Saxagliptin in Obese Patients with Impaired Glucose Tolerance
Obesity is a major cause of type 2 diabetes. When a person has diabetes, he or she will have reduced glucose uptake, altered lipogenesis, and increased glucose output by the liver. The cause of this disruption in insulin relates to a chronic inflammatory state, which leads to the induction of inducible nitric oxide synthase and the release of nitric oxide and reactive nitrogen species. All of this combined can ultimately cause modifications of the signaling proteins.
There are significant differences in the molecular mechanisms of insulin resistance in muscle versus liver. Firstly, hormones and cytokines from adipocytes can enhance or inhibit both glycemic sensing and insulin signaling. The central nervous system’s role is also important. Most therapies, therefore, aim to fix obesity-induced anomalies in the central nervous system and the peripheral tissues.
For most obese patients, glucose regulation has been significantly altered. Prediabetes is a metabolic disorder characterized by insulin resistance, reduction of insulin secretion, and a reduction of incretin effect, which increases the risk of incident type 2 diabetes. Impaired glucose tolerance (IGT) is a prediabetic state whose progression results from the deterioration of beta-cell function and aggravation of insulin resistance. IGT is associated with increased cardiovascular risk and might have harmful effects on other organs including the kidney.
At this time, type 2 diabetes incidence is rising to the point that it is now considered a major public health issue. IGT is a great stage for intervention which can possibly slow down or prevent progression to type 2 diabetes amongst obese individuals. Of course, there are also other important interventions, such as lifestyle programs, the use of pharmacological agents, or standardized meals. There are also new advanced techniques that have helped monitor glucose throughout the day, called continuous glucose monitoring (CGM). This allows doctors to precisely analyze postprandial glucose excursions.
Through the CGM data, researchers in this study showed that obese patients’ response to a standard breakfast of 75g carbohydrate shows strong similarities with response to 75g glucose via an oral glucose tolerance test (OGTT). CGM enables an accurate analysis of daily glucose variability. The acute effects of glycemic control on glucose variability have never been studied specifically in IGT patients.
Dipeptidyl peptidase-4 inhibitors are known to boost blood glucose regulation through increasing the activity levels of incretins, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP). By preventing the deactivation of f GLP-1 and GIP, they increase insulin release and decrease glucagon levels. These drugs may reduce beta-cell apoptosis and preserve beta cell function and might thus prevent the progression from prediabetes to T2D. These drugs were also studied and are known to offer a good safety profile.
The Study
ACCES (Acute and Chronic Effects of Saxagliptin) is a randomized, placebo-controlled, double-blind, controlled phase 2 pilot study that seeks to analyze obese patients with impaired glucose tolerance and the acute effects after 12 weeks of saxagliptin treatment on glucose levels at fasting and postprandially after breakfast. The study was conducted at Jean Verdier University Hospital in Bondy, France. It was approved by both the local ethics committee and by the French National Agency for Drug Security. The study had two parts. The first part was to study the acute and chronic effects of saxagliptin vs placebo on glucose tolerance. The second was the acute and chronic effect of saxagliptin vs. placebo on micro and macrovascular parameters. It was reported in another article.
Methods
The study consists of 24 obese patients with IGT. They were randomized to receive either 5mg of saxagliptin or placebo in the morning. Treatment started from the first visit until 12 weeks. Biochemical measurements were done before, one, two, and three hours after a standard breakfast. The patient’s glucose variability (GV) was also evaluated from visit 1 and it was monitored continuously for 24 hours. The second OGTT was performed at Visit 3. The inclusion criteria for this study were based on this:
- Patients with IGT according to an OGTT performed less than 3 weeks before the inclusion
- Age between 18 and 70 years
- Body mass index (BMI) ranging from 30 to 40 kg/m2
Statistical analyses
Variables were shown as mean SD or as percentages. The comparisons between groups at baseline were analyzed for continuous variables through analysis of variance as appropriate and by Chi-square test for categorical variables. The quantitative variables in the study were analyzed by mixed models of ANOVA for longitudinal data including factor treatment and factor time with 2 levels when comparing changes between visits or four levels when analyzing the test meal response.
Interaction between the 2 factors was used to test possible effects of treatment on time-dependent changes in studied parameters. Normalizing transformations were made if necessary. All tests were two-sided at a 5% significance level. Statistical analyses were performed with SAS version 9.4.
Results
From September 2012 to September 2014, the study had 24 patients with IGT. 12 were put in the saxagliptin group and 12 in the placebo group. The tests were stopped for one patient who had atypical chest pain. Overall, the mean BMI was 36.8 4.9 kg/m2, one-third of the patients had hypertension, 8.3% were smokers and 8.3% had obstructive sleep apnea syndrome. The two groups did not show any significant difference in age, BMI, gender, and blood pressure levels.
During the study, body weight decreased between Visit 1 and 2 in the saxagliptin group and in the placebo group, waist circumference also decreased during the study in the saxagliptin group but not for the placebo group. There were zero adverse effects in any patient during the study.
During fasting, there was no significant difference between the two groups at Visit 1 or Visit 2, for any of the metabolic parameters including FPG, HbA1c, fructosamine, lipid parameters; for hormone levels including leptin and adiponectin; and for renal function.
After the standard breakfast at visit 1, plasma glucose levels after breakfast differed significantly between the two treatment groups. Glucose response was lower in the saxagliptin group, the same effect was observed with a significantly lower glycemic increase after breakfast in the saxagliptin group. At Visit 1 and 2, plasma insulin increased after breakfast until 2 h and decreased at 3 h with no difference between treatment groups. Triglycerides decreased at Visit 1 postprandially without treatment effect at any visit. During both visits, glucose levels decreased markedly 2h after breakfast, Acute saxagliptin effect on glucose variability indexes. None of the indexes of 24 h glucose variability differed between saxagliptin and placebo groups. There were also no hypoglycemic episodes during twenty-four hours of the recordings.
During the OGTT performed before inclusion, glucose at fasting and 120 min was very similar in the two groups. OGTT has again performed at Visit 3 in 10 saxagliptin treated patients and 9 placebo-treated patients. Compared to OGTT results at baseline, OGTT at Visit 3 showed a decrease in plasma glucose at 120 min in both groups, which was greater for the saxagliptin-treated group. Nine of the 10 patients treated by saxagliptin were no longer glucose intolerant and 5 out of the 9 placebo-treated patients still had IGT (p < 0.01).
When comparing 3 h CGM data after the standard breakfast during Visit 1 in the patients who recovered a normal glucose tolerance and those who did not, whatever they were treated by saxagliptin or placebo, mean glucose, glucose peak, SD glucose, and AUC glucose were significantly lower in the former.
Compared with the placebo-treated patients, those who were treated with saxagliptin had lower 1h and 2h post-meal plasma glucose levels during the first visit. At visit 3, all patients but one in the saxagliptin group turned to normal glucose tolerance. Based on the study, saxagliptin has metabolically beneficial benefits for glucose-intolerant obese patients. The treatment effectively reduces postprandial blood glucose levels.
Conclusion
Based on the study, saxagliptin has positive metabolic benefits in obese glucose-intolerant patients; it can lower postprandial plasma glucose levels without having harmful effects on body weight. Saxagliptin also improved the patient’s glycemic status after 12 weeks of treatment. For the majority of the patients in this study, glucose levels normalized. Therefore, the researchers conclude that saxagliptin benefits may be seen as soon as right after taking the first tablet, as the improvement of glucose after the standard breakfast is predictive for the recovery of normal glucose tolerance after 12 weeks of treatment. The study is a useful addition to treatments that may be used for the management of prediabetes.
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