Key Aspects of Treatment



Key Aspects of Treatment






Introduction

Having a plan and taking action are key aspects of helping people manage their diabetes. It is also important to recognize that, because diabetes is a chronic lifelong condition, the needs of the patient and clinical support offered will need to change over time. This chapter focuses on key aspects of diabetes management at different points in the progression of diabetes. Early in diabetes a full-court press may be the best plan. However, in the chronic phase, building support is most important for people with diabetes. Finally, it is important to balance the risks and benefits of treatment, understanding that later in the disease, deintensification is prudent.





case questionsCASE QUESTIONS



1. Can type 2 diabetes be “reversed”?

View Answer

1. This is an important question, and the wording is key. There are plenty of references in the lay literature of “reversing” or “curing” type 2 diabetes. Current thinking is that it takes years of metabolic abnormalities and compensatory physiologic responses before a person becomes hyperglycemic from type 2 diabetes. While it is attractive to seek out a quick fix to “cure” type 2 diabetes, the truth is that there is no quick fix. It is important to remember that there are many pathways in the body that are altered in response to insulin resistance and abnormal insulin and glucose levels.

However, there are many studies that have demonstrated that type 2 diabetes can be put into remission. It is important to clarify the difference between remission and “curing” or “reversing” diabetes. When a patient has an early cancer, and the surgical team is able to resect it with no increased risk of a future recurrence, that is a cure. When a patient can maintain their glucose (HbA1c < 7.0% for many) without any medication, they are at goal. If this HbA1c (<6.5%) is maintained with normal glucose values for at least 3 months without any diabetes medication, this person has achieved “diabetes remission.”1 This is an important differentiation.

Most often this is achieved via significant dietary modification accompanied by substantial weight loss. The ability to maintain the benefit from interventions that helped a person achieve their glucose goals lasts only as long as the intervention’s effects persist. Thus, if the person gains weight, it is fair to assume their diabetes will return. They are at increased risk for recurrence for the rest of their life and will want to maintain the intervention to keep their diabetes in remission.

In this case study, it is best to inform the patient that his condition can be controlled without medications, but a “cure” is not a realistic or attainable goal.



2. What is the best treatment plan for this patient?

View Answer

2. For a patient who is newly diagnosed and just starting the education process, a continuous glucose monitor (CGM) can be an invaluable tool. By providing a patient with clear glucose goals, and then having them see how their glucose responds to diet and daily activities, with immediate feedback from a CGM, we can help inform effective change. For example, a patient might learn how much their morning latte increases their blood sugar. Or they can recognize that if they walk their dog their glucose improves. These “self-discoveries” help patients make changes on their own and may inspire them to explore the impact of other lifestyle modifications. Moreover, these “self-discoveries” are rooted in science, specifically cognitive behavioral therapy. Encouraging your patient to try different behavioral experiments with lifestyle modifications and then observe changes in their blood sugars is an excellent strategy to educate and empower your patients.

Including a CGM in your initial education process and referring patients to formal Diabetes Self-Management Education and Support (DSMES) training helps provide them with tools for success. DSMES has been shown to have substantial benefits for people with diabetes including a reduction in HbA1c, reduction in all-cause mortality, improved self-efficacy, improved coping, decreased diabetes-related distress, and improved quality of life.2

Sadly, less than 10% of people with diabetes attend diabetes education within the first year of diagnosis, consequently setting them up for failure.3 The rates are even lower for people with Medicare, which is unfortunate as diabetic education is a covered benefit.4 A referral, with positive reinforcement from the primary care clinician, is one of the best predictors that a patient will attend this important training.

Lifestyle interventions are a cornerstone of diabetes management. There is strong evidence that aggressive weight loss via very low-calorie diets can put type 2 diabetes in remission. The DiRECT trial was a very low-calorie diet study coordinated through primary care offices. Results showed that 46% of participants achieved diabetes remission at 12 months and 36% maintained remission at 24 months.5 The ReTUNE trial recently attempted a similar very low-calorie diet plan in people with type 2 diabetes but lower BMI.6 They found that a mean weight loss of 9% enabled 70% of people to achieve diabetes remission.7

An important thing to keep in mind is that all intensive lifestyle interventions, including very low-calorie diets, must be accompanied with high levels of support if they are to be successful. This requires a team-based approach that includes the health care professional (HCP), a dietitian, diabetes educator, and the patient’s family and friends. At first, they may require more support to initiate major changes and then the amount needed will vary based upon patient needs.



3. Should he start on medications? If yes, which ones?

View Answer

3. The 2022 American Diabetes Association (ADA) Standards of Care for people with diabetes has an algorithm to guide pharmacotherapy for people with type 2 diabetes.8 First and foremost, any pharmacotherapy should be coupled with therapeutic lifestyle change in conjunction with diabetes self-management education and support.

Until recently the initial pharmacologic management of type 2 diabetes mellitus (T2DM) was fairly straightforward; most patients were started on metformin. Metformin is generally safe, effective, and affordable. This process is evolving to support the selection of initial diabetes agents based on the patient’s coexisting medical conditions. As per the ADA’s 2022 Standards of Care, if a person has existing atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease (CKD), other medications are appropriate initial choices, either with metformin or in place of metformin.8 For example, if a person has known ASCVD, use of a GLP-1RA (glucagon-like peptide 1 receptor agonist), or an SGLT-2 (sodium-glucose cotransporter 2) inhibitor with proven cardiovascular benefit is recommended. Similarly, if the patient has either HFrEF (heart failure with reduced ejection fraction) or HFpEF (heart failure with reduced ejection fraction), an SGLT-2 inhibitor is preferred. An SGLT-2i is also reasonable if the patient has CKD, or if the estimated glomerular filtration rate (eGFR) is <30 mL/min, a GLP-1RA with known renal benefit can be used as an alternative.

An important concept when choosing an appropriate regimen is to identify how far the HbA1c needs to drop for the patient’s diabetes to be at target. This is dependent on one’s initial A1c and their A1c goal. We will address individualizing a patient’s A1c goal in later chapters.

A loose rule when selecting medications is to expect an approximate 1% decrease in HbA1c per medication used. Many patients at diagnosis have significantly elevated A1c levels. Therefore, it would make sense for a patient to require more than one agent to achieve their glycemic goal. Unfortunately, many physicians have been reluctant to begin an aggressive multidrug regimen at the time of diagnosis. More commonly, patients begin a step-therapy approach, where one drug is started, titrated to maximum dose, the A1c is rechecked, and if the A1c is not at goal, another medication is added. This is akin to Dr. DeFronzo’s previously described “treat to fail” practices.

An example of a potent initial regimen is metformin plus the dipeptidyl peptidase 4 inhibitor (DPP4i) sitagliptin. Patients whose first treatment was metformin and sitagliptin in combination achieved a 2.4% drop in HbA1c and more people achieved an A1c of less than 7% vs metformin alone.9 Another example is the concurrent use of metformin, the thiazolidinedione (TZD) pioglitazone, and the GLP-1RA exenatide as initial therapy. Using the three medications together was more effective in lowering HbA1c and helping with weight loss than sequentially added therapies.10



4. What is the strategy to get this patient off medications?

View Answer

4. Many studies have shown the benefit of intensive insulin therapy as the initial treatment of type 2 diabetes. These studies used either an intravenous insulin regimen at the time of T2DM diagnosis or a basal/bolus insulin regimen. The rationale of these early insulin strategies is to “rest the pancreas” and reverse glucotoxicity and lipotoxicity. Later it was found that this treatment allows for redifferentiation of the pancreatic beta cells.10,11,12,13,14,15,16,17,18,19,20,21,22

The goal of intensive insulin therapy is to quickly obtain glycemic control, have a period of stability for at least 2, but preferably 4 weeks, and then taper the insulin dose. Assuming this patient was taking full insulin replacement with both a basal insulin and a mealtime insulin, the approach would be to adjust the mealtime insulin first, reducing it by 50% for 1 week. This is repeated each week until the person is on 5 units or less of prandial insulin. If they successfully stop prandial insulin, the next down titration is their basal insulin dose. The approach is the same. Ideally, within 4 weeks the patient will have achieved glycemic targets and will no longer be on insulin. In previous studies of people with newly diagnosed type 2 diabetes who completed an intensive insulin protocol, 54% were able to go into remission at 1 year.22 In other studies patients had sustained remission for as long as 6 years.21

Finally, bariatric surgery is an option for patients with diabetes whose BMI is greater than 35 kg/m2. Studies have shown that patients who undergo a roux-en-y gastric bypass or gastric sleeve procedure are 5.9 times more likely to achieve diabetes remission.23,24,25


answers and explanationsANSWERS AND EXPLANATIONS

1. This is an important question, and the wording is key. There are plenty of references in the lay literature of “reversing” or “curing” type 2 diabetes. Current thinking is that it takes years of metabolic abnormalities and compensatory physiologic responses before a person becomes hyperglycemic from type 2 diabetes. While it is attractive to seek out a quick fix to “cure” type 2 diabetes, the truth is that there is no quick fix. It is important to remember that there are many pathways in the body that are altered in response to insulin resistance and abnormal insulin and glucose levels.

However, there are many studies that have demonstrated that type 2 diabetes can be put into remission. It is important to clarify the difference between remission and “curing” or “reversing” diabetes. When a patient has an early cancer, and the surgical team is able to resect it with no increased risk of a future recurrence, that is a cure. When a patient can maintain their glucose (HbA1c < 7.0% for many) without any medication, they are at goal. If this HbA1c (<6.5%) is maintained with normal glucose values for at least 3 months without any diabetes medication, this person has achieved “diabetes remission.”1 This is an important differentiation.

Most often this is achieved via significant dietary modification accompanied by substantial weight loss. The ability to maintain the benefit from interventions that helped a person achieve their glucose goals lasts only as long as the intervention’s effects persist. Thus, if the person gains weight, it is fair to assume their diabetes will return. They are at increased risk for recurrence for the rest of their life and will want to maintain the intervention to keep their diabetes in remission.

In this case study, it is best to inform the patient that his condition can be controlled without medications, but a “cure” is not a realistic or attainable goal.

2. For a patient who is newly diagnosed and just starting the education process, a continuous glucose monitor (CGM) can be an invaluable tool. By providing a patient with clear glucose goals, and then having them see how their glucose responds to diet and daily activities, with immediate feedback from a CGM, we can help inform effective change. For example, a patient might learn how much their morning latte increases their blood sugar. Or they can recognize that if they walk their dog their glucose improves. These “self-discoveries” help patients make changes on their own and may inspire them to explore the impact of other lifestyle modifications. Moreover, these “self-discoveries” are rooted in science, specifically cognitive behavioral therapy. Encouraging your patient to try different behavioral experiments with lifestyle modifications and then observe changes in their blood sugars is an excellent strategy to educate and empower your patients.


Including a CGM in your initial education process and referring patients to formal Diabetes Self-Management Education and Support (DSMES) training helps provide them with tools for success. DSMES has been shown to have substantial benefits for people with diabetes including a reduction in HbA1c, reduction in all-cause mortality, improved self-efficacy, improved coping, decreased diabetes-related distress, and improved quality of life.2

Sadly, less than 10% of people with diabetes attend diabetes education within the first year of diagnosis, consequently setting them up for failure.3 The rates are even lower for people with Medicare, which is unfortunate as diabetic education is a covered benefit.4 A referral, with positive reinforcement from the primary care clinician, is one of the best predictors that a patient will attend this important training.

Lifestyle interventions are a cornerstone of diabetes management. There is strong evidence that aggressive weight loss via very low-calorie diets can put type 2 diabetes in remission. The DiRECT trial was a very low-calorie diet study coordinated through primary care offices. Results showed that 46% of participants achieved diabetes remission at 12 months and 36% maintained remission at 24 months.5 The ReTUNE trial recently attempted a similar very low-calorie diet plan in people with type 2 diabetes but lower BMI.6 They found that a mean weight loss of 9% enabled 70% of people to achieve diabetes remission.7

An important thing to keep in mind is that all intensive lifestyle interventions, including very low-calorie diets, must be accompanied with high levels of support if they are to be successful. This requires a team-based approach that includes the health care professional (HCP), a dietitian, diabetes educator, and the patient’s family and friends. At first, they may require more support to initiate major changes and then the amount needed will vary based upon patient needs.

3. The 2022 American Diabetes Association (ADA) Standards of Care for people with diabetes has an algorithm to guide pharmacotherapy for people with type 2 diabetes.8 First and foremost, any pharmacotherapy should be coupled with therapeutic lifestyle change in conjunction with diabetes self-management education and support.

Until recently the initial pharmacologic management of type 2 diabetes mellitus (T2DM) was fairly straightforward; most patients were started on metformin. Metformin is generally safe, effective, and affordable. This process is evolving to support the selection of initial diabetes agents based on the patient’s coexisting medical conditions. As per the ADA’s 2022 Standards of Care, if a person has existing atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease (CKD), other medications are appropriate initial choices, either with metformin or in place of metformin.8 For example, if a person has known ASCVD, use of a GLP-1RA (glucagon-like peptide 1 receptor agonist), or an SGLT-2 (sodium-glucose cotransporter 2) inhibitor with proven cardiovascular benefit is recommended. Similarly, if the patient has either HFrEF (heart failure with reduced ejection fraction) or HFpEF (heart failure with reduced ejection fraction), an SGLT-2 inhibitor is preferred. An SGLT-2i is also reasonable if the patient has CKD, or if the estimated glomerular filtration rate (eGFR) is <30 mL/min, a GLP-1RA with known renal benefit can be used as an alternative.

An important concept when choosing an appropriate regimen is to identify how far the HbA1c needs to drop for the patient’s diabetes to be at target. This is
dependent on one’s initial A1c and their A1c goal. We will address individualizing a patient’s A1c goal in later chapters.

A loose rule when selecting medications is to expect an approximate 1% decrease in HbA1c per medication used. Many patients at diagnosis have significantly elevated A1c levels. Therefore, it would make sense for a patient to require more than one agent to achieve their glycemic goal. Unfortunately, many physicians have been reluctant to begin an aggressive multidrug regimen at the time of diagnosis. More commonly, patients begin a step-therapy approach, where one drug is started, titrated to maximum dose, the A1c is rechecked, and if the A1c is not at goal, another medication is added. This is akin to Dr. DeFronzo’s previously described “treat to fail” practices.

An example of a potent initial regimen is metformin plus the dipeptidyl peptidase 4 inhibitor (DPP4i) sitagliptin. Patients whose first treatment was metformin and sitagliptin in combination achieved a 2.4% drop in HbA1c and more people achieved an A1c of less than 7% vs metformin alone.9 Another example is the concurrent use of metformin, the thiazolidinedione (TZD) pioglitazone, and the GLP-1RA exenatide as initial therapy. Using the three medications together was more effective in lowering HbA1c and helping with weight loss than sequentially added therapies.10

4. Many studies have shown the benefit of intensive insulin therapy as the initial treatment of type 2 diabetes. These studies used either an intravenous insulin regimen at the time of T2DM diagnosis or a basal/bolus insulin regimen. The rationale of these early insulin strategies is to “rest the pancreas” and reverse glucotoxicity and lipotoxicity. Later it was found that this treatment allows for redifferentiation of the pancreatic beta cells.10,11,12,13,14,15,16,17,18,19,20,21,22

The goal of intensive insulin therapy is to quickly obtain glycemic control, have a period of stability for at least 2, but preferably 4 weeks, and then taper the insulin dose. Assuming this patient was taking full insulin replacement with both a basal insulin and a mealtime insulin, the approach would be to adjust the mealtime insulin first, reducing it by 50% for 1 week. This is repeated each week until the person is on 5 units or less of prandial insulin. If they successfully stop prandial insulin, the next down titration is their basal insulin dose. The approach is the same. Ideally, within 4 weeks the patient will have achieved glycemic targets and will no longer be on insulin. In previous studies of people with newly diagnosed type 2 diabetes who completed an intensive insulin protocol, 54% were able to go into remission at 1 year.22 In other studies patients had sustained remission for as long as 6 years.21

Finally, bariatric surgery is an option for patients with diabetes whose BMI is greater than 35 kg/m2. Studies have shown that patients who undergo a roux-en-y gastric bypass or gastric sleeve procedure are 5.9 times more likely to achieve diabetes remission.23,24,25


Case Summary and Closing Points

Diabetes remission is a goal wished for by many but achieved by few. The best chance for a person to achieve sustained diabetes remission is to get diagnosed with type 2 diabetes promptly and gain control quickly. Current evidence suggests that there are
multiple ways to achieve diabetes remission. This affords clinicians multiple options for patient care. Options include an intensive very low-calorie diet, metabolic surgery, and initial intensive insulin regimen.



References

1. Riddle MC, Cefalu WT, Evans PH, et al. Consensus report: definition and interpretation of remission in type 2 diabetes. Diabetes Care. 2021;44(10):2438-2444. doi:10.2337/dci21-0034

2. Strawbridge LM, Lloyd JT, Meadow A, Riley GF, Howell BL. Use of Medicare’s diabetes self-management training benefit. Health Educ Behav. 2015;42(4):530-538.

3. Powers MA, Bardsley JK, Cypress M, et al. Diabetes self-management education and support in adults with type 2 diabetes: a consensus report of the American diabetes association, the association of diabetes care & education specialists, the academy of nutrition and dietetics, the American academy of family physicians, the American academy of PAs, the American association of nurse practitioners, and the American pharmacists association. Diabetes Care. 2020;43(7):1636-1649. doi:10.2337/dci20-0023

4. Li R, Shrestha SS, Lipman R, Burrows NR, Kolb LE, Rutledge S; Centers for Disease Control and Prevention CDC. Diabetes self-management education and training among privately insured persons with newly diagnosed diabetes-United States, 2011-2012. MMWR Morb Mortal Wkly Rep. 2014;63(46):1045-1049.

5. Lean MEJ, Leslie WS, Barnes AC, et al. Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. Lancet Diabetes Endocrinol. 2019;7(5):344-355. doi:10.1016/S2213-8587(19)30068-3

6. Al-Mrabeh A, Barnes AC, Irvine KM, et al. Return to normal glucose control by weight loss in nonobese people with Type 2 diabetes: the ReTUNE study. Diabetes. 2021;70(suppl 1):1184-P.

7. Diabetes UK Professional Conference. Abstract A49 (P37); 2022. Presented April 1, 2022.

8. ADA Standards of Care for the person with diabetes. Chapter 9: Pharmacologic Approaches to Glycemic Control. https://diabetesjournals.org/care/article/45/Supplement_1/S125/138908/9-Pharmacologic-Approaches-to-Glycemic-Treatment

9. Reasner C, Olansky L, Seck TL, et al. The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2011;13(7):644-652. doi:10.1111/j.1463-1326.2011.01390.x

10. Abdul-Ghani MA, Puckett C, Triplitt C, et al. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015;17(3):268-275. doi:10.1111/dom.12417

11. Kramer CK, Zinman B, Retnakaran R. Short-term intensive insulin therapy in type 2 diabetes mellitus: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2013;1:28-34.

12. Kramer CK, Zinman B, Choi H, Retnakaran R. Predictors of sustained drug free diabetes remission over 48 weeks following short term intensive insulin therapy in early type 2 diabetes. BMJ Open Diabetes Res Care. 2016;4(1):e000270.

13. Lean ME, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018;391(10120):541-551. doi:10.1016/S0140-6736(17)33102-1

14. Al-Mrabeh A, Hollingsworth KG, Shaw JAM, et al. 2-year remission of type 2 diabetes and pancreas morphology: a post-hoc analysis of the DiRECT open-label, cluster-randomised trial. Lancet Diabetes Endocrinol. 2020;8(12):939-948. doi:10.1016/S2213-8587(20)30303-X

15. Retnakaran R, Choi H, Ye C, Kramer CK, Zinman B. Two-year trial of intermittent insulin therapy vs metformin for the preservation of β-cell function after initial short-term intensive insulin induction in early type 2 diabetes. Diabetes Obes Metab. 2018;20(6):1399-1407. doi:10.1111/dom.13236

16. Ryan EA, Imes S, Wallace C. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care. 2004;27(5):1028-1032.

17. Chandra ST, Priya G, Khurana ML, et al. Comparison of gliclazide with insulin as initial treatment modality in newly diagnosed type 2 diabetes. Diabetes Technol Ther. 2008;10(5):363-368.


18. Weng J, Li Y, XU W, et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet. 2008;371(9626):1753-1760.

19. Li Y, Xu W, Liao Z, et al. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of beta-cell function. Diabetes Care. 2004;27(11):2597-2602.

20. Hu Y, Li L, Xu Y, et al. Short-term intensive therapy in newly diagnosed type 2 diabetes partially restores both insulin sensitivity and beta cell function in subjects with long-term remission. Diabetes Care. 2011;34(8):1848-1853.

21. Shubrook JH, Jones SA. Basal-bolus analogue insulin therapy as initial treatment of type 2 diabetes mellitus: a case series. Insulin. 2010;5:100-105.

22. Presswala L, Shubrook JH. Intensive insulin therapy as the primary treatment of type 2 diabetes. Clin Diabetes. 2011;29(4):151-153.

23. Shubrook JH, Sathananthan A, Nakazawa M, Patel N, Mehta RJ, Schwartz FL. Inspire diabetes: a pulse of basal bolus analog insulin as the first treatment of T2DM. Presented at the American Diabetes Association Scientific Sessions 2014, San Francisco CA. LB-95 Poster.

24. Sheng B, Truong K, Spitler H, Zhang L, Tong X, Chen L. The long-term effects of bariatric surgery on type 2 diabetes remission, microvascular and macrovascular complications, and mortality: a systematic review and meta-analysis. Obes Surg. 2017;27(10):2724-2732. doi:10.1007/s11695-017-2866-4

25. Mingrone G, Panunzi S, De Gaetano A, et al. Metabolic surgery versus conventional medical therapy in patients with type 2 diabetes: 10-year follow-up of an open-label, single-centre, randomised controlled trial. Lancet. 2021;397(10271):293-304. doi:10.1016/S0140-6736(20)32649-0




case questionsCASE QUESTIONS



1. What should be the initial approach to the patient?

View Answer

1. This patient has latent autoimmune diabetes of the adult (LADA), a form of type 1 diabetes. It is very important that she knows what type of diabetes she has to allow her to have the tools to best manage her diabetes. As a reminder, it is not uncommon for people with LADA to be initially misdiagnosed; a middle-aged adult presenting with elevated glucose but not in DKA is typically assumed to have type 2 diabetes.

This patient is working hard to manage her diabetes. She is checking her glucose frequently, counting her carbohydrates, and calculating her insulin doses based upon her food intake and glucose levels. It appears that she has a good skill set. Acknowledging the effort, she is giving, and providing her with positive reinforcement is very important.

This patient seems knowledgeable about diabetes self-management and based on her HbA1c, her diabetes is well managed. However, it can be beneficial at an initial visit to get a more detailed sense of what her typical day entails. This would include the exact timing of her insulin doses, and whether they are consistent from day to day. You would also want to know the timing of her insulin doses in relation to her meals, the content of her meals, and when and how often she requires correction doses. This will help determine the adequacy of her carbohydrate ratio and correction scale. It can also be useful to learn when she is more physically active and if recurring life events impact her regular routine. Once the schedule has been determined, you should teach her the basic pharmacodynamics of her insulin products. This allows her to use insulin to better match her daily schedule and reduce her risk of hypoglycemia. While this may seem like a lot of detail, this information establishes the building blocks for an effective insulin regimen.

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Oct 25, 2023 | Posted by in CRITICAL CARE | Comments Off on Key Aspects of Treatment

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