single injectable. “I think one pill, one shot, you can control more than 90% of people with type 2 diabetes.” – 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.

CHICAGO — When treating patients with type 2 diabetes, physicians may have more success if they use combination therapy immediately rather than following the traditional method of waiting to intensify treatment, according to a speaker at the Cardiometabolic Health Congress.

rosenstock julio 2019 - Combining treatments shows major potential in type 2 diabetes

Julio Rosenstock

“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 trials in the past decade alone showcasing the positive effects of these medications, 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 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 repeats the same procedures and expects different outcomes.

pills shutterstock - Combining treatments shows major potential in type 2 diabetes 

When treating patients with type 2 diabetes, physicians may have more success if they use combination therapy immediately rather than following the traditional method of waiting to intensify treatment.

Source: Shutterstock

“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 an SGLT2 inhibitor.

“If I develop type 2 diabetes, I get started right away with metformin and an SGLT2 inhibitor. I see no reason [not to] whatsoever, 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.”

PAGE BREAK

“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 a DPP-IV inhibitor in addition to the metformin and SGLT2 inhibitor. As evidenced in the VERIFY study, DPP-IVs like vildagliptin can produce enhanced glycemic management 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 during larger 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

DPP-IV inhibitors are not the only medications that may work in the triple-therapy approach. Rosenstock also recommended the use of oral semaglutide (Ozempic, Novo Nordisk), a weekly GLP-1 receptor agonist or fixed-ratio basal insulin with a GLP-1 receptor agonist in addition to the initial combination therapy of metformin and an SGLT2 inhibitor.

Starting with oral semaglutide, this “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). Semaglutide has been further tested across the PIONEER study series, with comparisons against numerous agents. What makes 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.”

PAGE BREAK

Injectables like GLP-1 receptor agonists and basal insulin are also potential add-ons to the initial combination therapy of metformin and SGLT2 inhibitors and are what Rosenstock said he largely recommends 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 effective, but cost is once again a barrier.

For those who can afford such a treatment, the AWARD-9 and SUSTAIN 5 trials showed benefits for HbA1c reduction when using these two types of agents together while the GLP-1 receptor agonist essentially counterbalances basal insulin’s tendency to increase weight, according to Rosenstock. These benefits may be enhanced further if a fixed ratio is incorporated when combining these agents.

“I believe in basal insulin, that eventually most of the people with type 2 diabetes are going to need basal insulin, but why not give a better basal insulin if it’s available and it’s affordable?” Rosenstock asked, while noting that this would require a single pill and a single injectable. “I think one pill, one shot, you can control more than 90% of people with type 2 diabetes.” – 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.

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