What's After Metformin in Diabetes? 'This Is How You Do It'

June 11, 2016

NEW ORLEANS — Options for the sequence of medications that should following the ubiquitous first-line use of metformin in most patients with type 2 diabetes was the subject of a packed symposium this morning at the American Diabetes Association (ADA) 2016 Scientific Sessions.

Speakers discussed a wide range of options, including starting a glucagonlike-peptide 1 (GLP-1) agonist after metformin, beginning sodium-glucose cotransporter-2 (SGLT-2)–inhibitor therapy before this, using combination approaches, and the role of insulin.

Entitled, "This Is How You Do It: Medication Options, Sequence and Combination for Optimal Management of Type 2 Diabetes," practicing endocrinologists shared their tips with the audience.

Most important, as Christopher H Sorli MD, PhD, of the Billings Clinic, Montana, observed during his talk — "Bringing it All Together: What the Objective Clinician Should Do" — is to tailor therapy to the individual patient.

"The mantra is to individualize. It's called patient-centric therapy.

"In my clinic, every single patient I see has their HbA1c target documented in their electronic health record [EHR]," he stressed, noting that then, every healthcare professional involved in the care of that patient and the patient him- or herself knows that goal.

Metformin is a "No-Brainer"

Dr Sorli then proceeded to discuss all the options for choice of therapy to follow metformin, using three case studies of very different type 2 diabetes patients to illustrate how he would arrive at his decisions in each case.

Even metformin, which is pretty much universally used first line and "which we know is efficacious and reduces hepatic glucose production," is not the ideal therapy for everyone, he stressed.

"For the patient who is profoundly insulin sensitive, metformin may not be your drug of choice," he said, adding also that gastrointestinal tolerability of metformin "can be a clinical issue," as can vitamin B12 deficiency.

But overall, especially given its favorable cost, "for most patients, metformin is a no-brainer."

And still the most commonly prescribed second-line agents for type 2 diabetes are the sulfonylureas, he told the meeting. Sulfonylureas can — if a patient still has lots of beta cells — have "nice effects" in lowering blood glucose, he noted. But they cause weight gain — "in the population that I most want to avoid this in" — and are associated with hypoglycemia.

"What really drives sulfonylurea use is the cost," he asserted.

"For most patients, sulfonylureas are not going to be my first choice to follow metformin," he explained, but added that "if a patient cannot afford anything else," they are better than nothing.

Dr Sorli then went on to discuss pioglitazone.

Although "this is not used much anymore, I don't actually think it's a total nonstarter. It can be used in a patient population that is insulin resistant, and it lowers triglycerides, raises HDL, has benefits for nonalcoholic steatohepatitis [NASH], and may have some cardiovascular benefits."

Of course, "We do know about its weight gain and risk of heart failure, edema, and fracture risk," he noted, but "it is a potential add-on therapy that can have efficacy which outweighs safety in some patients."

The Newer Kids on the Block

Moving on to discuss the injectable GLP-1–receptor agonists, Dr Sorli said:

"Their efficacy is high and they are applicable across a broad spectrum of diabetes patients. They have a tendency to promote weight loss, which is a major [positive] factor for a patient with insulin resistance."

And that's not to mention the promised cardiovascular benefits hinted at by the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results — A Long Term Evaluation (LEADER) trial top-line results; full details are to be reported here on Monday, he noted.

However, gastrointestinal tolerability "is a major clinical barrier," with GLP-1 agonists.

But overall, "these are an exceedingly appealing option for some patients."

Moving on to the oral dipeptidyl peptidase-4 (DPP-4) inhibitors, Dr Sorli said, "Although their efficacy may not be quite as great as the GLP-1 agonists…these are exceptionally tolerable agents, with a low risk of hypoglycemia," although he noted they do not induce any weight loss.

As such, DPP-4 inhibitors are a good choice for older patients, he advised, noting that the American Diabetes Association Geriatric Treatment Guidelines "highly recommend" the use of DPP-4 inhibitors.

Is Empagliflozin a Game Changer?

Finally, the SGLT2 inhibitors, "which have a non–insulin-dependent mechanism of action that is highly applicable across the broad spectrum of diabetes patients," have glucose-lowering efficacy that is "similar to the DPP-4 inhibitors," Dr Sorli observed.

And although there are "volume-related aspects" that need to be considered when using these agents, they also have the benefit of promoting "moderate weight loss" and present "no hypoglycemia risk," he stressed.

And, of course, they have the "exceedingly impressive mortality data," in the form of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) results with one SGLT2 inhibitor in particular, empagliflozin (Jardiance, Boehringer Ingelheim/Lilly).

Indeed, one attendee asserted during the Q&A session that he believes empagliflozin is "a game changer."

Noting that "60% of our diabetes patients die from cardiovascular disease," this doctor pointed out that the Canadian Diabetes Association has recently updated its clinical practice schedule to state "that if your [diabetes] patient has cardiovascular disease then you should consider a SGLT2 inhibitor as second-line after metformin."

"Preventing cardiovascular death trumps any other parameter," he observed.

Insulin: The Little Black Dress of Diabetes Therapy

Meanwhile, speaking to the benefits of insulin in type 2 diabetes was Alice YY Cheng, MD, FRCPC, of the University of Toronto, Ottawa.

"Insulin remains the safest alternative after metformin when the pancreas starts to tire," she observed.

Dr Cheng cited the ORIGIN study as evidence that basal insulin is a good choice after metformin, noting, "We give metformin to address insulin resistance, and then we can use insulin."

However, she also said that, increasingly, type 2 diabetes therapy will encompass multiple, combination therapies, and "my argument is that we can combine insulin with our newer friends."

Asked by an audience member during the Q&A session why she didn't cite United Kingdom Prospective Diabetes Study (UKPDS) data, which "showed that insulin was no better than sulfonylureas," she replied that UKPDS is an older study, "and we have much better basal insulins now."

Dr Sorli said that prandial insulin is a good choice for type 2 diabetes "because it's titratable, so we can adjust and manage the dose."

But weight gain is a downside with insulin, he conceded.

Both he and Dr Cheng stressed that going in slow, with lower doses of insulin, early in type 2 diabetes to control fasting glucose can be a good strategy in certain patients.

And Dr Sorli also spoke to the promise of soon-to-be approved combinations of GLP-1 agonists and insulin, iDegLira and LixiLan .

These are "appealing" because of their high efficacy, and they are weight neutral, he observed, but noted that they won't "be a fit for everyone."

Dr Sorli reports being on advisory panels for Eli Lilly and Novo Nordisk; receiving research support from Eli Lilly, Johnson & Johnson, MannKind, MSD, Roche Pharmaceuticals, and Sanofi Deutschland; and being on speaker's bureau for Lily Lilly, Janssen Pharmaceuticals, and Novo Nordisk. All monies are paid directly to Billings Clinic.

Follow Lisa Nainggolan on Twitter: @LisaNainggolan1. For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

American Diabetes Association 2016 Scientific Sessions; June 11, 2016. New Orleans, Louisiana. Session 3-CT-SY20

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