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 Table of Contents  
REVIEW
Year : 2019  |  Volume : 4  |  Issue : 4  |  Page : 101-103

Management of type 2 diabetes mellitus in the elderly population with cardiovascular diseases


1 Medical University of South Carolina, Charleston; AnMed Health, Anderson, SC; Edward Via College of Osteopathic Medicine (VCOM), Blacksburg, VA, USA
2 Medical University of South Carolina, Charleston; AnMed Health, Anderson, SC, USA

Date of Submission02-Dec-2019
Date of Decision03-Dec-2019
Date of Acceptance27-Dec-2019
Date of Web Publication13-Jan-2020

Correspondence Address:
Ravi Kant
Medical University of South Carolina, Charleston; AnMed Health, Anderson, SC; Edward Via College of Osteopathic Medicine (VCOM), Blacksburg, VA
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-3975.274079

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  Abstract 


Addressing the glycemic control of the elderly patients with type 2 diabetes mellitus (T2DM) requires creating an individualized plan for each patient due to the heterogeneity among this population. The personalized plan should address topics such as comorbidities, polypharmacy, and cost of medications. One of the major comorbidities that necessitate consideration is cardiovascular disease (CVD), which makes it essential for clinicians to stay updated with literature on cardiovascular safety of diabetes medications. Metformin, along with dietary changes and adequate exercise, should be the first line treatment for patients with T2DM. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors should be considered for add-on therapy for elderly patients with CVD whom do not reach their hemoglobin A1c goal on metformin alone. All drugs in these two categories have been shown to be safe in patients with CVD and most of them have shown to reduce adverse cardiovascular events. Sulfonylureas should be used cautiously in elderly due to their high risk of hypoglycemia. Thiazolidinediones, saxagliptin and alogliptin should be avoided in patients with heart failure. With the high rate of major adverse cardiovascular events in elderly population, it is imperative to consider cardiovascular safety and efficacy of non-insulin diabetes medications in formulating management plan for elderly patients with concurrent T2DM and CVD.

Keywords: cardiovascular disease; elderly; glucagon-like peptide-1 receptor agonists; heart failure; newer diabetes medications; sodium-glucose cotransporter-2 inhibitors; type 2 diabetes mellitus


How to cite this article:
Kant R, Gilreath NA, Verma V. Management of type 2 diabetes mellitus in the elderly population with cardiovascular diseases. Clin Trials Degener Dis 2019;4:101-3

How to cite this URL:
Kant R, Gilreath NA, Verma V. Management of type 2 diabetes mellitus in the elderly population with cardiovascular diseases. Clin Trials Degener Dis [serial online] 2019 [cited 2020 Jan 18];4:101-3. Available from: http://www.clinicaltdd.com/text.asp?2019/4/4/101/274079




  Introduction Top


Patients over the age of 65 years, classically referred to as the elderly or geriatric population, represent the fastest growing population in the United States. This population also has the highest prevalence of diabetes among any age group, with 1 out of 4 patients classified as diabetic.[1] Addressing the glycemic control of the elderly population requires creating an individualized plan for each patient due to the heterogeneity among this population. The personalized plan should address topics such as comorbidities, polypharmacy, and cost of medications. One of the major comorbidities that necessitate consideration is cardiovascular disease (CVD). The American Heart Association reports at least 68% of diabetic patients over the age of 65 years die due to some form of heart disease and an additional 16% die due to stroke.[2] Recently, multiple studies have been conducted to observe cardiovascular risks and benefits of various glycemic agents.[3],[4],[5],[6],[7],[8],[9],[10],[11] It is vital to recognize the impact of such results when developing an individualized plan for an elderly patient with concurrent type 2 diabetes mellitus (T2DM) and CVD. This article reviews the cardiovascular safety and efficacy of non-insulin diabetes medications with particular focus on glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors.


  Database Search Strategy Top


An electronic search of the Medline database for literature on cardiovascular outcome trials of diabetes medications was completed. This included publications prior to September, 2019. The results were further screened by title and abstract to include only original studies and meta-analysis, and exclude animal studies. In addition, the authors searched the PubMed and Google scholar database to identify publications on management of T2DM in elderly population. English language and full-text articles published between January 2001 and September 2019 were included in this non-systematic review. The authors screened the reference list of included studies to identify potentially useful studies.


  Glycemic Goals in Elderly Patients Top


Developing an individualized treatment plan for an elderly patient with both diabetes and CVD must take into consideration that low hemoglobin A1c (HbA1c) targets have not been found to reduce the risk of macrovascular complications in this population.[12] In fact, one of the primary goals of treating diabetes in this population should be avoiding hypoglycemia, as patients who experienced hypoglycemic events were found to have a significantly higher risk of acute cardiovascular events, odds ratio = 1.79.[13] Currently, the American Geriatrics Society recommends an HbA1c goal of 7.5–8% in older patients with moderate comorbidities and a life expectancy less than 10 years.[14] In patients with more complex medical issues, the American Diabetes Association recommends an HbA1c goal of 8–8.5%.[15]


  Metformin Top


Metformin, along with dietary changes and adequate exercise, should be the first line treatment for patients with T2DM.[16] Metformin reduces glucose production by the liver and increases insulin sensitivity in peripheral tissues. There has been no evidence to suggest that metformin is unsafe in patients with concurrent CVD. In fact, metformin monotherapy in obese patients with new diagnosis of T2DM was associated with 36% reduction in all-cause mortality.[17] Patients with reduced renal function may require special consideration before beginning metformin.[16] Currently, the US Food and Drug Administration lists an estimated glomerular filtration rate (eGFR) < 30 mL/min as a direct contraindication to the continuing metformin usage. Patients may encounter dose limitations to metformin due to dose-dependent nausea and diarrhea.


  Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors Top


GLP-1RA and SGLT-2 inhibitors should be considered for add-on therapy for elderly patients with CVD whom do not reach their HbA1c goal on metformin alone.[16] All drugs in these two categories have been shown to be safe in patients with CVD and most of them have shown to reduce adverse cardiovascular events.[18] Several studies[3],[4],[5],[6],[7],[8],[9],[10],[11] have been conducted to observe the effects of these agents on the rate of major adverse cardiac events (MACE). MACE encompasses death from cardiovascular causes, nonfatal myocardial infarctions, and nonfatal strokes. Large cardiovascular (CV) outcome trials studying CV efficacy of GLP-1 RAs and SGLT-2 inhibitors have shown that glycemic agents in these categories may not have equivalent effects on CVD.[3],[4],[5],[6],[8],[9],[10] However, it is important to note that heterogeneity of CV efficacy could be due to differences in study design and no drug could be deemed superior to another agent in the same class due to lack of head to head randomized controlled trials.

Currently, the most beneficial GLP-1 RA in patients with concurrent T2DM and CVD has been found to be semaglutide, which was correlated to a 26% reduction of MACE, a 39% reduction in nonfatal stroke, and a 26% reduction in nonfatal myocardial infarction.[18] Liraglutide and exenatide were found to have a slightly lower decrease in MACE at 13% and 9% respectively. Interestingly, lixisenatide has not been found to significantly decrease the rate of MACE in patients with T2DM and recent MI or hospitalization for unstable angina.[18] Similar to the GLP-1 RA, the SGLT-2 inhibitors, empagliflozin and canagliflozin were found to decrease MACE by 14%, whereas dapagliflozin did not show a statistically significant decrease in MACE. These three SGLT-2 inhibitors were also found to significantly decrease hospital admissions due to heart failure by 27–35%.[18] In fact, US FDA has recently approved dapagliflozin to reduce the risk of hospitalization for heart failure in adult patients with T2DM and established CVD or multiple CV risk factors. These two classes of drugs have objectively shown to be beneficial to patients with T2DM and CVD.[18] When deciding which agent to use, it is important to remember that GLP-1 RA is not suitable for patients with cachexia and may cause nausea, diarrhea, and weight loss. In addition, SGLT-2 inhibitors have been linked to urinary tract and genital infections, an increase in the rates of diabetic ketoacidosis, and is less effective in reduced renal function (eGFR < 60 mL/min).[1]


  Other Hypoglycemic Agents Top


Dipeptidyl peptidase 4 inhibitors are an alternative to GLP-1 RA. These drugs are valuable as they similarly have no risk of hypoglycemia and have minimal interactions with other medications.[16] Several studies have raised the concern that saxagliptin and alogliptin may slightly increase the risk of heart failure.[5],[19],[20],[21]

Thiazolidinediones increase peripheral insulin sensitivity and decrease glucose production by the liver.[16] Pioglitazone, an agent of the thiazolidinedione class, is one of the few agents that can be used in patients with a severely reduced eGFR.[16] This is beneficial as DDP4 inhibitors, metformin, and SGLT-2 inhibitors are limited by renal function. Pioglitazone has also been found to reduce the risk of MACE and hepatic steatohepatitis.[16],[22] In patients with congestive heart failure, thiazolidinediones should be avoided.[23] Lastly, pioglitazone has been found to increase the risk of non-osteoporosis bone fractures and should be used cautiously in patients with fall risk.[24]

Sulfonylureas act by inducing insulin secretion in pancreatic B-cells.[16] As the oldest oral hypoglycemic prescription, these agents have been particularly effective at reducing the microvascular effects of diabetes; however these agents should be avoided due to their high risk of hypoglycemia.[16] A study looking at Medicare patients over the age of 65 years found the incidence of serious hypoglycemia was 1.23 episodes per 100 person-years for patients treated with sulfonylureas.[25] In addition, sulfonylureas have been linked to an increased risk of adverse CV events and mortality.[26]


  Conclusion Top


The elderly population with T2DM requires a personalized regimen when controlling their blood sugar. Topics such as polypharmacy, comorbidities, and cost of medications must be addressed. With the high rate of major adverse cardiovascular events in this population, it is imperative to consider CV risks and benefits of glycemic agents. We recommend the use of metformin as a first line agent and either a SGLT-2 inhibitor or GLP-1 RA for add-on therapy if HbA1c goals are not met on metformin alone. Specific therapies in these categories should be chosen based upon the patient’s comorbidities and proven superiority in reducing MACE.

Author contributions

RK designed the outline, reviewed the literature and performed the writing. NAG performed the writing and reviewed the literature. VV provided the input in writing the paper, reviewed the literature and edited the paper. All authors approved the final version of the manuscript.

Conflicts of interest

None declared.

Financial support

No financial support was received for writing this article.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

C-Editor: Zhao M; S-Editor: Li CH; L-Editors: Qiu Y, Wang L; T-Editor: Jia Y



 
  References Top

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Sesti G, Antonelli Incalzi R, Bonora E, et al. Management of diabetes in older adults. Nutr Metab Cardiovasc Dis. 2018;28:206-218.  Back to cited text no. 1
    
2.
Cardiovascular Disease and Diabetes. https://www.heart.org/en/health-topics/diabetes/why-diabetes-matters/cardiovascular-disease–diabetes. Accessed December 1, 2019.  Back to cited text no. 2
    
3.
Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015; 373: 2247-2257.  Back to cited text no. 3
    
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Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-322.  Back to cited text no. 4
    
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Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-1844.  Back to cited text no. 5
    
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Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228-1239.  Back to cited text no. 6
    
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Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018;6:105-113.  Back to cited text no. 7
    
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Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.  Back to cited text no. 8
    
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Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657.  Back to cited text no. 9
    
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Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380: 347-357  Back to cited text no. 10
    
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Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393:31-39.  Back to cited text no. 11
    
12.
Wilcox T, Blaum C, Newman JD. Diabetes management in older adults with cardiovascular disease. american college of cardiology. https://www.acc.org/latest-in-cardiology/articles/2018/02/28/12/19/diabetes-management-in-older-adults-with-cvd. Accessed December 1, 2019.  Back to cited text no. 12
    
13.
Johnston SS, Conner C, Aagren M, Smith DM, Bouchard J, Brett J. Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes. Diabetes Care. 2011;34:1164-1170.  Back to cited text no. 13
    
14.
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;61:2020-2026.  Back to cited text no. 14
    
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American Diabetes Association. Improving care and promoting health in populations: standards of medical care in diabetes - 2018. Diabetes Care. 2018;41:S7-12.  Back to cited text no. 15
    
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Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41:2669-2701.  Back to cited text no. 16
    
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UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-865.  Back to cited text no. 17
    
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Kant R, Munir KM, Kaur A, Verma V. Prevention of macrovascular complications in patients with type 2 diabetes mellitus: Review of cardiovascular safety and efficacy of newer diabetes medications. World J Diabetes. 2019;10:324-332.  Back to cited text no. 18
    
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Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326.  Back to cited text no. 19
    
20.
White WB, Cannon CP, Heller SR, et al. EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-1335.  Back to cited text no. 20
    
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Verma S, Goldenberg RM, Bhatt DL, et al. Dipeptidyl peptidase-4 inhibitors and the risk of heart failure: a systematic review and meta-analysis. CMAJ Open. 2017;5:E152-177.  Back to cited text no. 21
    
22.
Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005; 366:1279-1289.  Back to cited text no. 22
    
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Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. 2007;370:1129-1136.  Back to cited text no. 23
    
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