By Austin Ulrich, PharmD, BCACP
Consultant Pharmacist, Greensboro, NC
SYNOPSIS: At the 2023 American Diabetes Association Scientific Sessions, experts presented key updates, advances, and best practices for patient care. A selection of presentations relevant to the internal medicine and primary care community is presented here.
ADA Standards of Care: 2023 Updates
The American Diabetes Association (ADA) publishes annual updates to the Standards of Medical Care in Diabetes. In 2023, there were several notable updates highlighted at the ADA Scientific Sessions.1
Improving Care and Promoting Health in Populations
The 2023 standards place a strong emphasis on the role of community healthcare workers in diabetes treatment. These professionals are highlighted as vital members of the interprofessional diabetes care team. They can provide direct care to patients, support the care delivered by other healthcare providers, identify and access community resources, interpret and translate clinical information, provide care coordination, deliver culturally appropriate health education, and offer social support.1 Another significant change is the incorporation of person-first and inclusive language. This aims to empower individuals with diabetes by consistently using terminology that recognizes the patient at the center of diabetes care. Terms such as compliance, adherence, control, patient, and diabetic are avoided in favor of person-first language. For example, instead of referring to individuals as diabetics, the preferred terms are “people with diabetes” or “person with diabetes.” Similarly, terms like “compliance” and “adherence” are replaced with terms like “engagement,” “involvement,” or “medication-taking.” This shift in language reflects a more respectful and empowering approach to diabetes care, recognizing the individuality and dignity of each person.1
Prevention or Delay of Type 2 Diabetes and Associated Comorbidities
The 2023 standards include notable updates regarding the prevention or delay of type 2 diabetes (T2D) and associated comorbidities. Previously, the guidelines recommended referring all patients with prediabetes to lifestyle and behavioral change programs that were modeled after the National Diabetes Prevention Program (DPP). However, the standards authors recognized the population studied in the DPP differs from the older community-dwelling population in the Atherosclerosis Risk in Communities (ARIC) study. The ARIC study demonstrated that although the prevalence of prediabetes is high among older adults based on hemoglobin A1c (HbA1c) levels and fasting plasma glucose, the likelihood of progressing to diabetes is relatively low compared to regressing to normal glycemia or experiencing mortality. This discrepancy led to the realization that the ARIC community, which consists of an older community-dwelling population, differs from the population studied in the DPP, which served as the basis for previous guidelines.
The new guidelines outline specific criteria, such as body mass index (BMI), glucose levels, and history of gestational diabetes, to help identify individuals at a higher risk. The updated language refines the recommendation by specifying that overweight or obese adults who are at high risk of progressing to T2D, as typified by the DPP, should be referred to lifestyle and behavioral change programs.1
The updated guideline also focuses on screening and risk stratification for non-alcoholic fatty liver disease in adults with T2D or prediabetes, particularly those who are obese and living with cardiometabolic risk factors or cardiovascular disease. Clinically significant fibrosis, characterized by moderate to advanced fibrosis leading to cirrhosis, is the target for identification.
The fibrosis-4 (FIB-4) calculator, a simple tool derived from age, aspartate aminotransferase, alanine transaminase, and platelet levels, is recommended for assessing fibrosis, even when liver enzymes are normal. The FIB-4 calculator helps stratify patients based on their FIB-4 index, with values above 2.6 indicating high-risk patients. Implementing this recommendation globally can improve the detection of advanced fibrosis and potentially prevent disease progression and associated complications.1
Cardiovascular Disease and Risk Management
The 2023 standards authors established different targets for several measures of cardiovascular risk. The target blood pressure for individuals with diabetes was changed to lower than 130/80 mmHg, based on recent evidence. For individuals with diabetes age 40 to 75 years at higher cardiovascular risk, treatment with high-intensity statin is suggested, and low-density lipoprotein (LDL) cholesterol is recommended to be lowered by 50% or more of baseline and to a target of lower than 70 mg/dL. A high-intensity statin is recommended for individuals with atherosclerotic cardiovascular disease to reduce LDL cholesterol by 50% or more of baseline and to a target of lower than 55 mg/dL.1
Retatrutide, a Novel GIP, GLP-1, and Glucagon Receptor Agonist
The landscape of obesity treatment has been transforming rapidly. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is FDA-approved for treating obesity, and tirzepatide is in Phase III trials. Additional agents for treating obesity also are in development. The results of Phase II trials for retatrutide, an investigational agent for treating obesity, are available and Phase III trials are planned. Retatrutide is a once-weekly, injectable, triple hormone agonist of the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors.2
Retatrutide 48-Week Phase II Obesity Trial
Participants in the Phase II obesity trial of retatrutide were randomized to placebo or various doses of retatrutide (1 mg, 4 mg, 8 mg, and 12 mg) once weekly, with initial doses ranging from 1 mg to 4 mg. The primary outcome was percent change in body weight after 24 weeks from baseline. Secondary endpoints included percent change in body weight after 48 weeks from baseline, and weight reduction of 5%, 10%, and 15% or more.3 A total of 338 adults were included, and 51.8% were men. Baseline mean body weight was 107.7 kg and baseline BMI was 37.3 kg/m2. After 24 weeks, body weight reduction in the retatrutide groups was -7.2% (1 mg), -12.9% (4 mg), -17.3% (8 mg), and -17.5% (12 mg) vs. weight reduction of -1.6% in the placebo group.1 The most common adverse events in the retatrutide groups were gastrointestinal, dose-related, and generally mild to moderate. The authors observed faster heart rates, which peaked at 24 weeks after treatment initiation and slowed thereafter.3
Retatrutide 36-Week Phase II T2D Trial
Recent guidelines emphasize the importance of both glycemic control and body weight loss for holistic management of T2D. Preliminary evidence previously demonstrated positive effects of retatrutide on HbA1c and body weight in patients with T2D, prompting the Phase II trial in patients with T2D.4 Participants were randomized to groups that included two treatments: retatrutide placebo + dulaglutide placebo, retatrutide placebo + dulaglutide 1.5 mg, or retatrutide (0.5 mg, 4 mg, 8 mg, or 12 mg) + dulaglutide placebo. Patients in the retatrutide groups were titrated to target dose, except for the 0.5 mg group and one of the 4 mg groups.4 A total of 288 patients were included, and 56% were women. Baseline mean HbA1c was 8.3% and baseline BMI was 35 kg/m2. At 36 weeks after baseline, patients recorded mean reductions in HbA1c of -0.3%, -0.5%, -1.3%, -1.5%, -2.1%, -1.9%, -2.2%, and -1.4% for placebo, retatrutide 0.5 mg, retatrutide 2/4 mg, retatrutide 4 mg, retatrutide 2/4/8 mg, retatrutide 4/8 mg, retatrutide 2/4/8/12 mg, and dulaglutide 1.5 mg, respectively. Patients receiving retatrutide experienced a statistically significant reduction in HbA1c compared to placebo (P < 0.05). Additionally, patients in the retatrutide 8 mg group and the retatrutide 12 mg group recorded a statistically significant HbA1c reduction compared to dulaglutide 1.5 mg. Statistically significant reductions in fasting serum glucose and body weight showed similar patterns. Adverse events were similar to those in the Phase II retatrutide obesity trial.5 Among obese adults, 48 weeks of treatment with retatrutide resulted in substantial body weight reductions compared to placebo. Retatrutide also demonstrated significant, meaningful improvements in glycemic control and body weight in patients with T2D vs. dulaglutide 1.5 mg weekly and placebo.
Metabolic Surgery vs. Lifestyle/Medical Management of Type 2 Diabetes: Long-Term Results of the ARMMS-T2D Trial
The Alliance of Randomized Trials of Medicine versus Metabolic Surgery (ARMMS) study was a pooled, prospective, randomized trial that included many obese patients living with T2D.6,7 The authors assessed durability and longer-term effectiveness of metabolic surgery compared with medical/lifestyle management. Patients in the 316-person, prospective, observational cohort were enrolled based on previous randomization to surgery or medical/lifestyle management in the STAMPEDE, TRIABETES, SLIMM-T2D, and CROSSROADS trials.7 In this session, the long-term, diabetes-related outcomes of ARMMS were presented, including change in HbA1c, remission (HbA1c < 6.5% for at least three months, without anti-diabetes medications) and glycemic control at seven to 12 years.6
At seven years after baseline, the change in HbA1c was -1.6% (mean HbA1c 7.2%) for the surgical group and -0.2% (mean HbA1c 8.2%) for the medical/lifestyle group (P < 0.001), with similar patterns at 12 years. At 12 years after baseline, the change in HbA1c was -1.4% (mean HbA1c 7.3%) in the surgical group and -0.3% (mean HbA1c 8%) for the medical/lifestyle group (difference: -1.1%; P < 0.001). Despite higher baseline values, the surgical group recorded significantly lower HbA1c levels than the medical/lifestyle group at all points after study initiation.6
The authors evaluated the rates of diabetes remission over time in the two groups as a secondary outcome. Regardless of surgery procedure type, 50.8% of patients in the surgical group achieved remission at one year vs. 0.5% in the medical/lifestyle group. Over time, the percentage of participants achieving remission gradually decreased in the surgical group, but remission rates remained higher at all points compared with the medical/lifestyle group. At year seven, the remission rate was higher in the surgical group than the medical/lifestyle group (18.2% vs. 6.2%; OR = 3.4; P = 0.02). At year 12, the remission rate dropped to 12.7% in the surgical group and dropped to 0% in the medical/lifestyle group. Rates of remission were higher in the Roux-en-Y gastric bypass subgroup (24.5%) vs. the sleeve gastrectomy subgroup (15.2%) or adjustable gastric band subgroup (8.9%), but the difference between surgical procedures was not statistically significant. Despite loss of remission, glycemic control (HbA1c < 7%) was superior and sustained with surgery.6
The most common adverse events observed in the surgical group, compared to the medical lifestyle group, were gastrointestinal, such as abdominal pain (P = 0.02), dysphagia (P = 0.005), dumping syndrome (P = 0.03), and gastroparesis (P = 0.02). Additionally, the surgical group recorded lower hemoglobin, lower iron, higher vitamin B12, and higher vitamin D levels. Statistically significant serious adverse events occurring in the surgical group included initiation of dialysis (P = 0.048), blood transfusion for anemia (P = 0.01), and bone fractures (P = 0.03) compared to the medical/lifestyle group.6 Results of ARMMS show sustained, long-term weight loss for surgical patients with T2D. Diabetes remission off medication wanes with time, but glycemic control remains superior with surgery. Decision-making for patient care with T2D must be individualized and balance the risks and benefits. Clinicians should consider metabolic surgery as an option to improve diabetes-related outcomes, including for people with BMI less than 35 kg/m2.6
Diabetes Kidney Disease in Type 1 and Type 2 Diabetes
Diabetes kidney disease (DKD) is the most common cause of chronic kidney disease (CKD), and its prevalence has increased across the globe in recent years, driven by the rising cases of diabetes.8,9 Complications of DKD include end-stage kidney disease, cardiovascular disease, and premature death.9 There is a need to address the burden of DKD in the United States and globally.8
Many glucose-lowering drugs have been studied in DKD related to T2D, but investigations of these agents for type 1 diabetes (T1D) are sparse.8 If findings from T2D studies could be extrapolated to T1D, patients managing T1D could benefit from therapies that are effective for T2D.8 In the United States, the prevalence of patients with an estimated glomerular filtration rate (eGFR) lower than 60 mL/min/1.73 m2 has increased over the past 30 years, but the prevalence of albuminuria 30 mg/g or higher has decreased.8,10 These findings could be related to expanded use of angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors in clinical practice and the emergence of a more vascular phenotype of DKD.8
While intensive glycemic control helps delay kidney complications in patients with diabetes, patients with T1D or T2D still develop albuminuria and lower eGFR over time.8 Furthermore, data from the DCCT/EDIC study show intensive glycemic control in patients with T1D is associated with central obesity, weight gain, higher blood pressure, worsening insulin resistance, and dyslipidemia.11 Several drug classes are effective for mitigating adverse kidney outcomes in DKD related to T2D and T1D with variable evidence and efficacy.8
Overall, there is a substantial need for more trials of glucose-lowering agents that include individuals with T1D to prevent adverse kidney complications. Determining whether findings from T2D can be extrapolated to T1D in DKD is difficult, but in certain cases, extrapolation could be possible. The clinical presentation of T1D is changing and can be similar in some ways to T2D, which may suggest that therapies, such as DKD treatments in T2D, may be effective for T1D patients.8
Diabetes Foot Disease and Artificial Intelligence
Diabetes foot disease is a common complication of diabetes, resulting in higher mortality and morbidity rates.12,13 Evaluating diabetes foot disease can be challenging for patients and clinicians because of several factors, including logistical issues and time constraints. Delaying reviews of active ulcers can be detrimental to healing.
To aid patients and clinicians in managing diabetes foot disease, artificial intelligence (AI) applications have been developed in recent years.2 In this panel discussion, the participants explored the concept of AI and how it relates to medicine, with a focus on applications in diabetes foot disease.12
AI has been studied and used in various applications in medicine.12 AI is defined as a technology that mimics human intelligence to perform tasks, and it can iteratively improve with repeated information feedback. AI is intelligence demonstrated by machines as opposed to humans and other animals. It also can be thought of as the ability for a computer to “think” and “learn.”12
AI is a controversial topic in medicine. Interest in AI is growing, evidenced by the dramatic increase in AI-related PubMed searches in recent years.12,14 AI has been used to write scientific abstracts and even included as an author on research papers. Scientists, clinicians, and professional organizations have expressed different perspectives, both positive and negative, regarding AI. Regardless of opinion, AI is likely here to stay.12
Many products using AI for diabetes foot disease are on the market, and most are commercialized.12 Patients may come into the clinic asking about different products they have seen advertised. Clinicians must be prepared for these conversations to respond appropriately.
Examples of AI diabetes foot disease technology include smartphone thermal analysis of diabetes foot ulcer prevention and treatment, cloud-based deep learning framework for remote detection of diabetes foot ulcers, pressure and thermal sensors in shoe insoles, sensor-embedded “smart” socks that detect inflammation and possible skin breakdown, and remote temperature monitoring devices to predict foot ulceration.12
Ultimately, these AI tools are in the early stages of development, and some lack accuracy and reliability. Risk stratification based on AI devices for diabetes foot disease stratification does not save limbs, but what clinicians do with that information — taking action is what makes a difference.12
Major Advances and Discoveries in Type 1 Diabetes: The Year in Review
Although many advances and discoveries in diabetes have come to fruition in the past year, a few stand out as potentially practice-changing: FDA approval of teplizumab for T1D, and pivotal trial results of a “bionic pancreas” technology.15
The November 2022 FDA approval of teplizumab holds great promise as it could modify the disease course of T1D, delaying its onset and alleviating the need for insulin therapy. Teplizumab is an anti-CD3 therapy indicated for delaying the onset of stage 3 T1D in adults and children age 8 years and older who have been diagnosed with stage 2 T1D. The emergence of this agent also brings attention to the preclinical phase of hyperglycemia and immunologic abnormalities, reshaping our understanding of T1D and necessitating the development of effective screening tactics.15
Publication and dissemination of results from the pivotal trial of a bionic pancreas in T1D represents another significant advance. A total of 219 patients age 6 to 79 years who are living with T1D were randomized to either bionic pancreas or standard care. Over 13 weeks, the HbA1c level decreased from 7.9% to 7.3% in the bionic pancreas group and did not change in the standard care group (7.7% at baseline and study completion). Additionally, the percent of time the glucose level was below 54 mg/dL did not differ between the two groups.16
What makes this study noteworthy is the way we perceive the effect of treatment. Unlike certain drug therapies, where raising the dosage can lead to lower HbA1c levels, automated insulin delivery devices like the bionic pancreas target a specific glucose level. This approach suggests nearly all patients will achieve a similar level of HbA1c.15
The results demonstrate this technology profoundly affected the entire patient population, regardless of their baseline HbA1c. This is an intriguing and novel phenomenon. It challenges our traditional understanding of how therapies influence HbA1c levels, suggesting automated insulin delivery devices can democratize diabetes management by bringing patients to a similar level of HbA1c. These findings carry significant implications for the field of T1D management. The bionic pancreas presents a promising option that can provide consistent and effective glycemic control for patients living with T1D. Further research and development in this area could lead to more widespread adoption of these devices, revolutionizing the way we approach T1D care.15
REFERENCES
1. ElSayed NA, Aroda VR, Bruemmer D, et al. Updates in ADA’s Standards Of Care in Diabetes – 2023. ADA 2023. 83rd Scientific Sessions, San Diego, CA; June 25, 2023.
2. Jastreboff A. Retatrutide Obesity: Efficacy and Safety Results of the 48-week Obesity Phase 2 Trial. ADA 2023. 83rd Scientific Sessions, San Diego, CA; June 26, 2023.
3. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity - a phase 2 trial. N Engl J Med 2023; Jun 26. doi: 10.1056/NEJMoa2301972. [Online ahead of print].
4. Rosenstock J. Retatrutide T2D: Efficacy and Safety Results of the 36-Week Phase 2 Trial. ADA 2023. 83rd Scientific Sessions, San Diego, CA; June 26, 2023.
5. Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: A randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet 2023; Jun 26: S0140-6736(23)01053-X. doi: 10.1016/S0140-6736(23)01053-X. [Online ahead of print].
6. Courcoulas A. Long-Term Outcomes and Diabetes Remission at 7 to 12 Years in the ARMMS-T2D Randomized Trial. ADA 2023. 83rd Scientific Sessions, San Diego, CA; June 26, 2023.
7. Kirwan JP, Courcoulas AP, Cummings DE, et al. Diabetes Remission in the Alliance of Randomized Trials of Medicine Versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D). Diabetes Care 2022;45:1574-1583.
8. Srivastava A. Diabetes kidney disease in type 1 and type 2 diabetes: Can we extrapolate findings from type 2 diabetes trials to type 1 diabetes? ADA 2023. 83rd Scientific Sessions, San Diego, CA; June 24, 2023.
9. Tonneijck L, Muskiet MHA, Smits MM, et al. Glomerular hyperfiltration in diabetes: Mechanisms, clinical significance, and treatment. J Am Soc Nephrol 2017;28:1023-1039.
10. Afkarian M, Zelnick LR, Hall YN, et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014. JAMA 2016;316:602-610.
11. Purnell JQ, Zinman B, Brunzell FD; DCC/EDIC Research Group. The effect of excess weight gain with intensive diabetes mellitus treatment on cardiovascular disease risk factors and atherosclerosis in type 1 diabetes mellitus: Results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) study. Circulation 2013;127:180-187.
12. Najafi B, Vileikyte L, Rothenberg G, Aung B. The Future Is Now — Artificial Intelligence and Diabetes Foot. ADA 2023. 83rd Scientific Sessions, San Diego, CA; June 24, 2023.
13. Pappachan JM, Cassidy B, Fernandez CJ, et al. The role of artificial intelligence technology in the care of diabetic foot ulcers: The past, the present, and the future. World J Diabetes 2022;13:1131-1139.
14. Pettit RW, Fullem R, Cheng C, Amos CI. Artificial intelligence, machine learning, and deep learning for clinical outcome prediction. Emerg Top Life Sci 2021;5:729-745.
15. Buse JB. Major advances and discoveries in diabetes - the year in review. ADA 2023. 83rd Scientific Sessions, San Diego, CA; June 26, 2023.
16. Bionic Pancreas Research Group; Russel SJ, Beck RW, Damiano ER, et al. Multicenter, randomized trial of a bionic pancreas in in type 1 diabetes. N Engl J Med 2022;387:1161-1172.
At the 2023 American Diabetes Association Scientific Sessions, experts presented key updates, advances, and best practices for patient care. A selection of presentations relevant to the internal medicine and primary care community is presented here.
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