April 15, 2018, Dr Chee L Khoo
To get our patients with type 2 diabetes (T2D) to glycaemic target using oral agents, you can either use an SGLT2 inhibitor (SGLT2i) or a DPP4 inhibitor DPP4i) after metformin (with or without a sulphonylurea) but not both. If you stop a DPP4 inhibitor to start a SGLT2ior vice versa, in general, the HbA1c remain unchanged. If only we are allowed to use both agents together, we could get more of our patients with T2D to target. Well, from April 1, 2018, you can do just that although that is only limited to two brands at the moment (a bit later).
As you are aware, renal reabsorption of glucose is increased in T2D. This, naturally, contributes further to the hyperglycaemia. SGLT2i reduce renal tubular glucose reabsorption causing glycosuria with its caloric loss. In T2D, there is also an impaired response to incretin hormones as well as a reduction in incretion secretion. DPP4i reduce the breakdown of incretin hormones. Combining both agents would make sense as they work differently on the different defects of T2D.
In a systematic review with meta-analysis of studies that compared the combination of SGLT2i/DPP4i with placebo plus the DPP4 inhibitor alone, 7 studies selected. 3 studies compared simultaneous introduction of combined SGLT2i/DPP4i with DPP4i alone while 4 studies compared an SGLT2i added to placebo to SLGT2i added to a DPP4i. Only one trial permitted concurrent use of insulin therapy.
So, are two agents more potent in lowering glucose targets than one?
Overall, the SGLT2i/DPP4i group reduced HbA1c by an additional 0.59% compared with DPP4i alone. The reduction in fasting glucose and 2 hour glucose were already greater in the SGLT2i/DPP4i group. The proportion of patients that achieved HbA1c < 7.0% is also higher in the combination group as well.
But do two different agents mean two different sets of adverse effects?
Overall, the risk of hypoglycaemia appeared to be higher in the SGT2i/DPP4i group than placebo. But much of that increase risk appeared to be coming from the study that permitted concurrent use of insulin therapy. A sensitivity analysis after excluding that study revealed no increased risk of hypoglycaemia in the SGLT2i/DPP4i group compared with DPP4i alone.
When they compared SGLT2i/DPP4i and DPP4i alone, the risk of UTI and genital infection was not increased.
Are there additional benefits when you combine the two agents?
The SGLT2i/DPP4i group significantly increased serum HDL-C and LDL-C levels and showed a tendency to decrease serum triglyceride levels. The SGLT2i/DPP4i group also showed a 3.2 mmHg improvement in systolic blood pressure compared with the DPP4i alone group.
The SGLT2i/DPP4i group showed a significant reduction in body weight compared with DPP4i, which is expected considering the mechanism of action of the SGLT2i.
What do you do with patients who are already on a DPP4 inhibitor alone or SGLT2 inhibitor alone and are not at glycaemic target?
At moment only two brands of SGT2i/DPP4i are subsidised under the PBS authority scheme:
QTERN – combination of Dapagliflozin 5mg (Forxiga) and Saxagliptin 10mg (Onglyxa) available as streamline authority for 28 tablets with 5 repeats with a convenient once daily dose.
Glyxambi – combination of Empagliflozin 10mg, 25mg (Jardiance) and Linagliptin 5mg (Trajenta) available as streamline authority for 30 tablets with 5 repeats with a convenient once daily dose.
Both preparation do not come with metformin and as such, you will need to separately prescribe Metformin.
At the present moment, the other brands of DPP4i do not have a SGLT2/DPP4i combination yet.
While the PBS now allow the classic triple therapy of Metformin/SGLT2i/DPP4i, you cannot add an SGLT2i (like Jardiance or Forxiga) to an existing DPP4i.
Access the systematic review here.
Reference:
Min, SH et al. Combination of sodium-glucose cotransporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor in type 2 diabetes: a systematic review with meta-analysis. SCIENTIFIC REPORTS (2018) 8:4466