Benefits diabetic patients with dual GIP/GLP-1 receptor agonist
The Sustained Effects of a Dual GIP/GLP-1 Receptor Agonist, NNC0090-2746, in Patients with Type 2 Diabetes
Literature - Frias JP, Bastyr EJ 3rd, Vignati L, et al. - Cell Metab. 2017 Aug 1;26(2):343-352.e2Background
GLP-1 and glucose-dependent insulinotropic peptide (GIP) are gut hormones secreted from intestinal L cells and K cells, respectively, which account for most of the incretin effect in healthy adults [1]. So far, clinical research has focused on GLP-1, with much less attention given to GIP, due to data reporting promoted obesity and impaired lipid metabolism in animals by GIP [2]. Moreover, single-dose trials of GIP in type 2 diabetes mellitus (T2DM) patients, showed a worsening of postprandial hyperglycemia [3].
However, recent data support the hypothesis that the two incretins may complement one another, due to their ability to further decrease blood glucose and body weight when compared with peptides functioning by just one of the two mechanisms.
NNC0090-2746 (previously developed as RG7697) is a fatty-acylated GIP/GLP-1 dual agonist in clinical development for the treatment of T2DM [4]. In this phase 2a, multi-center, randomized, double-blind, parallel-group, placebo-controlled trial with open-label comparison study, the effects of NNC0090-2746 on glycemic control, body weight and other metabolic parameters were evaluated in T2DM patients, inadequately controlled with metformin (HbA1c ≥7.2% and ≤10.5%). For this purpose, 108 patients who were able to perform the self-injections satisfactorily were randomized into the 12-week double-blind treatment period in a 1:1:1 manner to NNC0090-2746, placebo or liraglutide 1.8 mg with a 2-week dose escalation. Primary endpoint was HbA1c change from baseline to week 8 and secondary/exploratory endpoints were evaluated at week 12 or 13.
Main results
- The HbA1c change from baseline was statistically significant with NNC0090-2746 compared with placebo, with estimated treatment differences (ETDs) of -0.63% (95% CI -0.93 to -0.33) at week 8 and -0.96% (95% CI -1.36 to -0.56) at week 12.
- The change from baseline in mean self-measured plasma glucose was statistically significant when comparing NNC0090-2746 with placebo (ETD week 8: -27.7 mg/dl, 95% CI -44.7 to -10.7; ETD week 12: -31.7 mg/dL, 95% CI -47.0 to -16.5).
- The change from baseline to week 12 in fasting plasma glucose was statistically significant when comparing NNC0090-2746 with placebo, with an ETD of -38.2 mg/dL (95% CI: -57.0 to -19.4).
- NNC0090-2746 improved insulin secretion compared to placebo, as the fasting C-peptide was significantly increased from baseline to week 12 with an estimated treatment ratio (ETR) of 1.29 (95% CI: 1.13-1.48).
- The fasting insulin concentration was somewhat higher for the NNC0090-2746 group than the placebo group (not significant).
- The percent change in body weight from baseline, with NNC0090-2746 compared to placebo, was significant at week 8 (ETD: -1.80%, 95% CI -3.24 to -0.37), but not at week 12 (ETD: -1.67%, 95% CI -3.43 to 0.09).
- Compared with placebo, NNC0090-2746 significantly reduced the 2-hr postprandial concentration of glucose from baseline to week 12 (ETD: -74.6 mg/dL, 95% CI 100.2 to -48.9) as well as the glucose area under the curve of (ETD: -181.3 mg*hr/dL, 95% CI -252.4 to -110.2).
- A decrease in total cholesterol (TC) levels was seen for the NNC0090-2746 group with an estimated mean value at week 13 of 169.7 mg/dL compared to 184.7 mg/dL for the placebo group. The change from baseline was significant, with a decrease of 8% to week 13 with NNC0090-2746 compared with placebo (ETR: 0.92, 95% CI 0.85-0.99).
- A trend for lowering lipids in general (LDL-C, TCs, free fatty acids and apo-B) was observed.
- The change in plasma leptin from baseline to week 12 was significant, with a reduction by 22% (ETR: 0.78, 95% CI 0.63-0.96) with NNC0090-2746 relative to placebo.
- In contrast, as also observed with some other GLP-1 receptor agonists, the open-label liraglutide arm of this trial did not exhibit any appreciable change in TC or LDL-C. The reduction in TC observed with NNC0090-2746 is driven by a reduction in LDL-C, although the LDL-C reduction was not statistically significant.
- Gastrointestinal-related adverse events were comparable to the 26-week liraglutide LEAD-2 trial (35.1 vs 44%, respectively) and to open-label liraglutide arm (31.4%). No additional safety concerns with NNC0090-2746 relative to liraglutide were observed.
Conclusion
In 108 T2DM patients inadequately controlled with metformin, NNC0090-2746 significantly improved glycemic control and reduced body weight, total cholesterol and leptin levels, compared with placebo. The treatment with NNC0090-2746 was generally safe and well tolerated. These data suggest that integrated GIP agonism may offer additional benefits on weight loss and total cholesterol.
References
1. Dupre, J., Ross, S.A., Watson, D., et al. (1973). Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J. Clin. Endocrinol. Metab. 37, 826–828.
2. Gault, V.A., Irwin, N., Green, B.D., et al. (2005). Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro3)GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-related diabetes. Diabetes 54, 2436–2446.
3. Chia, C.W., Carlson, O.D., Kim, W., et al. (2009). Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes. Diabetes 58, 1342–1349.
4. Finan, B., Ma, T., Ottaway, N., et al. (2013). Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl. Med. 5, 209ra151.
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