How best to decide whether to use one or a combination of the new treatments and individualize the treatment for your patients.
Type 2 diabetes (T2D) is a progressive, chronic disease characterized by hyperglycemia. Despite recent advances to early diagnosis and treatment, its prevalence is rising worldwide. Plus, more than half those diagnosed will not achieve control according to recent guidelines. Prior to 1950, we only had one oral drug to treat T2D. Today we have more than over 3 million possible combinations. The most recent treatment choices for the management of T2D are DPP-4 inhibitors (dipeptidyl dipeptidase 4), SGLT-2 inhibitors (sodium-glucose cotransporter 2) and GLP-1 receptor agonists (glucagon-like peptide 1). So, looking at these new treatments and understanding how they work can help to decide the best treatments for each individual patient.
When looking at the DPP-4 inhibitors and SGLT-2 inhibitors as monotherapy, researchers put together a meta-analysis of 25 randomized trials and compared the safety and efficacy of DPP-4 inhibitors and SGLT-2 inhibitors as monotherapy or in addition to metformin for the treatment of type 2 diabetes in 14,619 patients. There was a significantly greater reduction in HbA1c and fasting plasma glucose associated with the use of SGLT-2 inhibitors compared with DPP-4 inhibitors. The risk of hypoglycemic events was very small and similar between the two agents. The use of SGLT-2 inhibitors plus metformin was associated with a significantly greater decrease in fasting plasma glucose than the use of DPP-4 agents plus metformin. Again, the risk of hypoglycemic events was similar between the two agents when used in conjunction with metformin. So, in the final analysis, SGLT-2 inhibitors reduced HbA1c and fasting plasma glucose significantly more than DPP-4 inhibitors without causing more hypoglycemic events among patients with type 2 diabetes.
When looking at adding SGLT-2 inhibitors or DPP-4 inhibitors to the treatment plan for T2 patients whose diabetes is not controlled on basal insulin, they discovered for those who added the SGLT2 to their insulin therapy that they achieved better glycemic control and greater weight reduction than DPP-4 inhibitors without increasing the risk of hypoglycemia in patients with T2DM whose diabetes is inadequately controlled with insulin. In another study, they performed indirect meta-analysis comparing SGLT-2 inhibitors and DPP-4 inhibitors added to insulin therapy. Without increasing hypoglycemia, SGLT-2 inhibitors showed better glycemic control and greater weight reduction than DPP-4 inhibitors in patients with T2DM whose diabetes is inadequately controlled with insulin. The results of the current study could serve as the best available evidence in selecting oral agents to improve glycemic control in patients with type 2 who use insulin.
Now let’s look at combining two of the newer drugs, an SGLT-2 Inhibitor and a GLP-1 for those with type 2 diabetes and who have not reached their treatment goal. A study (Duration-8) was completed and published in The Lancet Diabetes & Endocrinology. It was a 28-week randomized controlled trial comparing the combination of the GLP-1 receptor agonist (2 mg once weekly) and the SGLT-2 inhibitor dapagliflozin (10 mg once daily) with either drug alone in patients with type 2 diabetes who have consistently high blood sugars (mean baseline HbA1c 9·3% ) despite the use of metformin.
According the results of the DURATION-8 trial, the combination of once-weekly exenatide (Bydureon) and dapagliflozin (Farxiga) as the next step after metformin improved type 2 diabetes control and weight loss better than either drug alone.
The primary endpoint of hemoglobin A1c improved by 2.0 percentage points from baseline to week 28 with the combination, a 0.4 percentage point greater effect than seen with exenatide alone and 0.6 percentage points greater than with dapagliflozin alone (P=0.004 and P<0.001). Exenatide plus dapagliflozin was also significantly better than either drug alone for all secondary efficacy endpoints.
The combination therapy provided a 3.41 kg (7.52 lbs) weight loss over baseline, compared with 1.54 kg (3.40 lbs) on exenatide alone and 2.19 kg (4.83 lbs) on dapagliflozin alone, both significant differences. Other secondary endpoints favored the combination as well: fasting plasma and postprandial glucose, proportion at HbA1c target of 7.0%, and reduction in systolic blood pressure.
So when compared to our treatment possibilities from the 1950’s to today, you can see that we are now in the era of combination therapy. The combinations that we should be using are combinations that don’t cause hypoglycemia and weight gain, and we should be using them early in treatment, which will provide visible benefits for the patient, thus motivating them to better care and help to prevent the complications from diabetes and provide a better quality of life.
When looking at the outcomes from these combinations especially when using SGLT-2 or GLP-1 treatments, probably the major benefit comes from the results of the current cardiovascular studies showing that they can reduce cardiovascular death, which impacts most type 2 patients. The two drugs used in combination in the study DECLARE-TMI 58 with cardiovascular results, are not expected until 2018 and 2019, respectively.
It will have to be future trials that will answer whether the combination of GLP-1 receptor agonists and SGLT-2 inhibitors might further reduce cardiovascular risk beyond what the individual drugs can do.
For a chart comparing the outcomes of a number of studies, see the Comparison Chart For SGLT-2 and GLP-1 Treatments.
- The combination therapy provided a 3.41 kg (7.52 lbs) weight loss over baseline, compared with 1.54 kg (3.40 lbs) on exenatide alone and 2.19 kg (4.83 lbs) on dapagliflozin alone.
- For the GLP-1 and SGLT-2 combination treatment, they found that not only did they lower blood sugars, reduced weight and blood pressure, but reduced the risk for cardiovascular issues.
- The most important aspect of this trial is that it reduced the risk of death.
Frias JP, et al “Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial” Lancet Diabetes Endocrinol 2106; DOI: 10.1016/ S2213-8587(16)30267-4.
Nauck MA, et al “GLP-1 receptor agonists and SGLT2 inhibitors: a couple at last?” Lancet Diabetes Endocrinol 2016; DOI: 10.1016/ S2213-8587(16)30263-7.