Implementing body weight reduction strategies in the treatment of patients with type 2 diabetes (T2D) has been shown to produce greater disease-modifying effects than any other glucose-lowering intervention, resulting in improved hypertension, dyslipidemia, and diabetes. By implementing an upstream intervention to weight loss, and using newer drugs (GIP agonists, GLP-1 receptor agonists, SGLT2 inhibitors), patients will experience improved effects earlier and for a longer duration.
Upstream Interventions for Managing Obesity in Patients with Type 2 Diabetes
Weight Loss as a Primary Target for T2D
Type 2 diabetes (T2D) is a common metabolic condition that can result from obesity. A loss of 15% or more of bodyweight has been shown to help lower blood glucose levels even more effectively than other treatments for the condition.1 Weight reduction may also have a positive effect on several other comorbidities associated with obesity or adiposopathy (Figure 1) and improve quality of life.
Figure 1. Obesity is the root cause of a multitude of medical complications and should be treated early.1
Clinical studies such as the open-label, cluster-randomized DiRECT trial have shown that weight loss may reverse the disease course of T2D.2 Conducted at 49 primary care practices, it enrolled patients aged 20 to 65 who had been diagnosed with T2D within the past 6 years, had a body mass index of 27 to 45, and were not taking insulin. Split into 2 arms, those in the control group received best practice care by guidelines while those in the intervention arm had to withdraw from antihypertensive drugs and use a total diet replacement (825 to 853 kcal/day formula diet for 3 to 5 months) followed by a stepped food reintroduction for 2 to 8 weeks. Intervention patients also received structured support for long-term weight loss maintenance. The coprimary outcomes from baseline to 12 months were: 1) weight loss ≥ 15 kg, achieved by 36 (24%) patients in the intervention arm and none in the control arm (P < 0.0001); and 2) remission of diabetes (defined as glycated hemoglobin [HbA1c] < 6.5% [< 48 mmol/mol] after at least 2 months off all antidiabetic medications), achieved by 68 (46%) patients in the intervention arm and 6 (4%) patients in the control arm (odds ratio 19.7, 95% CI 7.8-49.8; P < 0.0001). Figure 2 shows the stepped-up results of the percentage of patients achieving T2D remission as more weight was lost.
Figure 2. Remission of diabetes, in relation to weight loss achieved at 12 months (both arms combined).2
At 2-year follow-up of all patients, remissions were achieved by 8/154 (5.2%) participants who failed to achieve 5 kg of weight loss, 21/73 (28.8%) who maintained 5 to 10 kg of loss, 15/25 (60.0%) who maintained 10 to 15 kg of loss, 29/45 (64.4%) who maintained ≥10 kg of loss, and 14/20 (70.0%) of participants who lost 15 kg or more.3
A randomized controlled trial by Magkos et al. evaluated the effects of 5.1% ± 0.9% (n = 19), 10.8% ± 1.3% (n = 9), and 16.4% ± 2.1% (n = 9) weight loss and weight maintenance (n = 14) on metabolic outcomes.4 Subjects in the weight loss and weight maintenance groups participated in a lifestyle intervention program that included weekly individual behavior education sessions and dietary counseling. Even a 5% weight loss was associated with notable health benefits, including decreased intraabdominal and intrahepatic fat and increased multiorgan insulin sensitivity and β-cell function. Increased weight loss resulted in dose-dependent alterations in key adipose tissue biological pathways (Figure 3).
Figure 3. Progressive weight loss further improves many cardiometabolic outcomes.4
Pharmacologic Therapy for T2D and Weight Loss
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to be effective for treatment of T2D.5 They influence multiple systems, including binding pancreatic GLP-1 receptors to increase insulin secretion and reduce glucagon secretion to help lower HbA1c. GLP-1 RAs also assist with weight loss by controlling food intake and satiety signals in the brain and delaying gastric emptying of the stomach.
Another treatment option is glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, which increase insulin secretion while also exerting different cardiometabolic effects than GLP-1 RAs (Figure 4).5-10
Figure 4. Cardiometabolic effects of GLP-1 and GIP.5-10
Tirzepatide is a novel, dual-agonist single molecule containing both a GIP and a GLP-1 RA. Research on tirzepatide shows that the therapeutic actions of the 2 agents combined may exceed those of a GIP or a GLP-1 single-receptor agonist alone.6,7
Tirzepatide was tested in an open-label, 40-week, phase 3 trial of 1,879 T2D patients who had inadequate T2D control with at least 1500 mg per day of metformin.11 Patients were assigned randomly in a 1:1:1:1 ratio to receive tirzepatide at a dose of 5 mg, 10 mg, or 15 mg (by injection) or semaglutide, a GLP-1 RA, at a dose of 1 mg (by injection). At baseline, participants’ mean glycated hemoglobin level was 8.28%, mean age was 56.6 years, and mean weight was 93.7 kg. The primary endpoint was change in glycated hemoglobin level from baseline to 40 weeks. As shown in Figure 5A, all doses of tirzepatide significantly lowered the glycated hemoglobin level compared to semaglutide.
Figure 5A. Least-squares mean (±SE) change from baseline in the glycated hemoglobin level at 40 weeks.11
Figure 5B shows similar results for the change in body weight compared to baseline at 40 weeks.
Figure 5B. Least-squares mean (±SE) change from baseline in body weight at 40 weeks.11
Starting the Weight Loss Journey Early
The benefits of weight loss on the course of T2D and other cardiometabolic outcomes are compelling. Clinicians should promote therapeutic interventions that are effective for weight loss intervention early in the treatment journey of patients who have not achieved appropriate levels of glucose, blood pressure, or lipid control while steadily gaining weight despite diet and lifestyle changes.
For patients who have not met treatment goals, the American Diabetes Association (ADA) recommends prioritizing timely and appropriate intensification of lifestyle and/or pharmacological therapy, including weight management, which can lead to a reduction in risk of cardiovascular disease.12 According to the Centers for Disease Control and Prevention, patients with diabetes are twice as likely to have heart disease or a stroke—and at a younger age—than those who do not have diabetes. Therefore, loss of even modest amounts of weight (eg, 5% to 7% of body weight, or just 10 to 14 lbs for a 200-lb person) should be encouraged to lower triglycerides and blood sugar.13
Clinicians should be aware of barriers to weight loss, including food insecurity, which is defined by the ADA as the unreliable availability of nutritious food and the inability to consistently obtain food without resorting to socially unacceptable practices.12 The risk for T2D is 2 times greater in those with food insecurity than those without, and they may be more inclined to purchase inexpensive and more energy- and carbohydrate-dense processed foods instead of nutritious foods.
In a patient who has lost weight through diet control, physiological changes in energy expenditure, substrate metabolism, and hormone pathways in appetite regulation may actually prompt their body to regain the weight.14 Therefore, long-term strategies are needed to overcome these physiological changes to help patients maintain weight loss.
One helpful resource for patients is the ADA’s Diabetes Food Hub, a cooking and recipe website for people living with diabetes and their families.15 It provides heathy tips from ADA food and nutrition experts and has an interactive meal planner that generates an editable grocery list. Recipes are also available in Spanish.
Intensification Strategies for Weight Loss and Glycemic Control
Intensification strategies are needed in patients recently diagnosed with T2D who are obese and have elevated A1c, triglycerides, and blood pressure indicative of poor glucose control. The ADA recommends that such strategies be implemented without delay when patients are not meeting their treatment goals.16 When treatment intensification is employed, it has been associated with improvement in A1c, hyperlipidemia, and hypertension control.12
The ADA notes that in 35% of patients with diabetes, a lack of treatment intensification, defined as a failure to either increase a drug dose or change a drug class, was associated with uncontrolled A1c, lipids, or blood pressure.12 The trend for medication intensification to treat T2D has not improved with time, as illustrated by a recent analysis by Raghavan et al. that looked at timing and glycemia levels associated with the initiation of second-line T2D treatments. In a group of 199,042 adults treated by the US Department of Veterans Affairs from 2005 to 2013,17 the cumulative 5-year incidence of second-line medication initiation declined from 47% among metformin initiators in 2005 to 36% in their 2013 counterparts (P < 0.0001). Those who received second-line treatment within 5 years of initiation of metformin had a mean HbA1c of 7.74% ± 1.66% in 2005 versus 8.55% ± 1.92% in 2013.
To address treatment inertia, the ADA has published the Provider Guide Overcoming Resistance to Therapy Intensification in Type 2 Diabetes.18 A companion to the patient self-assessment tool, Your Type 2 Diabetes Treatment: Get Ready for Your Visit, the publication provides clinicians with practical information that can be used when counseling patients during clinical visits about how to overcome treatment inertia and improve their A1c levels.
In patients with T2D, weight loss has the potential to improve A1c, reverse the disease trajectory, improve quality of life, and address the many comorbidities associated with obesity, such as hypertension, hyperlipidemia, and coronary artery disease, which may lead to macrovascular complications. When a patient with T2D is not meeting their individual treatment goals, treatment intensification as early as possible is recommended to obtain weight loss and A1c control and maximize the associated clinical benefits. GIP and GLP-1 RA medications have historically been used to lower A1c and weight, and research now shows that a dual GIP/GLP-1 receptor agonist, tirzepatide, can significantly reduce A1c and weight compared to a GLP-1 RA alone (semaglutide).
- Lingvay I, Sumithran P, Cohen RV, le Roux CW. Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation. Lancet. 2022;399(10322):394-405. doi:10.1016/S0140-6736(21)01919-X
- 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
- 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
- Magkos F, Fraterrigo G, Yoshino J, et al. Effects of moderate and subsequent progressive weight loss on metabolic function and adipose tissue biology in humans with obesity. Cell Metab. 2016;23(4):591-601. doi:10.1016/j.cmet.2016.02.005
- Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: similarities and differences. J Diabetes Investig. 2010;1(1-2):8-23. doi:10.1111/j.2040-1124.2010.00022.x
- Samms RJ, Coghlan MP, Sloop KW. How may GIP enhance the therapeutic efficacy of GLP-1? Trends Endocrinol Metab. 2020;31(6):410-421. doi:10.1016/j.tem.2020.02.006
- Bastin M, Andreelli F. Dual GIP–GLP1-receptor agonists in the treatment of type 2 diabetes: a short review on emerging data and therapeutic potential. Diabetes Metab Syndr Obes. 2019;12:1973-1985. doi:10.2147/DMSO.S191438
- Müller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130. doi:10.1016/j.molmet.2019.09.010
- Fukuda M. The role of GIP receptor in the CNS for the pathogenesis of obesity. Diabetes. 2021;70(9):1929-1937. doi:10.2337/dbi21-0001
- Nauck MA, Quast DR, Wefers J, Pfeiffer AFH. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: a pathophysiological update. Diabetes Obes Metab. 2021;23 Suppl 3:5-29. doi:10.1111/dom.14496
- Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503-515. doi:10.1056/NEJMoa2107519
- American Diabetes Association. 1. Strategies for improving care. Diabetes Care. 2016;39 Suppl 1):S6-S12. doi:10.2337/dc16-S004
- Centers for Disease Control and Prevention. Diabetes and your heart. June 20, 2022. Accessed September 25, 2022. https://www.cdc.gov/diabetes/library/features/diabetes-and-heart.html
- Sumithran P, Proietto J. The defence of body weight: a physiological basis for weight regain after weight loss. Clin Sci (Lond). 2013;124(4):231-241. doi:10.1042/CS20120223
- American Diabetes Association. Diabetes Food Hub. Accessed September 23, 2022. https://www.diabetesfoodhub.org/
- American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S111-S124. doi:10.2337/dc21-S009
- Raghavan S, Warsavage T, Liu WG, et al. Trends in timing of and glycemia at initiation of second-line type 2 diabetes treatment in U.S. adults. Diabetes Care. 2022;45(6):1335-1345. doi:10.2337/dc21-2492
- American Diabetes Association. Overcoming resistance to therapy intensification in type 2 diabetes. Accessed September 23, 2022. https://professional.diabetes.org/files/media/ada_providerguide_final-2021-03-17.pdf
In accordance with the ACCME Standards for Integrity and Independence, Global Learning Collaborative (GLC) requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any ineligible company. GLC mitigates all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs.
Juan P. Frias, MD
Medical Director and Principal Investigator
Velocity Clinical Research
Los Angeles, CA
Commercial Interest Speakers Bureau: Eli Lilly, Sanofi
Consulting Fees: 89bio, Akero, Altimmune, Axcella Health, Becton Dickinson, Boehringer Ingelheim, Carmot Therapeutics, Echosens, Eli Lilly, Gilead, Intercept, Metacrine, Merck, Novo Nordisk, Pfizer, Sanofi
Research Support: 89bio, Akero, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Intercept, IONIS, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxel, Sanofi
Donna Ryan, MD
Pennington Biomedical Research Center
Baton Rouge, LA
Commercial Interest Speakers Bureau: Novo Nordisk
Consulting Fees: Altimmune, Amgen, Boehringer Ingelheim, Calibrate, Carmot, Epitomee, Gila Therapeutics, IFA Celtics, Lilly, Novo Nordisk, Real Appeal (UnitedHealthcare), Scientific Intake, Wondr Health, Xeno Biosciences, YSOPIA, Zealand
Ownership Interest: Calibrate, Epitomee, Roman, Scientific Intake
- Stephen Chavez has nothing to disclose.
- Cindy Davidson has nothing to disclose.
- Amanda Hilferty has nothing to disclose.
- Libby Lurwick has nothing to disclose.
- Brian P. McDonough, MD, FAAFP, has nothing to disclose.
- Colleen Resnick has nothing to disclose.
- Katie Sheridan, PhD, has nothing to disclose.
After participating in this educational activity, participants should be better able to:
- Identify weight loss as a primary target of treatment in people with type 2 diabetes and obesity
- Formulate strategies to intensify individualized treatment combinations that focus on weight loss and glycemic control
This activity is designed to meet the educational needs of endocrinologists, primary care physicians, and other professionals who manage patients who are overweight/obese with type 2 diabetes.
In support of improving patient care, Global Learning Collaborative (GLC) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team.
Global Learning Collaborative (GLC) designates this enduring activity for a maximum of 0.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Global Learning Collaborative (GLC) designates this activity for 0.25 nursing contact hours. Nurses should claim only the credit commensurate with the extent of their participation in the activity.
Global Learning Collaborative (GLC) has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 0.25 AAPA Category 1 CME credits. Approval is valid until October 20, 2023. PAs should claim only the credit commensurate with the extent of their participation in the activity.
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