Gravicentric approach to Type 2 Diabetes therapy.
The success prediction. A proof-of-concept
Authors: Levit Shmuel , Torban Naum , Boaz Mona , Weichman Maria , Azuri Joseph , Manisterski Yossi , Merzon Eugene , Ryder Darian , Ginossar Gideon , Gavra Tali , Levit Vyacheslav , Domuschiev Ivan , Musin Ildar , Ryder Chen Hanna 
Published: June 2020

This study is the proof-of-concept of our "Gravicentric" theory. This concept is based on several fundamental points: obesity as the main foe; rapid reversibility of the disease; as well as a new perspective on the roles different pharmacological classes play in general, and the role of insulin and GLP-1 analogs, in particular. The paper presents and discusses our experience of the implementation of insulin and GLP-1 analogs. The possibility of "insulin weaning"; the therapeutic approach for over-treated patients; and physiological dosing of insulin is also discussed therein.
Objectives
Primary: To evaluate the long-term efficacy of GLP-1 analogs in insulin-treated Type 2 Diabetes Mellitus (T2DM) patients.
Secondary: To analyze which patient would most likely benefit from this combined treatment.
Methods
In 54 T2DM patients with a mean disease duration of 17.5 years and a mean extent of insulin therapy of 4.5 years, additional GLP-1 analogs therapy was prescribed. Mean duration of GLP-1 treatment was 25.8 months (2.15 years).
During the intervention, clinical, biochemical, and anthropometric parameters were analyzed. Compliance, Hypoglycemia and Metabolic Index (MI) assessments were implemented.
Results
Mean Glycated hemoglobin (HbA1C) decreased from 9.28 1.43 to 8.54 1.4% on GLP-1 analogs, p 0.01. Total Daily dose of Insulin (TDI) showed considerable reduction: 80.6 42.7 U/day before starting GLP-1 vs.41.0 30.7 U/day on GLP-1, p 0.01. These changes were directly linked to weight loss: BMI has dropped from 35.1 4.8 kg/cm2 before, to 32.8 5.0 kg/cm2 on GLP-1 analogs, with patients losing 6.7 kg on average. Moreover, 13 (24%) participants discontinued at least one kind of insulin, while 7 (13%) stopped taking insulin completely, with simultaneous improvement in diabetes control. No clinically significant hypoglycemia was observed.
Post-hoc, the participants were categorized according to each patients ability to reduce TDI by more than 20 U/day, and then split into two groups. Group A 34 patients (64.2%) who successfully reduced TDI; Group B 19 patients (35.8%) who failed to do so. The comparison of the two groups showed the following:

Significantly larger virtually twice as large baseline TDI in Group A (97.440.4 U/day vs. 52.231.0 U/day), p 0.001.
Very effective BMI reduction (BMI 3.3 2.4 kg/cm2 0.9 1.2 kg/cm2, p 0.001) and much better compliance (1.4 1.1 vs. 2.2 1.0, p 0.02) in Group A.
A considerable decline of insulin requirements in group A, on GLP-1 therapy (TDI on GLP-1 was -62.4 31.9 U/day) with no TDI reduction in Group B (TDI on GLP-1 was +0.03 14.1 U/day, p 0.001).

Thus, in spite of the fact that on GLP1 therapy HbA1C has declined to the same levels in both groups, patients from group A became much leaner and metabolically healthier.
We suggest overtreatment as the critical factor of obesity in Group A.
Conclusions
Adding GLP-1 analogs to insulin in poorly controlled, insulin-treated T2DM patients resulted in an impressive weight (BMI) reduction with significant improvements in glucose control. This provided for a further decline in insulin resistance and insulin requirements. We suggest that the best candidate for successful GLP-1 analogs therapy is an obese, overtreated and compliant T2DM person. Changes in Metabolic Index (MI) rather than surrogate glycemic parameters (HbA1C) are better predictors of a successful T2DM therapy. Neither the duration of diabetes nor the length of insulin therapy in the past is likely to have a critical role in predicting success. These findings are proof-of-concept of our Gravicentric theory in T2DM.