Which Combination Drug Therapy is Best for You?

Drug-specific and patient-specific factors determine the most appropriate
drug therapies.

The Drugs in Context article we cited in September, when we wrote about the cardioprotective benefit of adding a GLP-1 Receptor Agonist to one’s treatment plan, pointed out that an ideal T2D drug “would have favorable effects on weight, blood pressure, and lipids” along with glucose control. When we revisited the GLP-1 class earlier this month after one of the manufacturers had introduced a weekly dose formula to its product line, we referenced the American Diabetes Association’s 2018 recommendation that the proper time to consider adding a GLP-1 to metformin or to another traditional therapy was after looking at drug-specific and patient-specific factors.

The Drug-Specific Factors

All the drugs in the class which have obtained FDA safety and effectiveness clearance, except one (Saxenda liraglutide) are indicated first for use as adjuncts to diet and exercise to improve glucose control in T2D patients. Saxenda’s first indicated use is weight control. All drugs in the class are offered as aids to weight control, even though promotional materials, prescribing information, and professional-and-patient guides are consistent in stating that products may help with weight loss. Below we provide links to medication guides. Medication guides are summary documents that are usually published in the same document as the full text prescribing information (sometimes referred to as the “label” or “package insert”).

Exenatides:      AstraZeneca Bydureon and Byetta

Liraglutides:    Novo Nordisk Victoza and Saxenda

Semaglutide:   Novo Nordisk Ozempic

Dulaglutide:    Eli Lilly Trulicity

Lixisenatides: Zealand / Sanofi Aventis Adlyxin and Lyxumia

Novo Nordisk, which recently gained FDA clearance for its weekly-dose Ozempic, has an oral drug in the pipeline which the company describes as a once-weekly semaglutide. There are also a number of fixed dose GLP-1/insulin combinations. Xultophy, another Novo product, combines Victoza and ultra long-acting Tresiba (degludec) insulin. Sanofi’s Lixilan combines Lyxumia and Adlyxin with long-acting Lantus (glargine).These combination products are thought to present less risk of hypoglycemia and greater weight control than insulin or GLP-1 alone.

By our count, there have been 60 studies, available at the National Institutes of Health clinical trial library, comparing effectiveness of GLP-1 products “head to head,” meaning within the GLP-1 class, and against metformin and sulfonylurea products, but fewer studies on DPP-4 inhibitors, thiazolodinediones, or meglitinides. Patient-specific factors described below determine when best to add a drug to a metformin/GLP-1 regimen.The treatment decision may depend entirely upon whether a drug that works by suppressing a glucose control response will also suppress the effectiveness of the existing combination drug therapy.

The Patient-Specific Factors

The American Diabetes Association emphasizes a patient-centered approach in all areas of diabetes care including choice of medications. Its 2018 Part 8 Update to the Standards of Medical Care proposes that efficacy be the first factor to consider among therapies. Then, because GLP-1 drugs are not first line measures, the physician must assess likelihood of its side effects and interactions with the patient’s existing drug regimen. History of cardiovascular disease would auger in favor of a GLP-1; potential for renal complications auger against adopting an SGLT-2, as are outlined below. A flow chart (Figure 8.1 on page S76 of the Standards if you’re following along at home) helps illustrate the sequential decision points beginning at initial diagnosis:

  • Monotherapy: At diagnosis, set an A1c target, initiate lifestyle changes, and initiate pharmacologic therapy based on likely effectiveness in achieving an improved A1c. Where A1c is less than 9%, metformin is the first line intervention, and one that will likely promote weight control. Remember for the succeeding steps that “monotherapy” in ADA’s view is lifestyle modification along with the drug of choice. If at three and six month follow-ups the target A1c has been maintained, continue with metformin; if not, discuss the patient’s compliance with the drug and lifestyle change to consider adopting dual therapy.
  • Dual therapy: If the initial blood testing shows A1c at 9% or greater, the additional drug should be one proven effective to reduce risk of major adverse cardiovascular events, or mortality. Testing has shown that each added class of non-insulin drugs can lower A1c another 0.7% to 1.0%. Here, selection of a GLP-1 agonist over a sulfonylurea (glipizide) or DPP-4 inhibitor (Merck Januvia sitagliptin, AstraZeneca Onglyza saxagliptin, Lilly Trajenta linagliptin) is pretty much a given, as DPP-4 drugs actually inhibit the action of GLP-1 drugs, and the natural glucagon peptide response, in working with the body’s glucose-control mechanisms. Moreover, sulfonylureas used in combination with other anti-diabetic medicines can send the body into severe lows. In addition, GLP-1 drugs can have a beneficial effect on weight gain.

An SGLT-2 inhibitor, which stimulates the kidneys to trap glucose and route it into the urinary tract before it can be recirculated into the bloodstream, is also a highly preferable option, provided that it’s not likely to overstress the urinary system. At three and six months after introducing the second tier drug with no improvement in reaching the A1c target, it is appropriate to confirm with the patient that he or she is pursuing lifestyle changes before moving any further.

  • Triple therapy: Throughout the protocol, metformin is to be continued because of its reliability and its levelling effect on glucose concentration. But at this point, the decision tree widens to include a selection among basal and prandial insulins. Here again, regular follow-up is required to assess the efficacy of the adopted drug combinations. If the patient continues to have difficulty maintaining target A1c, it’s time to consider adding a rapid-acting insulin before the largest meal of the day or a pre-mixed analogue at all three daily meals.

As always, we recommend that the protocol be undertaken in close consultation with your physician. Keeping a log of your daily dosing and times, exercise routine, and diet will help, along with being candid about your daily results when you visit with your doctor or Certified Diabetes Educator. The log needn’t be as detailed as in the examples, but it will help immeasurably in settling into the treatment strategy that will work best for you.



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Jim Cahill is a senior writer for Insulin Nation and Type 2 Nation. Before turning to writing, he was a lawyer in government and private practice who focused on consumer protection and regulatory law. He can be contacted at jcahill@epscomm.com.