Main Research Findings

1) Semaglutide successfully lowered levels of HbA1c in a dose dependent manner and resulted in a significant loss in body weight without any episodes of excessive hypoglycemia.

2) Oral administration of semaglutide led to a notable reduction in levels of HbA1c in test subjects diagnosed with type 2 diabetes.

3) After 56 weeks of treatment, a 1.0 mg dose of semaglutide was successful in reducing body weight and improving glycemic control.

Selected Data

1) The research team of Nauck et. Al examined how semaglutide affects glycemic control in participants presenting with type two diabetes. As it was previously mentioned semaglutide has a structure similar to GLP-1, however, three modifications were made to the peptide in order to ensure the safety of once-weekly semaglutide administration for clinical use. The three modifications included: amino acid substitution at position 8 changing alanine to alpha-aminoisobutyric acid, and position 34, changing lysine to arginine, as well as acylation of the lysine in position 26 with a spacer and a C-18 fatty acid chain. Amino acid substitution at position 8 allows semaglutide to resist degradation by dipeptidyl peptidase-4. The presence of the spacer and fatty acid chain at position 26 mediates a strong binding to albumin and reduces renal clearance. After modifications are made the half-life of semaglutide varies from 165-184 hours indicating that once-weekly injection is safe and appropriate for the experimental procedures of the study [2].

The primary objective of this study is to examine the dose-response relationship of semaglutide and glycemic control in order to determine an optimal dose and administration regiment. This study took place over a 12-week time period while all subjects were randomized and the experiment was double-blinded for semaglutide versus a placebo compound and an active control. In order to qualify for the study patients had to be at least 18 years of age with a diagnosis of type 2 diabetes and treated for at least three months with diet and exercise and/or a stable regiment of metformin, as well as an HbA1c level of 7-10% and a body weight of 60-110 kg. Participants were excluded from the study if the received antidiabetic agents other than metformin; impaired liver or renal functioning; clinically significant cardiovascular disease; uncontrolled high blood pressure, defined as systolic blood pressure greater than or equal to 160 mmHG and/or a diastolic blood pressure greater than or equal to 100 mmHg; retinopathy; or cancer excluding basal or squamous cell skin cancer.

Test subjects were randomly assigned to one of nine experimental treatments including once-weekly semaglutide in doses of 0.1, 0.2, 0.4, or 0.8 mg, once-weekly semaglutide with dose escalation (E) (0.8 or 1.6 mg E), once-daily active control (1.2 or 1.8 mg), or once-weekly placebo. Both semaglutide and the placebo compound were administered via subcutaneous injection in the abdomen, thigh, or upper arm via NordiPen injection device. Patients were injected with the compound at the same time every week at the same injection area. The active control was available as an active drug subcutaneously injected on a daily basis in the abdomen, upper arm, or thigh via FlexPen injector. The 12-week treatment period was followed by a 5 weeks period of monitoring residual effects and a follow-up visit on week 17 [2].

The primary efficacy endpoint assessed by the research team was the change from baseline in HbA1c levels following the 12 week experimental treatment period. Secondary efficacy measures included changes from baseline in: fast plasma glucose (FPG), postprandial plasma glucose (PPG), area under the curve, insulin, C-peptide, glucagon, insulin/proinsulin ratio, body measurements, and fasting lipid profiles. According to the American Diabetes Association (ADA) the HbA1c target value should be less than 7% while the American Association of Clinical Endocrinologists (AACE) suggests less than or equal to 6.5%. In addition to recording the number of patients that reached the target HbA1c levels, the research team also reported the proportion of patients that lost 5-10% of body weight loss [2].

2) The research team of Davies et. Al examined the effects of oral and subcutaneous administration of semaglutide on glycemic control in patients diagnosed with type 2 diabetes. The study took place over a 26-week experimental period; it was a randomized, parallel-grouped, phase 2 trial. Once-daily oral semaglutide was administered to test subjects diagnosed with type 2 diabetes in doses of either 2.5, 5, 10, 20, or 40 mg and compared to a placebo compound as well as a once-weekly subcutaneous administration of semaglutide. The 26-week experimental period was followed by a follow-up period lasting 5 weeks and a follow-up visit at week 31 [3].

Patients were deemed eligible for participation if they were at least 18 years of age, diagnosed with type 2 diabetes and insufficient glycemic control, measured by HbA1c levels, as well as treatment with diet and exercise or a stable dose of metformin. Changes in HbA1c levels from baseline to week 26 was the primary efficacy endpoint measure by the research team while the secondary efficacy endpoints measure at week 26 included the proportion of patients achieving HbA1c target levels of less than 7.0%; a change from baseline in fasting plasma glucose, insulin, glucagon, fasting C-peptide, insulin resistance, beta-cell function, body weight, waist circumference, and BMI; and the proportion of patients achieving body weight loss of 5-10% [3].

3) The efficacy and safety of a once-weekly subcutaneous administration of 1.0 mg semaglutide was examined by the research team of Ahmann et. Al. This experiment took place over 56 weeks and was considered a phase 3a, open-label, parallel-group, randomized controlled trial that included 813 participants diagnosed with type 2 diabetes being actively treated with oral antidiabetic drugs. Test subjects were included in the study if they were at least 18 years of age with a type 2 diabetes diagnosis and stable treatment with metformin, thiazolidinediones, and/or sulfonylureas, for at least 90 days prior to the initiation of the experiment. Participants were excluded from the study if there was an estimated glomerular filtration rate of greater than 60 mL/min?1.73 m^2 per the MDRD formula; if the patient underwent chronic treatment with glucose-lowering agents; a history of chronic or idiopathic acute pancreatitis; or an adverse acute coronary or cerebrovascular event [4].

As it was previously mentioned, the primary endpoint was the change from baseline in levels of HbA1c after 56 of experimental protocol. Secondary efficacy endpoints included the proportion of subjects who achieved levels of HbA1c of less than or equal to 7.0%; changes in fasting plasma glucose; mean self-measured plasma glucose; mean seven-point profiles; beta-cell function and glucose metabolism; the proportion of subjects that achieved weight loss of 5-10%; and changes from baseline in BMI, waist circumference, blood pressure, and fasting lipids. The participants of the study also completed patient-reported outcome questionnaires assessed by status scores of the Diabetes Treatment Satisfaction Questionnaire [4].

Discussion

1) The study conducted by Nauck et. Al resulted in the screening of 711 total patients; 415 of which were randomly assigned to receive varying doses of the semaglutide while the remaining participants received a placebo. Out of all of the patients treated with the experimental drug 82.2% were able to complete the 12-week treatment period. In order to assess glycemic control the research team measured levels of HbA1c at baseline and in response to treatment. The results reported that HbA1c decreased in a dose-dependent manner with doses of 0.2-1.6 mg of semaglutide causing a significant decrease in HbA1c levels, in comparison to the placebo group. Additionally, when comparing patients’ HbA1c levels to the ADA and AACE target levels (<7% and <6.5%, respectively), 81% of the patients met the ADA target while 63% of the patients met the AACE target. This was compared to the 36% of patients that met the target levels after administration of an active control and the 4% of patients that met the target levels after administration of a placebo [2].

Levels of fasting plasma glucose decreased in a dose dependent manner. At the end of the 12 week experimental treatment period the research team reported that in comparison to the placebo, the patients receiving doses of semaglutide ranging from 0.4-1.6 experienced a greater reduction in levels of fasting plasma glucose. It was also noted that in comparison to a 1.2 mg dose of the active control, doses of semaglutide ranging from 0.8-1.6 resulted in a greater reduction in fasting plasma glucose. Reductions in the levels of fasting plasma glucose were identifiable in all of the treatment groups as early as week 1. Within the first 3 weeks of the study, fasting plasma glucose levels stabilized and were maintained throughout the remainder of the treatment period. The research team also noticed that levels of fasting plasma glucagon decreased in a dose dependent manner, however, the reduction was only statistically significant in the treatment group administered a 1.6 mg dose of semaglutide. No apparent differences in fasting plasma glucose were detected in the patients administered lower doses of semaglutide.

Each study participant received identical meals of 2 MJ in energy content. Despite the standardization, food consumption of the patients administered semaglutide or an active control decreased by up to 39.8 grams by week 12 of the experimental treatment period. Treatment with doses of semaglutide ranging from 0.2-1.6 mg experienced a significant reduction (up to 35%) in levels of PPG AUC and AUC (0-240 min). A similar effect was observed in the patients receiving dose of the active control as there was up to a 27% decrease in PPG AUC and AUC (0-240 min). The values of C-max and incremental AUCs (iAUCs) for glucose were also significantly reduced in response to administration of semaglutide in doses ranging from 0.4-1.6 mg. C-max decreased by up to 30% while iAUC decreased by up to 56% [2].

The body weight of the patients treated with semaglutide decreased in a dose dependent manner. By week 12 of the experimental treatment period, the patients administered doses of semaglutide from 0.8-1.6 mg experienced a decrease in weight ranging from -3.4 to -4.8 kg. This was in comparison to the placebo group that only experienced a -1.2 kg reduction in body weight.. Doses of semaglutide ranging from 0.1-1.6 mg resulted in a 2.1%, 7.0%, 13.0%, 37.5%, 51.2%, and 63.6% respective dose-dependent increases in the proportion of patients that achieved a 5%, or greater, reduction in weight loss. With the same doses of semaglutide, there was a resulting 2.1%, 0%, 0%, 2.5%, 4.7%, and 9.1% respective increases in the proportion of patients achieving a 10%, or greater, reduction in weight loss. The research team noted that the reduction in body weight was not related to any nausea or vomiting reported by the patients [2].

Figure 1: Measured changes in HbA1c, body weight, and fasting plasma glucose in response to varying doses of semaglutide, an active control, or a placebo

2) The research team of Davies et. Al screened a total of 1106 participants for their study examining the effects of semaglutide. Out of all patients screened, 632 were randomized and 630 were administered varying doses of the experimental drug. Changes in glycemic control were observed by measuring and recording levels of HbA1c in response to doses of semaglutide. All doses of the peptide significantly reduced the average level of HbA1c in a dose-dependent manner. The treatment group receiving a 2.5 mg oral dose of semaglutide resulted in a -0.4% estimated treatment difference; the treatment group receiving a 5.0 mg oral dose of semaglutide resulted in a -0.9% estimated treatment difference; the treatment group receiving a 10 mg oral dose of semaglutide resulted in a -1.2% estimated treatment difference; the treatment group receiving a 20.0 mg oral dose of semaglutide resulted in a -1.4% estimated treatment difference; and the treatment group receiving a 40 mg oral dose of semaglutide resulted in a -1.6% estimated treatment difference. Additionally, the average level of HbA1c was also shown to significantly decrease when semaglutide was administered via subcutaneous injection rather than orally [3].

Figure 2: changes in HbA1c levels over the 26 week experimental treatment period.

For the groups administered semaglutide both subcutaneously and orally, a majority of the patients achieved the ADA target HbA1c target level of less than 7%. When orally administered the peptide 44% of patients in the 2.5 mg treatment group reached the target levels; compared to 81% in the 5 mg treatment group; 84% in the 10 mg treatment group, 86% in the 20 mg treatment group, and 90% in the 40 mg treatment group. These results were compared to those of the individuals receiving a placebo treatment and those administered semaglutide via subcutaneous injection; respectively, 28% and 93% of the patients included in these groups reached the target HbA1c level of less than 7%. Furthermore, by week 26 there was a significant dose-dependent decrease in mean fasting plasma glucose in response to semaglutide. These results were observed in the test subjects regardless of whether the peptide was administered orally or subcutaneously.

The research team also thought it was important to mention that by week 26 of the experimental period, treatment with semaglutide led to a dose-dependent decrease in mean body weight. The 2.5 mg treatment group experienced a -0.9 kg reduction in body weight; the 5 mg treatment group experienced a -1.5 kg reduction; the 10 mg treatment group experienced a -3.6 kg reduction in body weight; the 20 mg treatment group experienced a -5.0 kg reduction in body weight; and the 40 mg treatment group experienced a -5.7 kg reduction in body weight. In addition to the average body weight decreasing, the proportion of patients achieving a 5% weight loss was drastically higher in the groups administered doses of 10 mg and above. 56% of the patients in the 10 mg treatment group achieved a 5% decrease in body weight; 64% in the 20 mg treatment group; and 71% in the 40 mg treatment group. This was compared to the 13% of patients in the placebo group that achieved a 5% loss of body weight, as well as the 66% of patients receiving subcutaneous administration of semaglutide that achieved a 5% loss of body weight [3].

Figure 3: Changes in fasting plasma glucose and body weight in response to varying doses of semaglutide

3) Between December of 2013 and April of 2014, the research team of Ahmann et. AL randomized 813 subjects and exposed 809 of them to experimental treatment with semaglutide. The primary outcome assessed in this study was the average HbA1c levels. Results of the study reported that HbA1c decreased by 1.5% after treatment with semaglutide. Overall, 67% of the subjects treated with semaglutide achieved the ADA target HbA1c level of less than 7%, however, only 56% of the semaglutide-treated subjects achieved the target level without symptoms of hypoglycemia or weight gain. 47% of the subjects treated with semaglutide achieved the AACE target HbA1c level of less than 6.5%. In addition to HbA1c levels, fasting plasma glucose, fasting insulin, plasma glucagon, proinsulin, proinsulin-to-insulin ratio, and HOMA-insulin resistance were all significantly reduced after 56 weeks of treatment with semaglutide [4].

The body weight of the individuals treated with semaglutide also decreased by an average of 5.6 kg; the results were supported by multiple statistical sensitivity analyses performed by the research team. 52% of the semaglutide-treated test subjects achieved a weight loss response of greater than 5%, while a weight loss response of greater than 10% was achieved by 21% of the test subjects treated with the peptide. Semaglutide treatment also resulted in a reduction in BMI and waist circumference. There was also a notable decrease in the levels of free fatty acids, VLDL cholesterol, and triglycerides in the semaglutide-treated patients, as well as a reduction in systolic blood pressure by 4.6 mmHg. By week 56, the subjects treated with semaglutide reported experiencing a greater improvement in overall treatment satisfaction [4].

Disclaimer

**LAB USE ONLY**
*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

Citations

[1] Surampudi, Vijaya. “Semaglutide for weight loss – what you need to know.” UCLA Health, 12 January 2023. Accessed 13 August 2023.

[2] Nauck MA, Petrie JR, Sesti G, Mannucci E, Courrèges JP, Lindegaard ML, Jensen CB, Atkin SL; Study 1821 Investigators. A Phase 2, Randomized, Dose-Finding Study of the Novel Once-Weekly Human GLP-1 Analog, Semaglutide, Compared With Placebo and Open-Label Liraglutide in Patients With Type 2 Diabetes. Diabetes Care. 2016 Feb;39(2):231-41. doi: 10.2337/dc15-0165. Epub 2015 Sep 10. PMID: 26358288.

[3] Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA. 2017 Oct 17;318(15):1460-1470. doi: 10.1001/jama.2017.14752. PMID: 29049653; PMCID: PMC5817971.

[4] Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, Holst AG, Annett MP, Aroda VR. Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes Care. 2018 Feb;41(2):258-266. doi: 10.2337/dc17-0417. Epub 2017 Dec 15. PMID: 29246950.

PEPTIDES PREFER THE COLD
Keep peptide vials refrigerated at all times to reduce peptide bond breakdown. DO NOT FREEZE. Most peptides, especially shorter ones, can be preserved for weeks if careful.
Always swab the top of the vial with an alcohol wipe, rubbing alcohol or 95% ethanol before use.
Before drawing solution from any dissolved peptide vial, fill the pin with air to the same measurement you will be filling with solution, ie. if you plan to take 0.1 ml, first fill the pin with 0.1ml of air, push the air into the vial, and then draw the peptide back up to the 0.1 ml marker. Doing so will maintain even pressure in the vial. Always remember to remove air bubbles from the pin by flicking it gently, pin side up, and pushing bubbles out. In addition, push out a tiny amount of solution to ensure there is no air left in the metal tip.

ONLY MIX WITH STERILE BACTERIOSTATIC WATER
The purity and sterility of bacteriostatic water are essential to prevent contamination and to preserve the shelf-life of dissolved peptides.
Push the pin through the rubber stopper at a slight angle, so that you inject the bacteriostatic water toward the inside wall of the vial, not directly onto the powder.
Lyophilized peptide should be stored at -20°C (freezer), and the reconstituted peptide solution at 4°C (refrigerated). Do not freeze once reconstituted.
NEVER SHAKE A VIAL TO MIX.

Air bubbles are unfavorable to the stability of proteins.

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