Table 3

Questions for future research

Epidemiology1. What is the extent to which associations between glycemia and CVD events apply to the oldest adults?
2. In light of the high prevalence of undiagnosed diabetes and dysglycemia/prediabetes in older adults, do heterogeneous glycemic subgroups matter in terms of future risk, and what are their implications for screening?
3. Which subgroups are the best candidates for intervention?
4. Are the diabetes risk factors or their magnitudes of association different for older adults than young and middle-aged adults?
5. What additional information is needed to improve risk stratification for intervention?
6. What are significant racial/ethnic disparities in older adults with diabetes, and what are the best approaches to address them?
7. To what extent are late-life health inequalities a legacy of early-life factors, such as reduced access to care?
8. How will quality metrics distinguish between true racial/ethnic inequalities in access to or quality of care vs. appropriate compliance with geriatric recommendations for individualized care?
Pathophysiology1. Are mechanisms of aging- and diabetes-related impairments of pancreatic β-cell function similar or different? Additive or multiplicative?
2. Are any of these mechanisms reversible or preventable?
3. Would prevention of aging effects slow the progression to diabetes in at-risk individuals?
4. How can insulin resistance be prevented?
5. What causes age-related declines in mitochondrial function, and how do they and declines in insulin sensitivity and β-cell function contribute to the age-related increase in risk for diabetes?
6. What causes age-related sarcopenia, and what is its impact on diabetes progression and complications?
7. What are the independent and common mechanisms underlying the interaction between advancing age and diabetes on arterial stiffness and endothelial dysfunction, and how are they modulated by insulin resistance, elevated glucose levels, and other common risk factors, such as hyperlipidemia, abdominal obesity, or hypertension?
8. How does the resultant vascular dysfunction relate to CVD risk?
9. How does the myocardium change with age?
10. What is the time course of processes underlying diabetes and CVD, and what is the trajectory of potential compensatory mechanisms?
11. Can medications associated with comorbidities contribute to the pathophysiology of diabetes and risk for CVD complications?
12. What are the glucose-sensing mechanisms in the brain, and how are they affected by age?
13. What changes are apparent in the prediabetic brain?
Complications and CVD risk1. Do mild episodes of hypoglycemia affect CVD risk?
2. Does severe hypoglycemia affect nonfatal CVD outcomes in type 2 diabetes?
3. What mediates the relationship between severe hypoglycemia and mortality risk? If this relationship is a marker of “vulnerability,” what factors underlie such vulnerability?
4. What is the significance of hypoglycemia-induced changes in oxidative stress, clotting, and inflammation?
5. Why do older patients with type 2 diabetes have a blunted counterregulatory response and reduced symptoms of hypoglycemia?
6. What is the true relationship between mortality risk for older patients with diabetes and the A1C level?
7. What are the mechanisms underlying non-CVD mortality in patients with diabetes, and how do they relate to mechanisms underlying other complications? How does the pathologic basis of diabetic kidney disease compare with that for other complications?
8. How does the brain drive insulin and glucose metabolism in the periphery?
Screening, diagnosis, and intervention1. Should postload hyperglycemia be used as a screening tool to aid early intervention?
2. What intervention measures can prevent age-related declines in mitochondrial number/function?
3. Does the failure of glucose-lowering interventions to reduce CVD outcomes arise from suboptimal targeting of therapies, particularly in older adults?
4. Is β-cell replacement therapy feasible in older patients?
5. What are the most effective preventive and treatment strategies for CVD? Does prevention of or improvement in vascular dysfunction reduce risk of CVD?
6. Can targeted therapies and prevention approaches be developed to address diabetic dyslipidemia and other risk factors for CVD?
7. What level of blood pressure elevation should be treated in patients with diabetes, what drugs should be used, and by how much should blood pressure be lowered?
8. How important is an aggressive lifestyle intervention in addressing dyslipidemia in patients with diabetes?
9. What are potential beneficial pleiotropic effects of statin therapy in older patients with diabetes, and should statins be used in patients aged older than 80 years with diabetes?
10. Is there age-related cognitive impairment associated with statin therapy?
11. Should triglyceride and HDL cholesterol levels be addressed in older patients with diabetes?
12. What are the best treatment options for diabetic patients with left main or diffuse CAD?
13. What are the best treatment options for diabetic patients who have received PCI and need repeat revascularization?
14. What are the best treatment options for diabetic patients who are at higher risk for adverse outcomes associated with PCI or CABG?
15. How should the presence of diabetic kidney disease affect current clinical management of diabetes?
16. Do novel kidney disease CVD pathways offer new opportunities for intervention?
17. Can diabetic kidney disease be prevented or reversed, and does that alter CVD risk?
18. How clinically effective and safe are lifestyle interventions in older adults?
19. What is the feasibility of lifestyle interventions in real-world settings?
20. Are the effects of lifestyle interventions maintained in the long term, and what mechanisms and behaviors underlie such maintenance?
21. What are the mechanisms of action underlying the effects of weight loss, and how do they differ from those underlying the effects of unintended weight loss and frailty?
22. What are the mechanisms of action for nutraceutical or pharmacological strategies, such as antioxidants, nitric oxide boosters, anti-inflammatory agents, glucose/insulin-regulating or CVD risk-reducing drugs, and modulators of energy-sensing pathways and mitochondrial function?
23. Are there racial and ethnic differences in screening for diabetes and prediabetes?
24. Do differences in cultural beliefs and/or acculturation across minority subgroups have an impact on lifestyle, medication adherence, and outcomes?
25. What targeted interventions could further reduce health inequalities in older patients after broadly effective preventive measures, such as risk factor control and lifestyle changes, already have been applied population-wide?
26. What is the impact of quality-improvement programs and culturally tailored interventions in older adults with diabetes?
27. What other sources of heterogeneity are most important clinically, and how can improved understanding of these sources be used to define and choose new management strategies and set appropriate glucose and cardiovascular targets?
28. Despite the presence of heterogeneity, can crosscutting, appropriate, and high-quality diabetes care be defined?
29. Does the cost-effectiveness of prevention vs. treatment for type 2 diabetes differ by age?