Type 2 diabetes

ADA 2021: Second line diabetes drugs ranked in GRADE


A head-to-head comparison of the four most commonly used classes of second line medications used in conjunction with metformin has found liraglutide and insulin were the most effective at keeping HbA1C levels less than 7% in patients with type 2 diabetes.

The Glycaemia Reduction Approaches in Diabetes—A Comparative Effectiveness (GRADE) study, presented at the virtual 81st Scientific Sessions of the American Diabetes Association (ADA), enrolled more than 5,000 patients with an average age of 57 years and an average duration of diabetes of four years.

Patients already on metformin ≥ 1000 mg were randomised to the sulfonylurea glimepiride, DPP-4 inhibitor sitagliptin, insulin glargine and GLP-1 receptor agonist liraglutide. The multicentre US study had started in 2013 just prior to the approval of SGLT2 inhibitors.

Professor David Nathan, director of diabetes at the Massachusetts General Hospital, told the Scientific Sessions there was a plethora of glucose-lowering medications available for type 2 diabetes but little high quality comparative data to guide the choice of which medications to add to metformin.

“There was also very little data to guide individualisation of therapy,” he said.

The preliminary data presented at the ADA meeting represented almost four years of treatment and four years of follow up.

Professor John Lachin, from the George Washington University and a principal investigator of the GRADE study, told the Sessions the glargine and liraglutide groups met the primary metabolic failure outcome of HbA1c ≥ 7.0% less frequently and later than the glimeprimide and sitagliptin groups.

For example, the mean time to HbA1c ≥ 7.0% was 2.4 years with liraglutide or glargine, 2.2 years with glimepiride and 1.9 years with sitagliptin.

In a secondary metabolic outcome, glargine was significantly more effective at maintaining HbA1c in the target range <7.5% than liraglutide which in turn was more effective than glimeprimide and sitagliptin.

The GRADE study found a significantly lower rate of any cardiovascular disease with liraglutide than with the other medications.

However there were no significant differences between the four medications in MACE, hospitalised heart failure, or total mortality rates, although a trend for lower event rates with liraglutide was observed.

There were also no significant differences across treatment groups with regards to microvascular outcomes including nephropathy, severely increased albuminuria, eGFR <60 ml/min/1.73m2, or distal sensory polyneuropathy.

Participants in the groups treated with liraglutide and sitagliptin lost more bodyweight than those treated with glimepiride, while the participants assigned to insulin glargine had stable weight over time.

Liraglutide had more gastrointestinal side effects, including nausea, abdominal pain, and diarrhoea, than the other three medications. There were no differences between the groups in serious adverse events.

Severe hypoglycaemic events were rare but more common with glimepiride (2.3%) compared to glargine (1.4%, liraglutide (0.9%), and sitagliptin (0.7%).

“The ultimate goal of GRADE is to help clinicians select the therapies that will work best for individual patients, as diabetes care is not a one-size-fits all approach,” Professor Nathan said.

“We believe these results will provide value to both patients and their providers when deciding which medication is needed to meet their appropriate blood glucose target and we are encouraged that these findings can be applied to a very diverse range of patients.”

GRADE has yet to report on other outcomes including cognitive function, quality of life and cost effectiveness of the treatments.

Commenting on the study during the session, Emeritus Professor David Matthews from the University of Oxford, said one of the limitations of the study was that it did not include an SGLT2 inhibitor.

However Associate Professor Deborah Wexler, from Massachusetts General Hospital and a PI on the GRADE study, said the four classes of medications in GRADE continue to be widely used.

“Results from GRADE will inform medication selection today and into the future,” she said in the Q&A.

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