UCSD’s Dr. Jeremy Pettus moderated a session with three expert presenters from across the world: Dr. Irene Hramiak (Western University), Dr. Tina Vilsboll (Steno Diabetes Center Copenhagen), and Dr. Chantal Mathieu (University Hospital Gasthuisberg Leuven).
Dr. Hramiak kicked things off discussing the current challenges and risks of insulin therapy, including hypoglycemia, weight gain, glucose variability, and diabetic ketoacidosis (DKA).
According to data from the T1D Exchange in USA, average A1C levels have not improved in the last decade, and adolescents continue to be a difficult group for glycemic management, despite increased use of pumps and continuous glucose monitors (CGM). How can adjunctive therapies (added to insulin) help?
The REMOVAL study looked at the effects of metformin in people with type 1 diabetes (40 years of age or older). Over three years, participants taking metformin saw the following benefits compared to those taking a placebo:
- A decrease in A1C of 0.13 percentage points
- A reduction in insulin dose by 1.2 units
- No change in the rate of minor or severe hypoglycemia
- From a baseline body weight of 193 lbs (87.7 kg), a weight loss of 2.6 lbs (1.17 kg)
- A reduction in LDL (“bad”) cholesterol by 0.13 mmol/L (5 mg/dL)
These data suggest that metformin did not have a clinically meaningful impact on glycemic management but may improve cardiovascular health in adults with type 1 diabetes. That’s disappointing, but something we’ve all wondered for years – now we know!
Dr. Vilsboll continued the conversation by discussing GLP-1 agonists for type 1 diabetes. She reminded that adjunctive therapy has several important goals but does not replace insulin – which is the main treatment for people with type 1 diabetes.
Dr. Vilsboll provided an overview of the effect of GLP-1 drugs in the pancreas (on insulin-producing beta cells), liver, brain, kidneys, and other organs before sharing data from a trial on GLP-1agonists in type 1 diabetes.
The LIRA-1 Study evaluated 24 weeks of GLP-1 agonist use in people with type 1 diabetes and excess weight and found that GLP-1 treatment:
- Did not have a statistically significant (meaningful) reduction in A1C compared to placebo.
- Reduced body weight by 13.4 lbs (6.1 kg) compared to placebo (from a baseline of about 205 lbs, or 93 kg).
- Increased gastrointestinal side effects (nausea, diarrhea).
- Did not decrease the amount of bolus insulin required but reduced basal insulin by about five to six units per day.
The ADJUNCT trial was the longest such trial, involving 1,400 people with type 1 diabetes with an A1C between 7%-10%. In this trial, participants taking GLP-1 agonists experienced:
- A clinically significant reduction in A1C of 0.54 percentage points compared to a baseline of 8.2% after 52 weeks.
- A reduction in body weight that correlated with the dose of GLP-1 agonist: 10.8 lbs (4.9 kg) of weight loss with a 1.8 mg dose of GLP-1 agonist; 7.9 lbs (3.6 kg) with a 1.2 mg dose; and 4.9 lbs (2.2 kg) with a 0.6 mg dose.
- An increased rate of symptomatic hypoglycemia, but no increase in severe hypoglycemia or DKA.
In a more recent trial, MAG1C, researchers examined the use of GLP-1 agonist exenatide (Byetta) over 26 weeks in adults with type 1 diabetes. Researchers found that compared to placebo, the GLP-1 agonist did not decrease A1C but did decrease insulin dose and body weight. Researchers concluded that the GLP-1 agonist does not have a future as an add-on treatment to insulin in type 1 diabetes. We are not certain this is the correct answer, because it seems like TIR would’ve been useful to measure – but, there’s no fighting city hall.
The session concluded with Dr. Chantal Mathieu discussing the role of SLGT-2 inhibitors in people with type 1 diabetes. She pointed to three main trials: DEPICT with Farxiga, InTANDEM with Zynquista, and EASE with Jardiance.
Compared to placebo, participants taking Farxiga (either 5mg or 10mg dose) experienced:
- Approximately a 0.45 percentage point drop in A1C by 24 weeks, and 0.2 to 0.3 percentage point decrease in A1C after 52 weeks.
- A time in range increase of about 10% – a gain of almost two more hours of time in range per day
- A 10% decrease in both basal and bolus insulin.
- A decrease in body weight of about 5.5 lbs (2.5 kg) with a 5mg dose, and about 7.7 lbs (3.5 kg) with a 10mg dose (from a baseline of 179 lbs, or 81 kg).
- An increased risk of genital infection and urinary tract infections.
- No increase in hypoglycemia.
- An increased risk of DKA that rises with a larger dose.
The inTandem trial also showed a drop in A1C: after 24 weeks, participants taking Zynquista experienced a 0.5 percentage point drop in A1C compared to those taking placebo. Time in range also increased with Zynquista. There was a 77-minute increase in time in range with the 200 mg dose, and almost a three-hour increase for people taking the 400mg dose. The increased risks of DKA and genital infections were also observed in this trial.
The EASE trial provided evidence that supported the effects of SGLT-2 inhibitors on the reduction of A1C – about 0.3-0.4 percentage points after 52 weeks. This study also used a much lower dose of 2.5 mg, which offered an intermediate effect – lowering A1C by about 0.2 percentage points and reducing body weight by 4 lbs (1.8 kg). Interestingly, there was no difference in DKA with the 2.5 mg dose compared to placebo.
Dr. Mathieu concluded by sharing her “bottom line” on the use of SGLT-2 inhibitors in type 1 diabetes and preventing DKA.
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