A triple therapy approach to Type 1 diabetes

By Lisa Foster-McNulty, MSN, RN, CDE

Type 1 diabetes treatment doesn’t have to be about just insulin anymore.  There are many new  medications on the market aimed at treating Type 2 that provide glucose control through various pathways.  Type 1 management is starting to incorporate some of these agents for improving glucose control.

With all forms of diabetes, the goal is to adequately control the disease and prevent target organ damage.  Poor control can lead to complications such as retinopathy (eye disease), nephropathy (kidney disease), and neuropathy (nerve damage).  These complications have a negative effect on quality of life! 

Researchers have developed various treatment approaches  to trial in Type 1 diabetes.  Recent research has investigated the advantages of SGLT-2 inhibitors and the effect they have on cardiovascular events and mortality.  The EMPAREG OUTCOME study investigated the impact of these agents on Type 2 patients and found that using empagliflozin (Jardiance) reduced all-cause mortality, cardiovascular mortality, and heart attack, with no increase in the risk of stroke.  It is thought that Type 1 patients may see the similar benefit, but more study is needed.

An earlier study on canagliflozin (Invokana) demonstrated a higher incidence of Diabetic Ketoacidosis (DKA) in patients with Type 1 diabetes.  It is thought that the DKA is linked to increased insulin resistance stemming from an increase in glucagon and free fatty acids in the blood stream.  This can make patients vulnerable to kidney complications.  On the other hand, a more recent study demonstrated improved kidney function in patients taking dapagliflozin (Farxiga)because of a lower incidence of poor blood flow to the kidneys.  These findings aren’t noted in patients taking liraglutide (Victoza)due to the suppression of the production of ketones.

Researcher Nitesh Kuhadiya and colleagues recently expanded upon the use of SGLT-2 inhibitors in patients with Type 1 diabetes.  Their randomized clinical trial investigated the reduction in BG levels and body weight from adding dapagliflozin to existing treatments of insulin and liraglutide.  They thought that adding dapagliflozin to an existing therapy regimen of insulin and liraglutide should improve BG levels without increasing levels of glucagon and other factors that cause ketone production.

Thirty patients participated in the study.  In a 2:1 ratio, they received either dapagliflozin 10 mg or placebo for 12 weeks.  Inclusion criteria included being age 18-75 with Type 1 diabetes, having a fasting C-peptide level of   A dietitian documented consistency of carbohydrate intake.  The primary end point of the study was a change in A1c following 12 weeks of dapagliflozin.  As secondary end points, researchers measured participants’ body weight, blood pressure, carbohydrate intake, and factors that could influence the production of ketones.  Twenty six participants finished the study, of which 17 were part of the group receiving dapagliflozin.  Subjects in the intervention group actually received dapagliflozin 5 mg daily for one week followed by 11 weeks of 10 mg daily.  Insulin was dosed with the intent of keeping BG levels in the range of 68-158 mg/dl (3.8-8.8 mmol/L).

The researchers concluded that when compared to placebo, triple therapy with liraglutide, insulin, and dapagliflozin lowered the A1c by 0.66%.  In patients receiving triple therapy, no severe hypoglycemia was reported.  No significant changes were reported in the placebo group.  Compared to placebo, weight dropped by 1.9 +/-.54 kg in the triple therapy group.  There was also a significant increase in ketosis mediators.  Additionally, total cholesterol rose by 6%, and LDL-C (the “bad” cholesterol) rose by 8%.  In both groups, there was no change to blood pressure.  The researchers determined that triple therapy can significantly decrease A1c and weight, but this approach requires caution because these patients can be predisposed to developing DKA.

This research is very interesting because it demonstrates that in a small population of Type 1 patients, liraglutide mitigates the risk of DKA that comes from use of an SGLT-2 inhibitor.  Triple therapy does reduce BG levels without raising the risk of hypoglycemia.  In Type 1 patients, we can lower both weight and A1c while getting heart and kidney protection, but we do have to closely watch for undesirable increases in total and LDL cholesterol.  Since triple therapy increases glucagon and free fatty acid levels in the body, we need to monitor closely for DKA.