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Fixed-ratio combination of basal insulin and GLP-1 receptor agonist: Role in T2DM treatment

Dr. Andrew Ho
08 Jan 2021
Treatment intensification is required for patients with inadequately controlled type 2 diabetes mellitus (T2DM). At the 22nd Diabetes and Cardiovascular Risk Factors East Meets West Symposium, Dr Andrew Ho, Specialist in Endocrinology, Diabetes & Metabolism in Hong Kong, discussed clinical trial results and real-world experience with a fixed-ratio combination (FRC) of basal insulin glargine (IGlar) and the glucagon-like peptide-1 receptor agonist (GLA-1 RA) lixisenatide (IGlarLixi) in T2DM treatment.

Rationale for FRC of basal insulin and GLP-1 RA

“Postprandial hyperglycaemia is a major obstacle to achieving better glycaemic control in T2DM patients,” said Ho. [Diabetes Care 2011;34:2508-2514]

While basal insulin therapy reduces fasting plasma glucose (FPG), GLP-1 RAs reduce postprandial glucose (PPG). Their complementary mechanisms of action are an effective approach to improving glycaemic control. FRC of basal insulin and GLP-1 RA can also mitigate the weight gain associated with basal insulin alone, with no additional risk of hypoglyceamia, and improved gastrointestinal (GI) tolerability compared with GLP-1 RA alone. [Diabetes Care 2016;39:2026-2035]

Furthermore, since medication adherence decreases with the number of prescribed daily doses, a titratable FRC of basal insulin and GLP-1 RA in a single daily injection can simplify patient management and help improve adherence. [Clin Ther 2001;23:1296-1310; Clin Ther 2013;35:795-807; Diabetes Care 2016:39:2026-2035]

IGlarLixi in T2DM inadequately controlled by basal insulin

In a randomized, open-label, parallel-group, 30-week treatment trial, once-daily IGlarLixi (n=367) was compared with once-daily IGlar alone (n=369) in T2DM patients inadequately controlled by basal insulin ± ≤2 OADs. Patients included had received basal insulin for 6 months, with a stable basal insulin dose of 15–40 U/day ± OADs, HbA1c of ≥7.5–10 percent, and FPG of ≤180–200 mg/dL.  [Diabetes Care 2016;39:1972-1980]

The primary endpoint of reduction in HbA1c from baseline at week 30 was significantly greater with IGlarLixi vs IGlar alone (mean: -1.1 percent vs -0.6 percent; p<0.0001) (mean final HbA1c, 6.9 percent vs 7.5 percent). (Figure 1) In addition, significantly more patients achieved glycaemic targets with IGlarLixi vs IGlar alone (week 30 HbA1c <7 percent: 54.9 percent vs 29.6 percent; p<0.0001) (week 30 HbA1c ≤6.5 percent: 33.9 percent vs 14.2 percent; p<0.0001). Mean body weight decreased by 0.7 kg in the IGlarLixi group and increased by 0.7 kg in the IGlar alone group (1.4 kg difference; p<0.0001). Documented symptomatic hypoglycaemia was comparable between groups. “More patients in the IGlarLixi group achieved the composite endpoint of HbA1c <7 percent without weight gain and hypoglycaemia than in the IGlar alone group [20 percent vs 9 percent; p<0.0001],” said Ho.

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IGlarLixi vs premixed or basal-bolus insulin intensification regimens

Although there have been no head-to-head trials comparing IGlarLixi with premixed or basal-bolus insulin intensification regimens, comparative analyses of data from randomized controlled trials (RCTs) may provide insight into their relative efficacy.

In a Bayesian network meta-analysis (NMA), IGlarLixi was compared with premixed and other basal insulin intensification options in patients with T2DM inadequately controlled by basal insulin. Eight RCTs with study duration of 24–30 weeks, involving 3,538 patients, were included. The base-case network grouped trial interventions into five different treatment regimens: IGlarLixi, intensified basal insulin, premixed insulin, 3x meal-time + basal insulin, and basal-plus insulin. Direct evidence was available for five of the 10 potential pairwise comparisons. Compared with premixed insulin, IGlarLixi provided superior HbA1c reduction, with lower rates of both confirmed and symptomatic hypoglycaemia (probability that IGlarLixi was better, 85 percent and 93 percent, respectively) and lower weight gain (probability that IGlarLixi was better, 98 percent). [Diabetes Ther 2020;22:2179-2188]

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A propensity score matched (PSM) analysis of two RCTs (LixiLan-L and GetGoal Duo-2) compared IGlarLixi with basal-bolus insulin in T2DM patients inadequately controlled by basal insulin. Outcomes of 195 patients on IGlarLixi in the LixiLan-L trial were compared with those of 195 patients on basal-bolus insulin in the GetGoal Duo-2 trial matched for key characteristics. [Diabetes Ther 2020;11:305-318]

At study endpoint, estimated treatment differences for basal-bolus insulin vs IGlarLixi were -0.28 percent (p=0.0002) for HbA1c reduction, -1.32 kg (p<0.0001) for weight change, and 2.85 (p<0.0001) for ratio of hypoglycaemia events per patient-year, all favouring IGlarLixi. (Figure 3) Higher proportions of patients treated with IGlarLixi achieved individual and composite goals (HbA1c <7 percent, no weight gain, and no hypoglycaemia) vs basal-bolus insulin.

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These trial comparisons suggest that IGlarLixi offers an effective alternative to premixed or basal-bolus insulin as intensification therapy. IGlarLixi also has the advantage of being a once-daily injection, compared with several daily injections required for premixed and basal-bolus insulin regimens.

IGlarLixi in T2DM inadequately controlled on OADs

In a randomized, open-label, parallel-group, 30-week treatment trial, T2DM patients inadequately controlled on OADs received IGlarLixi (n=469), IGlar (n=467), or lixisenatide (n=234). At baseline, the patients were on metformin ± an additional OAD, with HbA1c of 7–9 percent on two OADs or 7.5–10 percent on metformin alone. [Diabetes Care 2016;39:2026-20353]

The primary endpoint of reduction in HbA1c at week 30 was greater with IGlarLixi than with IGlar or lixisenatide alone (-1.6 percent vs -1.3 percent and -0.9 percent, respectively; p<0.0001 for both) (mean final HbA1c level, 6.5 percent vs 6.8 percent and 7.3 percent, respectively; p<0.0001 for both). Significantly more patients reached the glycaemic target of HbA1c <7 percent with IGlarLixi (74 percent) than with either IGlar (59 percent) or lixisenatide (33 percent), p<0.0001 for all. Glycaemic targets were also achieved more rapidly with IGlarLixi, with FPG and PPG control demonstrated. At week 30, mean body weight decreased in the IGlarLixi and lixisenatide groups, but increased in the IGlar group. Patients in the IGlarLixi group had fewer nausea and vomiting events than those on lixisenatide alone.

“For T2DM patients inadequately controlled on OADs, IGlarLixi may be considered as a first injectable therapy,” suggested Ho.

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Most Read Articles
06 Jan 2021
Optimal therapy for heart failure with reduced ejection fraction (HFrEF) remains underused due to clinical inertia. A recent post hoc analysis of the DAPA-HF trial serves as a call for change, as patients with longer duration of HFrEF survivorship were found to have higher rates of worsening heart failure (HF) and cardiovascular (CV) death. Importantly, benefits of the sodium-glucose co-transporter 2 (SGLT2) inhibitor, dapagliflozin, on these outcomes were shown to be consistent across the spectrum of HF duration, with the greatest absolute benefit seen in longest-duration HF.
Jairia Dela Cruz, 4 days ago
For inflammatory bowel disease (IBD) patients, smoking cigarettes or just being exposed to secondhand smoke raises the risk of developing colorectal neoplasia, a study has found.
5 days ago
Daily intake of cow’s milk formula in early life helps prevent the development of cow’s milk allergy later on without competing with breastfeeding, a recent study has found.
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