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When a doctor finds that a Type 2 diabetes patient is not controlling blood glucose levels with maximum dosing of metformin, and the patient's HbA1c is creeping towards 8% or higher, the challenge is what to do next.

And the treatment goal may have more to do with patient desires than the physician's playbook, researchers said here at the (ADA).

"The next step in treatment is not what I would use, but what the patient would use -- because the only drug that works is a drug the patient takes," said John Buse, MD, PhD, of the University of North Carolina at Chapel Hill.

"If a patient has an insurance scheme where an SGLT-2 inhibitor is going to cost them $400 to $500 a month and they are on Social Security, they are not going to be able to afford that drug. It doesn't matter how great the drug is; it's about whether the patient can take it," Buse told MedPage Today.

Even then, if patient and doctor and the third-party payer are all on the same page, that doesn't mean the treatment goal is the same either, said Alvin Powers, MD, director of the Vanderbilt Diabetes Center in Nashville.

"The treatment goal for a person who is 48 is different from that of a person who is 68 and different from a person who is 78."

Robert Eckel, MD, of the University of Colorado Anschutz Campus in Aurora, said, "What you do next after metformin is based on age; it is based on comorbidities such as existing cardiovascular disease; and if the patient is blind or has end-stage renal disease, then the goals for treatment can be different."

"The key to all diabetes treatment is to individualize it to fit the needs of the patient," said Powers, who is the ADA's immediate past president of medicine and science. "Part of that need is to consider the cost of the medication."

Buse said that when he discusses next steps after maximum metformin use, he tells patients that all the classes of second-line treatment are good, and all have advantages and disadvantages.

SGL2 Inhibitors

If the patient has documented cardiovascular disease, the SGLT-2 inhibitors are Buse's choice, he said. "The SGLT2 inhibitors are a once-a-day pill that rarely have discomforting side effects; they carry no risk of hypoglycemia; they are associated with weight loss; they improve blood pressure and in people with clinical cardiovascular disease, reduce heart attacks, strokes, and cardiovascular death, [SGLT-2 inhibitors] are a great choice, but they are expensive."

GLP-1 Receptor Agonists

"The GLP-1 receptor agonists have a very similar story," he said. "They are injected, some of them once a week, and some have 'magical devices' that inject without a needle. But with these drugs there is no risk of hypoglycemia, they are associated with weight loss, and they improve cardiovascular outcomes and renal outcomes. These are great drugs – but are really expensive. If people have clinical cardiovascular disease, I think the compelling indication is that they should take an SGLT inhibitor of a GLP-1 receptor agonist.

"I would press these patients in that direction if they have had a prior heart attack, stroke, and if the balance of the events are more of angina, stents, or hospitalization for blockages, I would push patients a bit more toward the GLP-1 receptor agonists where the data is a little bit stronger for heart attack reduction. If the patient's problem is heart failure and admission for heart failure, I would definitely push them toward SGLT inhibitors. But again, if they can't afford it, they can't afford it, and it doesn't matter how good the drug is."

Pioglitazone

Buse said that pioglitazone – a thiazolidinedione – may also be considered: "The thiazolidinediones have some tangential evidence that they reduce cardiovascular events. My guess is that pioglitazone does reduce cardiovascular events, but are associated with weight gain, fluid retention, and increased risk of heart failure. They are not 'cheap, cheap,' but are more like a dollar a day rather than $10 a day. They are now generic. If you have an insurance plan, they are often free.

"The sulfonylureas are dirt cheap. They are very effective blood sugar-lowering drugs. There is a concern, particularly with high doses, that they 'strip the gears of the beta cell,' and you will progress to insulin more quickly, but with patients with resource challenges, these may be the only choice, frankly, and we shouldn't hesitate to use them. The best evidence is that they are associated with hypoglycemia and weight gain, so they clearly have their issues."

Insulin

"And then there is insulin, which is an extremely effective drug," Buse continued. "It requires injection, and you can use it in a pen, which makes it convenient. It is clearly associated with hypoglycemia, and clearly associated with weight gain, and it has been around for almost 100 years so there are no surprises with its use."

Successful treatment comes with letting the patient help make the decision for treatment, Buse emphasized. "If they participate in the decision-making around what drug to take, it will determine if they are going to take it."

Eckel told MedPage Today that much of his decision-making in taking the move from metformin is weighty. "The decision may depend as to whether weight loss is desirable. If weight loss is desirable, than the SGLT inhibitors or the GPL-1 receptor agonists are an appropriate next step -- although the amount of weight loss with those agents doesn't knock your socks off. It's around 3-4% of body weight."

Low-Dose Thiazolidinediones

"I like low-dose thiazolidinediones as my next step," Eckel said. "I like the low dose because it mitigates edema and weight gain, but only if the patient has no signs of heart failure. Drugs like pioglitazone would be contraindicated if that condition existed. Low-dose pioglitazone will get you to a goal of HbA1c of 7% if the patient is around 8%."

Gliptins

"The DPP-4 inhibitors – the gliptins – might be useful for patients with HbA1c of 7.3% or 7.4% in hopes of getting to 7% or lower. We have a lot of patients on them because there are few side effects."

Bariatric Surgery

Eckel and Buse both said that a discussion of next steps might also include bariatric surgery. Patients with a body mass index of 35 or greater who have had diagnosed diabetes for less than 5 years might be good candidates for the radical surgery, Eckel said. "In many cases, the surgery is curative for Type 2 diabetes."

He suggested that patients who have had diabetes for a longer period could reduce body weight, but might not be able to have much effect on diabetes.

"This area of treatment definitely is a major challenges for doctors," Powers said. "There are treatment algorithms, but there are no rules and no definite course of action. In the end it all depends on individualizing treatment in line with what works for the patient."

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