Older adults with type 2 diabetes mellitus are a large, heterogeneous and growing population who are at high risk for adverse cardiovascular events.¹ Unfortunately, there is a paucity of randomized control data on cardiovascular outcomes in patients with diabetes who are over the age of 80. Mean age of participants in the three major relevant trials, VADT (Veterans Affairs Diabetes Trial), ACORRD (Action to Control Cardiovascular Risk in Diabetes) and ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), were 60, 62 and 66 years respectively.^2-4 The ASCVD risk calculator, which helps clinicians make decisions about prescribing statins and aspirin based on a patient's cardiovascular risk factors, including diabetes, is based on a pooled cohort analysis from five studies of patients aged 40-79.⁵ Therefore caring for patients over age 80 requires an individualized rather than guideline driven approach.⁶ Choosing Wisely, a collective initiative of multiple professional societies that focuses on reducing medical tests and treatment that may be harmful or of marginal medical value, supports this patient-based approach.

In many older patients, the risks of over-treating diabetes outweigh the benefits. The American Geriatrics Society recommends a goal a1c of 7.5-8% in older patients with moderate comorbidities and life expectancy less than 10 years;⁷ the American Diabetes Association recommends a more relaxed goal of 8-8.5% for older patients with complex medical issues.¹ These recommendations are supported by evidence that low a1c targets did not reduce risk of macrovascular complications in VADT, ADVANCE and ACCORD.^2-4 In fact, strict glycemic control increased cardiovascular events in patients who experienced hypoglycemic episodes. Secondary analysis of ADVANCE data found that participants with severe hypoglycemic episodes had significantly higher adjusted risk of major cardiovascular events and death from major cardiovascular events.¹⁰ This is explained by the pathophysiology of hypoglycemia in patients with underlying cardiovascular disease, in whom low blood glucose and the resultant catecholamine surge can induce cardiac arrhythmias, contribute to sudden cardiac death, and cause ischemic cerebral damage.^8,9

According to US Veterans Affairs data, risk factors for hypoglycemia are present in as many as 50% of older patients being treated for diabetes.¹¹ Risk factors for hypoglycemia include advanced age, renal impairment, memory problems and sulfonylurea use. In ADVANCE participants, advanced age was an independent risk factor for severe hypoglycemic episodes.³ Similarly, ACCORD subjects who screened positive for memory problems were at high risk for hypoglycemia.⁴ In retrospective studies of emergency room visits, older patients taking sulfonylureas were at twice the risk of hypoglycemia,¹² and CKD further increases this risk.¹³ Additionally, severe hypoglycemic episodes be associated with increased risk of dementia.¹⁴

Despite these risks, glycemic control should not be completely abandoned in older patients. Better glucose control in the elderly has been associated with improvement in cognitive functioning and lower mortality following myocardial infarction.^15,16 Metformin is the American Diabetes Association's recommended first line agent based on efficacy and side effect profile.¹ Metformin decreases insulin resistance, decreases gut resorption of glucose, inhibits hepatic gluconeogenesis, reduces weight gain, and has been associated with decreased blood pressure and plasma lipid levels. Additionally, metformin is safe in the elderly and may even increase longevity based on evidence from animal models.¹⁷ Metformin's major adverse effect is a type B lactic acidosis that may develop at the upper therapeutic limit. This risk is higher in patients with low GFR, limiting use of the drug in older people. Current US Food and Drug Administration guidelines contraindicate metformin at GFR <30 and do not recommend initiating the drug at GFR between 30-45.¹⁸ However, for patients tolerating the drug who experience a drop in GFR, new guidelines state reduced renal dosing is a safe option.¹⁹ Additionally, risk of type B lactic acidosis increases when the body's metabolic demands are high. Some nephrologists suggest that temporarily stopping metformin during "sick days" would mitigate this problem, however randomized control trials are needed.²⁰

If renally-dosed Metformin does not provide adequate control, a second agent may be necessary. The American Diabetes Association recommends adding a second oral anti-hyperglycemic agent if a1c is not at goal after 3 months of monotherapy. The choice of second agent should be based on an individual patient's co-morbidities; no single choice is favorable. Long acting sulfonylureas are contraindicated in the elderly, short acting sulfonylureas should avoided in those at risk for hypoglycemia, and thiazolidinediones should be avoided in patients with heart failure.²¹ Evidence from the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) and GLP1 RA trials suggests that SGLT-2 inhibitors may decrease risk of all-cause mortality, cardiovascular events and hospitalization for heart failure in diabetic patients with established cardiovascular disease.^22,23 However, older patients were largely under-represented in these trials, and the associated increased risk of urinary tract infections presents a major drawback in older adults. Oral dipeptidyl peptidase 4 inhibitors have few side effects and low risk of hypoglycemia, however a systemic review found these medications do not decrease risk of major cardiovascular events.²⁴

In summary, risk factors for hypoglycemia, including renal impairment, memory problems and sulfonylurea use, are common in older patients being treated for diabetes. Hypoglycemia puts patients at risk for adverse cardiovascular events. Individualized a1c targets should be adopted in older adults, with more lenient a1c goals in frail, high risk patients. Metformin is not associated with increased risk of hypoglycemia, and can be continued in patients with GFR >30. More research is needed to establish the risks and benefits of second line agents.

References

1. American Diabetes Association. Improving care and promoting health in populations: standards of medical care in diabetes - 2018. Diabetes Care 2018;41:S7-12.
2. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-39.
3. ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72.
4. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.
5. Goff DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2935-59.
6. Blaum C, Cigolle CT, Boyd C, et al. Clinical complexity in middle-aged and older adults with diabetes: the Health and Retirement Study. Med Care 2010;48:327-34.
7. American Geriatrics Society Expert Panel on Care of Older Adults with Diabetes Mellitus, Moreno G, Mangione CM, Kimbro L, Vaisberg E. Guidelines abstracted from the American Geriatrics Society guidelines for improving the care of older adults with diabetes mellitus: 2013 update. J Am Geriatr Soc 2013;61:2020-6.
8. Snell-Bergeon JK, Wadwa RP. Hypoglycemia, diabetes, and cardiovascular disease. Diabetes Technol Ther 2012;14:S51-8.
9. Launer LJ, Miller ME, Williamson JD, et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol 2011;10:969-77.
10. Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010;363:1410-8.
11. US Department of Veterans Affairs. Quality, Safety & Value for Clinicians. https://www.qualityandsafety.va.gov/ChoosingWiselyHealth-SafetyInitiative/HypoglycemiaSite/For_Clinicians.asp. Accessed Feb 1 2018.
12. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011;365:2002-12.
13. Moen MF, Zhan M, Hsu VD, et al. Frequency of hypoglycemia and its significance in chronic kidney disease. Clin J Am Soc Nephrol 2009;4:1121-7.
14. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 2009;301:1565-72.
15. Yaffe K, Falvey C, Hamilton N, et al. Diabetes, glucose control, and 9-year cognitive decline among older adults without dementia. Arch Neurol 2012;69:1170-5.
16. Kosiborod M, Rathore SS, Inzucchi SE, et al. Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes. Circulation 2005;111:3078-86.
17. Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun 2013;4:2192.
18. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011;34:1431-7.
19. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA 2014;312:2668-75.
20. Heaf J. Metformin in chronic kidney disease: time for a rethink. Perit Dial Int 2014;34:353-7.
21. American Diabetes Association. Standards of medical care in diabetes - 2016 abridged for primary care providers. Clin Diabets 2016;34:3-21.
22. Zinman B, Wanner C, Lachin JM, et al. Empaglifloxin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
23. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
24. Rotz ME, Ganetsky VS, Sen S, Thomas TF. Implications of incretin-based therapies on cardiovascular disease. Int J Clin Pract 2015;69:531-49.

Keywords: Blood Glucose, Diabetes Mellitus, Type 2, Diabetes Mellitus, Thiazolidinediones, Gliclazide, Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Metformin, Glycated Hemoglobin A, Insulin Resistance, Acidosis, Lactic, Cardiovascular Diseases, Weight Gain, Aspirin, Geriatrics, Blood Pressure, Hypoglycemia, Glucosides, Benzhydryl Compounds, Perindopril, Myocardial Infarction, Heart Failure, Arrhythmias, Cardiac, Vascular Diseases, Lipids, Renal Insufficiency, Chronic, Metabolic Syndrome

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