Little Difference Between Basal Insulin Analogs for Type 2 Diabetes

Miriam E. Tucker

July 17, 2018

Basal insulin analogs don't differ substantially in their glucose-lowering effect in patients with type 2 diabetes, although some may be associated with less nocturnal hypoglycemia or weight gain, new research suggests.

The findings from a systematic review and meta-analysis involving 39 trials of 10 basal insulin analogs were published online July 10 in Annals of Internal Medicine, by Anastasia-Vasiliki Madenidou, MD, of Aristotle University of Thessaloniki, Greece, and colleagues.

Newer-generation long-acting insulin analogs, such as degludec (Tresiba, Novo Nordisk), were developed to provide more stable and prolonged glycemic control, along with minimal risk for hypoglycemia and weight gain, compared with the older analogs, glargine (Lantus, Sanofi) and detemir (Levemir, Novo Nordisk).

But conclusive evidence about comparative efficacy in type 2 diabetes is lacking, Madenidou and colleagues note.

The current review was meant to fill that gap, but the overall quality of the evidence is low, they caution. "Confidence in our findings for glycemic efficacy and hypoglycemia was low due to imprecision, inconsistency, and individual study limitations."

The authors note concerns about bias for approximately half of the eligible studies on change in HbA1c and almost all the trials examining nocturnal hypoglycemia.  In addition, conclusions about the comparative effects of newer long-acting basal insulin analogs were based mostly on indirect comparisons; that is, most studies compared them with glargine rather than to one another.

'A Real Call to Action'

Asked to comment, endocrinologist Kasia J. Lipska, MD, of Yale University School of Medicine, New Haven, Connecticut, observed, "The biggest message from this network meta-analysis is that we have very low quality evidence with respect to comparative effectiveness and safety of various insulin regimens. The authors evaluated each randomized trial and found high overall bias in the randomization processes and in the measurement of nocturnal and severe hypoglycemia. This is a major problem."

Lipska recently published a study finding that basal insulin analogs were no better than the old — and far less expensive — human neutral protamine Hagedorn (NPH) insulin (JAMA. 2018;320:53-62), which wasn't examined in studies included in the current review.

"Insulin is increasingly expensive and we need high-quality evidence to guide prescribing. Instead, what we have are many options, high price tags, and little ability to discern the potential benefits of one basal analog versus another," Lipska told Medscape Medical News.

"I think it's a real call to action," she added.

A Few Differences Seen Among Analogs, But Evidence Low Quality

The authors analyzed 39 randomized controlled trials that lasted at least 12 weeks. Patients were a mean age of 58.4 years and had type 2 diabetes for a median 10.6 years.

Three times-weekly degludec was significantly less effective at reducing HbA1c, with mean differences ranging from 0.21% versus degludec 100 U/mL to 0.32% versus glargine 300 U/mL (Toujeo, Sanofi).

Similarly, detemir was inferior to both glargine 100 U/mL and 300 U/mL (mean differences 0.15% and 0.20%, respectively).

Significantly more patients achieved HbA1c < 7% who were treated with glargine 100 U/mL compared with some of the others, with odds ratios ranging from 1.28 versus detemir to 1.45 versus triweekly degludec.    

Detemir emerged as the weight-loss winner against all comparators, with weighted mean differences ranging from –0.68 kg compared with glargine 300 U/mL to 1.76 kg with LY2963016 (Basaglar, Eli Lilly). Patients treated with glargine 300 U/mL also had less weight gain than with the other comparators.

Definitions of hypoglycemia varied across trials, but based on 21 trials there were no significant differences in the incidence of hypoglycemia with any basal regimen, however, the rate was lower for degludec 100 U/mL compared with glargine 100 U/mL (odds ratio, 0.64).

For nocturnal hypoglycemia, degludec 100 U/mL, degludec 200 U/mL, and glargine 300 U/mL were associated with lower rates than comparators. Also, neutral protamine lispro (the "75" component in Lilly's Humalog Mix 75/25, sold separately as a basal insulin in some countries) was associated with increased risk over all the others except triweekly degludec (odds ratio, 1.35).

Severe hypoglycemia, defined as an episode requiring assistance, did not differ among most insulin regimens, but neutral protamine lispro was associated with a higher risk.

Overall, "low- and very-low-quality evidence suggests some regimens may be associated with lower risk for nocturnal hypoglycemia (degludec 100 U/mL, degludec 200 U/mL, and glargine 300 U/mL) or less weight gain (detemir and glargine 300 U/mL)," Madenidou and colleagues conclude.

"In addition to short-term efficacy and safety, effects of individual drugs on long-term cardiovascular outcomes and cost-effectiveness data should be considered for optimal therapeutic decision-making."

Madenidou has reported no relevant financial relationships. Lipska has received support from the Centers for Medicare & Medicaid Services.

Ann Intern Med. Published online July 10, 2018. Abstract

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