The Importance of the new peptides-
As of 2021, five AOMs have been authorized for long-term administration in the United States:
Previously utilized AOM’s such as orlistat, phentermine/topiramate,naltrexone/bupropion generally resulted in 3%–7% greater weight loss than placebo.
The weight-losing effects of semaglutide 2.4 mg and tirzepatide 15 mg are highly significant in light of this.
Despite recognition of the severe medical and socioeconomic burden of obesity, the weight-loss effects of pre-existing AOMs are insufficient to overcome obesity-associated complications.
The recently introduced peptides semaglutide and tirzepatide can be administered once weekly and have demonstrated substantially improved weight-losing effects within a tolerable safety margin in a series of STEP and SURPASS trials. These highly effective medications enable a considerable proportion of their users to achieve sufficient weight loss to alleviate obesity-associated metabolic diseases.
Primarily summarized into 3 main MOA:
MOA: Increases Insulin release/sensitivity, decreases glucagon release
MOA: Slows gastric emptying (gastric peristalsis)
MOA: Appetite Suppression
#1 MOA: Increases Insulin release/sensitivity, decreases glucagon release
Patho 101: Plasma glucose is maintained by a tug-of-war between the hypoglycemic effect of insulin and the hyperglycaemic effect of glucagon.
Pharmacology 101: GLP-1 RAs mimic the action of GLP-1 by binding to and activating the GLP-1 receptor, a protein found on the surface of cells in the pancreas, gut, and brain. This causes an increase in glucose-dependent insulin secretion which results in a decrease in glucagon secretion (by stimulating the release of insulin and suppressing the release of glucagon,the body thinks it has enough insulin and the body will in return slow down glucagon production/release). -> leads to sugar metabolism.
#2 MOA: Slows gastric emptying (gastric peristalsis)
Patho 101: Gastric peristalsis is the process of contraction and relaxation of the stomach muscles that propels food through the digestive system. Motilin is a hormone produced by the small intestine that regulates gastric motility by stimulating the contraction of the muscles in the stomach.
Pharmacology 101: Activation of the GLP-1 receptor by GLP-1 RAs inhibits the release of the hormone motilin, which plays a key role in stimulating gastric motility.
#3 MOA: Appetite Suppression
Patho 101: GLP-1 receptors are found in areas of the brain involved in appetite regulation, such as the hypothalamus, and activation of these receptors can lead to decreased food intake and increased feelings of fullness.The exact mechanisms by which GLP-1 receptor agonists affect brain satiety are not fully understood, but research suggests that they may act through a number of different pathways. One possible mechanism is through the modulation of neurotransmitters involved in appetite regulation, such as dopamine and serotonin. GLP-1 receptor agonists have been shown to increase dopamine and serotonin release in the brain, which may contribute to their effects on appetite and satiety.
Pharmacology 101: GLP-1 RAs can increase the sensation of fullness and satiety by activating GLP-1 receptors in the brain. This can lead to a decrease in appetite and food intake, which can further slow down gastric motility and delay the emptying of the stomach.
Weight Loss/General Basic Wellness Labs:
GLP-1 RA medications such as Semaglutide or Tirzepatideis a medication used to treat type 2 diabetes, and it works by stimulating insulin release and reducing glucose production in the liver. As with any medication, it is important for healthcare providers to monitor patients taking semaglutide to ensure it is being used safely and effectively.
Lab recommendations for patients taking semaglutide typically include regular monitoring of blood glucose levels and hemoglobin A1c (HbA1c), a measure of average blood glucose levels over the past 2-3 months. Patients should also have their kidney function tested periodically, as semaglutide can affect kidney function in some cases.
In addition to these standard lab tests, healthcare providers may also recommend monitoring of certain electrolytes, such as potassium and magnesium, as well as liver function tests. This is because semaglutide can affect electrolyte balance and liver enzymes in some patients.
Patients taking semaglutide may also be advised to monitor their blood pressure and lipid levels, as these can be affected by diabetes and may be further impacted by the medication.
Includes:
(C917) CBC without differential
(C901) CMP
(C157) TSH
(C145) Hemoglobin AIC
(C906) Lipid Panel
Studies:
In 4 RCTs, patients (baseline weight 96 to 105 kg) were treated for weight loss with 2.4 mg of subcutaneous SGT weekly and lifestyle interventions (counseling, diet, and physical activity). PC=Placebo
An RCT of nondiabetic patients (N = 1961)1: After 68 weeks, mean weight loss was 15% (15 kg) versus 2% (3 kg) PC.
The proportion of those who lost weight (≥ 5%) was 86% versus 32% (PC), with a number needed to treat (NNT) = 2, while the proportion who lost more weight (≥ 10%) was 69% versus 12% (PC), NNT = 2. Weight loss plateaued around week 60.
Gastrointestinal adverse effects (AEs): 74% versus 48% (PC), number needed to harm (NNH) = 3. Withdrawals due to AEs were 7% versus 3% (PC), NNH = 25.
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-Dose-finding RCT3 of diabetic patients (N = 1210) given either 2.4 mg of SGT weekly, 1.0 mg of SGT weekly, or PC: After 68 weeks, mean weight loss was 10% (2.4 mg), 7% (1.0 mg), and 3% (PC). Proportion who lost weight (≥ 5%) was 69% (2.4 mg) versus 57% (1.0 mg) versus 29% (PC). For 2.4 mg versus 1.0 mg, NNT = 9.
The AEs were similar between doses.
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Weight-maintenance RCT (N = 803)4: Nondiabetic participants were given 2.4 mg of SGT weekly for 20 weeks and then randomized to either continued SGT or PC. After 48 weeks, the continued SGT group lost 8% body weight compared with a 7% weight gain in the PC group.
Bottom Line
Used with lifestyle changes, 2.4 mg of subcutaneous SGT weekly resulted in a mean 10% to 15% weight loss (10 to 15 kg) over 68 weeks versus 2% to 3% (3 to 4 kg) with placebo (PC).
Most (70% to 80%) lost 5% or more of their body weight.
About 75% had gastrointestinal side effects, but few discontinued treatment.
Weight was regained on medication discontinuation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589135/pdf/0670842.pdf
Consider discontinuation if at least 5% of baseline body weight loss has not been achieved within 3 months.
The Importance:
While reducing 5% of baseline weight is conventionally regarded as clinically significant, a greater amount of weight loss influences different organs to varying extents.
Moderate weight loss of 5 to 10% ameliorates cardiovascular risk factors such as hyperglycemia,hypertension, or dyslipidemia;
70% to 80% of patients treated with semaglutide or tirzepatide reached this goal (semaglutide 2.4 mg and tirzepatide 15 mg)
A greater weight loss of up to 10% is associated with improvements in obstructive sleep apnea or non-alcoholic steatohepatitis
15% loss is associated with T2DM remission and mortality reduction.
Approximately half of patients treated with semaglutide 2.4 mg or tirzepatide 15 mg experienced body weight losses of at least 10% and 15%, respectively.
But don’t forget the apple vs the pear…..
Achieving a healthy body composition rather than merely losing weight is the ultimate goal of AOMs.
The risk of comorbidities, including T2DM, cardiovascular disease, dyslipidemia, and atherosclerosis, is independently correlated with visceral fat mass that is inadequately distinguished by BMI or total body fat.
Subpopulation analysis in STEP 1, which involved only non-diabetic obese patients, revealed that weekly semaglutide 2.4 mg eliminated 6.99 kg and 0.27 kg more total and visceral fat mass, respectively, than placebo as measured by dual emission X-ray absorptiometry.
Clinical Pearls
Semaglutide
Missed dose: Missed dose should be administered as soon as possible within 5 days; resume usual schedule thereafter. If >5 days have elapsed, skip the missed dose and resume administration at the next scheduled weekly dose. If 2 or more consecutive doses are missed, resume dosing as scheduled; alternatively, may re-initiate dosage adjustment schedule.
Tirzepatide:
Note: If changing the day of administration is necessary, allow at least 72 hours between 2 doses.
Missed dose: Missed dose should be administered as soon as possible within 4 days; resume usual schedule thereafter. If >4 days have elapsed, skip the missed dose and resume administration at the next scheduled weekly dose.
Rare but serious side effects (<1%)
Hypoglycemia
Pancreatitis
Thyroid cancer
Gallbladder/cholecystitis
AKI
Diabetic Retinopathy
Hypoglycemia (low blood sugar) is a rare but serious side effect. Signs and symptoms include:An irregular or fast heartbeat, Fatigue, Pale skin, Shakiness, Anxiety, Sweating, Hunger, Irritability, Tingling or numbness of the lips, tongue, or cheek. As hypoglycemia worsens, signs and symptoms can include: Confusion, abnormal behavior, or both, such as the inability to complete routine tasks, Visual disturbances, such as blurred vision, Seizures, Loss of consciousness. If you feel your blood sugar may be on the low side, immediately eat a simple sugar (i.e. piece of candy, orange juice, etc.) followed by a more complex carbohydrate such as a piece of bread to stabilize blood sugar for a longer duration of time. If you are diabetic and on any medications for blood sugar control, make sure your provider is aware of this before starting Semaglutide.
Classification of hypoglycemia (ADA 2022):
Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.
Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.
Hypoglycemic events defined as blood glucose levels less than 56 mg/dL were reported in 5.7% of patients on semaglutide 2.4 mg and 3% on placebo in STEP 2.
Episodes of glucose below 70 mg/dL occurred in 6.6% of cases with tirzepatide 15 mg in contrast to only 0.9% with placebo in SURPASS-1.
However, in SURPASS-2 an overall low rate of hypoglycemia was displayed despite the low glucose level (less than 54 mg/dL) for confirming hypoglycemia (1.7% for tirzepatide 15 mg vs. 0.4% for semaglutide 1 mg).
Medullary Thyroid Carcinoma
In rodents, semaglutide was found to be correlated with dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether semaglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. This correlation has been demonstrated in rodents but not in human studies thus far with Semaglutide but other GLP-1 agonist medications have had documented reports of this. For this reason; we will NOT accept patients who have a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) without medical clearance from their endocrinologist or oncologist is needed prior to initiating treatment with Nervana Medical.
*Thyroid cancer is DIFFERENT than hypo/hyperthyroid- most people who have thyroid issues as part of their past medical history are more likely to hypo/hashimoto's ->autoimmune etiology rather than carcinoma. Hyper is a different story. If any thyroid history, ensure that they were never biopsied and diagnosed with malignancy.
We recommend self monitoring of any new lumps/bumps upon palpation of your thyroid, any voice changes/hoarseness should be reported to the Nervana Medical Director/Nervana Provider and the medication should be immediately stopped and the patient should be sent for further diagnostic follow up (thyroid ultrasound/labs) from their primary care physician- We can help facilitate this process if they do not have a PCP at the time.
Gallbladder disease and biliary tract disease:(<1%)
Including cholelithiasis and cholecystitis, have been reported with glucagon-like peptide-1 (GLP-1) receptor agonists, including semaglutide; some have required hospitalization or cholecystectomy. Resolution of biliary stones following discontinuation has been documented with other GLP-1 receptor agonists .
Mechanism: Dose- and time-related; not fully understood. Animal studies and in vitro data have demonstrated that GLP-1 enhances the proliferation and functional activity of cholangiocytes, which may result in gallbladder diseases . Some authors have postulated a change in bile acid production and secretion, suppressed secretion of cholecystokinin, decreased gallbladder emptying, prolonged gallbladder refilling, weight loss, or potentially a combination of these factors.
Onset: Varied, an increased risk was seen following >26 weeks of therapy.
Risk factors:
Higher doses (eg, ≥1 mg SUBQ)
Longer duration of treatment (eg, >26 weeks)
Substantial or rapid weight loss
Pancreatitis (<1%)
Cases of acute pancreatitis (including hemorrhagic pancreatitis and necrotizing pancreatitis with some fatalities), chronic pancreatitis, and pancreatic adenocarcinoma have been reported with use of incretin-based therapies (eg, dipeptidyl peptidase 4 [DPP-4] inhibitors, glucagon-like peptide-1 [GLP-1] receptor agonists). Acute pancreatitis was observed with semaglutide at rates similar to placebo during the SUSTAIN-6 trial.
Mechanism: Causality has not been firmly established . GLP-1 receptor agonists directly stimulate GLP-1 receptors in pancreatic islet beta cells and exocrine duct cells which may cause an overgrowth of the cells that cover the smaller ducts, thereby resulting in hyperplasia, increased pancreatic weight, duct occlusion, back pressure, and subsequent acute or chronic pancreatic inflammation.
Onset: Not well characterized.
Risk factors
Patients with a prior history of pancreatitis may be at an increased risk for acute pancreatitis.
**I would recommend asking anyone who has had a cholecystectomy further details regarding etiology leading to the need for a cholecystectomy
Patients with acute pancreatitis due to any cause are at an increased risk for progression to recurrent acute pancreatitis and then to chronic pancreatitis; patients with chronic pancreatitis are at an increased risk for pancreatic cancer.
Risk factors for pancreatitis due to any cause include, but are not limited to, hypertriglyceridemia, cholelithiasis, alcohol use, and obesity.
Diabetic retinopathy (DR) was reported with tirzepatide during the SURPASS-2 study, a clinical trial evaluating the safety and efficacy of tirzepatide compared to semaglutide in patients with type 2 diabetes;
-patients with a prior history of DR were excluded from this trial
-In addition, rapid reductions in HbA1c are associated with an early worsening of DR
-In an analysis of DR complications due to the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide, the increased risk of DR was mainly observed in patients with preexisting DR and primarily attributable to the magnitude and rapidity of reduction in HbA1c
Mechanism: Unknown. In general, worsening of preexisting DR is a known consequence of rapid improvement of hyperglycemia, especially in patients with uncontrolled diabetes. Although unlikely, a direct toxic effect or potential angiogenic action of tirzepatide has not been ruled out
Onset: Varied; clinicians should note that DR is a progressive condition, and the onset of DR complications may vary.
Risk factors: Preexisting DR; In general, the risk of early worsening of DR is increased when intensive treatment is initiated in patient with long-standing poor glycemic control (Ref)
But I’m not losing enough…..
Low Dose Naltrexone –Naltrexone - 4.5mg Ideal for patients who suffer from squelched metabolism (specifically due to low-functioning thyroid) and gut health. Improves fatigue, lethargy, aches, and pains. Suppresses appetite, some patients may experience mild nausea (with or without vomiting) and abdominal pain that improves with use. Daytime drowsiness occurs if the PM capsule is taken very late at night without adequate sleep hours. Unlike High Dose Naltrexone – Alcohol can be taken with LDN without any side effects, but the “feel-good” factor is reduced from alcohol intake due to LDN’s opiate receptor blocking effects.
Phentermine- has been successful in stimulating patients who plateaued on semaglutide and we have found that adding it to their regimen, it successfully helped kick start their loss again more times than not. I would only do it for a few months though (no more than 4 months). I also tell patients that I hate this medication for the risk of overuse/chronic use and cardiac remodeling. Advise against its use in patients with a hx of HTN- See phentermine consent for additional details/ medication packet regarding phentermine. This is a controlled substance and must not be stopped abruptly****
Fat Blaster Intramuscular shots: (1-3x/wk) Lipotropic agents (methionine, inositol, choline, cyanocobalamin, carnitine, B1,2,6 and 12) that help with the breakdown of fat during metabolism and help turn fat into energy. These components have also been found to improve mental function and feelings of depression.
Carnitine:Carnitine is found in nearly all cells of the body and plays a critical role in the production of energy. It transports long-chain fatty acids into the mitochondria so they can be oxidized or burned to produce energy. Carnitine also transports toxic compounds out of the cellular organelles, preventing any accumulation. Given these functions, carnitine is concentrated in tissues that utilize fatty acids as fuel, like skeletal and cardiac muscles.It is critical to heart and brain function, muscle movement, and several other body processes. Insufficient carnitine can lead to problems in the liver, heart, and muscles.
Taurine: Can modulate fat metabolism. Acute supplementation of taurine can increase lipolysis and reduce the contribution from glycolytic metabolism, thereby altering the fuel utilization and metabolic efficacy of exercise. This is accomplished in part because taurine induces fibroblast growth factors. It may also help with improved muscle recovery as well as decreases in lactate, creatine kinase, phosphorus, inflammatory markers, and improved glycolytic/ fat oxidation markers.
Skinny Mini- Ener”genie” Premium Injection: A magical concoction of high dose B12 (4,000 mcg) and your choice of a fat blaster (MICC or Lipo B) + carnitine OR taurine = Not to exceed 3 ml total
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Possible Benefits:
Helps convert fat into energy
Enhances athletic performance
Improves overall mood
Boosts your metabolism
Promotes thyroid health
Supports the production of glutathione, the body's master antioxidant
See Wellness Dose: Energy + Metabolism IV Protocol
Bioidentical Hormone Replacement/ Optimization: Hormones play a vital role in our daily functioning, serving as messengers from our brain that tell our organs how to function. Everything from our metabolism to the health of our skin is impacted by the balance of hormones in our body, so it’s understandable that hormone imbalances can make daily functioning difficult. As we reach middle age our natural hormone production begins to steadily decline resulting in an insufficiency of hormones to regulate normal body functions. Unfortunately, traditional medicine has viewed many diseases such as cardiovascular disease, stroke, cancer, and Alzheimer's as an outcome of aging rather than viewing aging as a disease itself. Bioidentical Hormone Replacement Therapy (BHRT) is the process of supplementing our natural hormone production with bioidentical hormones. These hormones are derived from plant sources and are identical to those that the body produces itself. This process, combined with a healthy diet, exercise, and nutritional supplementation have been shown to slow the aging process by stopping cellular degeneration.
Nutritional: We recommend increasing your protein intake ;aim for a daily protein intake between 1.6 and 2.2 grams of protein per kilogram of body weight (0.73 and 1 grams per pound). Athletes and heavy exercisers should consume 2.2-3.4 grams of protein per kilogram (1-1.5 grams per pound) if aiming for weight loss. By replacing carbs and fat with protein, you reduce the hunger hormone and boost several satiety hormones. This leads to a major reduction in hunger and is the main reason protein helps you lose weight. It can make you eat fewer calories automatically.
Physical Activity: Exercise — Although less potent than dietary restriction in promoting weight loss, increasing energy expenditure through physical activity is a strong predictor of weight loss maintenance. In addition, physical activity can attenuate the loss of lean mass (eg, muscle) during active weight loss. Physical activity should be performed for approximately 30 minutes or more, five to seven days a week, to prevent weight gain and to improve cardiovascular health. There appears to be a dose effect for physical activity and weight loss, and much greater amounts of exercise are necessary to produce significant weight loss in the absence of a calorically restricted diet. Therefore, when weight loss is the desired goal, a calorie-restricted diet should be combined with less sedentary time and increased physical activity; the activity should be gradually increased over time as tolerated. A multicomponent program that includes aerobic and resistance training is preferred. Existing medical conditions, age, and preferences for types of exercise should all be considered in the decisions.
If you are interested in an exercise coach; we are happy to refer you to some of our favorites!
Behavior Modification — Behavior modification or behavior therapy is one cornerstone in the treatment for obesity. The goal of behavioral therapy is to help patients make long-term changes in their eating behavior by modifying and monitoring their food intake, modifying their physical activity, and controlling cues and stimuli in the environment that trigger eating. These concepts are usually included in programs conducted by psychologists or other trained personnel as well as many self-help groups.
GLP1 RA Patient Expectations Education
At the point where a patient feels they have either met their goal weight or are not progressing in the way they had expected to, we ask that an appointment be made to discuss options moving forward.
What constitutes “unresponsive”: Clinically, per manufacture, a patient should not be considered as unresponsive to therapy until less than 5% weight loss over the course of 3 months of Semaglutide at 2.4 mg=100 units/wk has been established.
It is important to note that weight loss is more than just a number.
While reducing 5% of baseline weight is conventionally regarded as clinically significant, a greater amount of weight loss influences different organs to varying extents.
Moderate weight loss of 5 to 10% ameliorates cardiovascular risk factors such as hyperglycemia, hypertension, and dyslipidemia;
A greater weight loss of up to 10% is associated with improvements in obstructive sleep apnea or non-alcoholic steatohepatitis.
15% loss is associated with T2DM remission and mortality reduction.
According to the STEP + SURPASS studies 70% to 80% of patients treated with Semaglutide or Tirzepatide reached this goal (Semaglutide 2.4 mg/100 units and Tirzepatide 15 mg over the course of 60 weeks.
Approximately half of patients treated with Semaglutide 2.4 mg/100 units or Tirzepatide 15 mg experienced body weight losses of at least 10% and 15%, respectively. This is remarkable progress given the historical trends with previous anti-obesity medications used (i.e. Phentermine, Low Dose Naltrexone, Orlistat,etc.) were only noted to produce an average of 3-7% total percentage of body weight lost.
GLP-1 RA medications such as Semaglutide (Ozempic/Wegovy), Tirzepatide (Mounjaro), etc. have some common side effects (>10%) including but not limited to; Nausea, constipation, or diarrhea, loss of appetite/feeling of fullness and acid reflux. Over time this, like other side effects associated with GLP-1 RA medications will improve in time (usually 2-4 weeks after a dose increase). If some of these side effects are left untreated and become severe, serious health consequences can occur, including renal failure and even death. We have compiled some specific recommendations that we hope you find helpful in managing some of these side effects should you suffer from any of them.
Weight Loss/General Basic Wellness Labs
GLP1-RA medications such as Semaglutide or Tirzepatide are medications used to treat type 2 diabetes, and they work by stimulating insulin release and reducing glucose production in the liver. As with any medication, it is important for healthcare providers to monitor patients taking GLP1-RAs to ensure they are being used safely and effectively.
Lab recommendations for patients taking GLP1-RAs typically include regular monitoring of blood glucose levels and hemoglobin A1c (HbA1c), a measure of average blood glucose levels over the past 2-3 months. Patients should also have their kidney function tested periodically, as GLP1-RAs can affect kidney function in some cases.
In addition to these standard lab tests, healthcare providers may also recommend monitoring of certain electrolytes, such as potassium and magnesium, as well as liver function tests. This is because GLP1-RAs can affect electrolyte balance and liver enzymes in some patients.
Patients taking GLP1-RAs may also be advised to monitor their blood pressure and lipid levels, as these can be affected by diabetes and may be further impacted by the medication.
Overall, the specific lab recommendations for patients taking GLP1-RAs will depend on their individual health status and any other medications they may be taking. Healthcare providers will work with each patient to develop an individualized monitoring plan to ensure the medication is being used safely and effectively.
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