The incidence and prevalence of diabetes mellitus (DM) continues to rise globally, with 463 million adults worldwide currently living with DM.¹ In the United States (US), every one in ten individuals have DM and approximately 1.5 million new cases are diagnosed annually.² Patients with type 2 diabetes mellitus (T2DM) might remain undiagnosed for over 10 years, thus both functional and structural damages caused by hyperglycemia will contribute to the development of macro and/or microvascular complications.³ As a result, T2DM patients often have comorbidities with unexpected health burden when diagnosed. Over the past few decades, there have been emerging efforts on early DM detection in the US.⁴ Strategies include screening for asymptomatic high-risk adults, reducing the diagnostic threshold of fasting glucose level from 140 mg/dL to 126 mg/dL, and adding hemoglobin A1c (HbA1c) >=6.5% as the new diagnostic criterion for DM. These revisions have potentially reduced the time between disease onset and clinical diagnosis.

A recent study by Fang and Selvin⁵ has extensively described the trend of complications in US adults with newly diagnosed T2DM over the last 30 years. From 1988 to 2018, there were significant decreases in prevalent albuminuria as well as improvements in glycemic, blood pressure (BP), and lipid control, but with the burden of other major complications remained relatively high. Approximately 26% newly diagnosed T2DM patients have chronic kidney disease (CKD), 24% have lower-extremity disease, 12% have retinopathy, 17% have a history of cardiovascular disease (CVD), with no significant change of the prevalence over years. These complications are more likely to occur among older, lower income, less educated and obese patients at the time of their diagnosis. The study is unique given its national representative sample from National Health and Nutrition Examination Survey (NHANES) with rigorous and consistent clinical measurement across decades. However, these numbers should also be viewed with caution as the quality of assessment tools have improved over years and CVD complications solely relied on self-report. Certain complications have limited sample size, thus small changes of prevalence over time might not be detected. Lastly, the cross-sectional design of NHANES precludes determining the temporality of any association.

Among T2DM patients, hyperglycemia may affect particular cell types such as mesangial cells in the renal glomerulus, neurons and Schwann cells in the peripheral nerves, and capillary endothelial cells in the retina.⁶ Thus, nephropathy, neuropathy and retinopathy are the most common microvascular complications affecting one-fourth of newly diagnosed T2DM patients.⁵ The current evidence supports a direct relationship between BP and glycemic control and progression of microvascular complications.⁷ However, controversy exists regarding the independent role of dyslipidemia on these outcomes. The study from Fang and Selvin showed a significantly improved lipid profile over time; however, meta-analysis of studies examining the contribution of serum lipids to the risk of diabetic microvascular events confirmed limited association in between.⁸ Statin therapy, targeting elevated levels of low-density lipoprotein cholesterol (LDL-C), significantly reduces the risk of new-onset foot ulcers,⁹ macular edema,¹⁰ albuminuria and urinary albumin excretion rate,¹¹ despite its role in macrovascular risk reduction. But it remains unclear whether the beneficial effects of these therapies are the result of a pleiotropic action of the drug, independent of its lipid-lowering effect.

Intensive risk factor control may have legacy effects in the long-term which highlights the importance of early intervention.¹² Meta-analysis among several randomized controlled trials over the last 2 decades have suggested the sufficient benefits from intensive glycemic management on both microvascular¹³ and macrovascular outcomes.¹⁴ With improved clinical risk factor control over years, however, the prevalence of CVD has stayed relatively high without significant change in trend. The concept of composite risk factor control is usually under-appreciated. In Fang & Selvin's study, composite risk factor control of HbA1c, BP, and total cholesterol (TC) was shown to have increased from 9.4% to 33.0% among newly diagnosed T2DM over the last 3 decades. Notably, this is higher than previously reported composite risk factor control in general T2DM patients of only 15%.¹⁵ Although further studies are needed to evaluate the efficacy of early intervention of multiple risk factors on DM complications, a pooled analysis of community-based cohorts showed that being at target control for all three major factors, BP, LDL-C, and HbA1c was associated with 62% lower risk of CVD events among general DM patients.¹⁶ Therefore, composite risk factor control needs to be further emphasized for macrovascular event prevention in practice.

Improvement of glycemic control may be partially due to the increased prescription of anti-diabetes drugs (ADD) in clinical visits. Over the last decade, prescription of first-line therapy of metformin has increased from 60% to 77%, and about half of T2DM patients initiate a second ADD with undesired HbA1c control.¹⁷ The prescription rate was noted to be slightly lower (60.2% to 65.3%) among newly diagnosed T2DM patients based on Fang & Selvin's study and remains unchanged over recent years. The VERIFY clinical trial suggested initial combination therapy is superior to sequential addition of medications for durable long-term benefits compared with the current standard-of-care benefits of initial metformin monotherapy for newly diagnosed T2DM patients.¹⁸ Novel ADD therapy,¹⁹ including sodium-glucose cotransporter-2 (SGLT-2) inhibitors, a class of medication that inhibits the reabsorption of glucose thus promoting glucosuria to reduce glycemic level, have shown both macro and microvascular benefits. Empagliflozin showed a 14% relative risk reduction of the composite CVD death, myocardial infarction (MI), and stroke among T2DM patients, and dapagliflozin has shown a 27% relative risk reduction in hospitalization for heart failure with improved peripheral microvascular endothelial function. Incretin-based therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with a small delay for the need of insulin initiation and have macrovascular benefits. The LEADER trial has shown a 13% relative risk reduction of major adverse cardiovascular events from liraglutide, and a higher risk reduction of 26% was observed from semaglutide from the SUSTAIN-6 trial. The updated American Diabetes Association (ADA) guideline has recommended SGLT-2 inhibitors or GLP-1RA therapy as part of the glucose-lowering regimen that should be considered irrespective of HbA1c goals among T2DM patients with established or at high risk of ASCVD.²⁰

In conclusion, Fang and Selvin's study has found a significant decrease in prevalent albuminuria with other complications remaining stable and relatively high among newly diagnosed T2DM patients over the last few decades. Intensive combination treatment as well as novel ADD should be advocated for primary and secondary prevention in clinical practice.

References

1. IDF Diabetes Atlas 9th Edition 2019 (Diabetes Atlas website). 2019. Available at: www.diabetesatlas.org. Accessed 09/01/2021.
2. National Diabetes Statistics Report, 2020 (CDC website). 2020. Available at: https://www.cdc.gov/diabetes/data/statistics-report/index.html. Accessed 09/01/2021.
3. Bonora E, Trombetta M, Dauriz M, et al. Chronic complications in patients with newly diagnosed type 2 diabetes: prevalence and related metabolic and clinical features: the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 9. BMJ Open Diabetes Res Care 2020;Aug 1:[Epub ahead of print].
4. Selvin E, Ali MK. Declines in the incidence of diabetes in the U.S. -- real progress or artifact? Diabetes Care 2017;40:1139–43.
5. Fang M, Selvin E. Thirty-year trends in complications in US adults with newly diagnosed type 2 diabetes. Diabetes Care 2021;44:699-706.
6. Rajchgot T, Thomas SC, Wang JC, et al. Neurons and microglia; a sickly-sweet duo in diabetic pain neuropathy. Front Neurosci 2019;13:25.
7. Khalil H. Diabetes microvascular complications—a clinical update. Diabetes Metab Syndr 2017;11:S133-39.
8. Zhou Y, Wang C, Shi K, Yin X. Relationship between dyslipidemia and diabetic retinopathy: a systematic review and meta-analysis. Medicine (Baltimore) 2018;97:e12283.
9. Kang EYC, Chen TH, Garg SJ, et al. Association of statin therapy with prevention of vision-threatening diabetic retinopathy. JAMA Ophthalmol 2019;137:363-71.
10. Chung YR, Park SW, Choi SY, et al. Association of statin use and hypertriglyceridemia with diabetic macular edema in patients with type 2 diabetes and diabetic retinopathy. Cardiovasc Diabetol 2017;16:4.
11. Shen X, Zhang Z, Zhang X, et al. Efficacy of statins in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials. Lipids Health Dis 2016;15:179.
12. Laiteerapong N, Ham SA, Gao Y, et al. The legacy effect in type 2 diabetes: impact of early glycemic control on future complications (the Diabetes & Aging Study). Diabetes Care 2019;42:416-26.
13. Zoungas S, Arima H, Gerstein HC, et al. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomized controlled trials. Lancet Diabetes Endocrinol 2017;5:431-37.
14. Fang HJ, Zhou YH, Tian YJ, Du HY, Sun YX, Zhong LY. Effects of intensive glucose lowering in treatment of type 2 diabetes mellitus on cardiovascular outcomes: a meta-analysis of data from 58,160 patients in 13 randomized controlled trials. Int J Cardiol 2016;218:50-58.
15. Fan W, Song Y, Inzucchi SE, et al. Composite cardiovascular risk factor target achievement and its predictors in US adults with diabetes: The Diabetes Collaborative Registry. Diabetes Obes Metab 2019;21:1121-27.
16. Wong ND, Zhao Y, Patel R, et al. Cardiovascular risk factor targets and cardiovascular disease event risk in diabetes: a pooling project of the Atherosclerosis Risk in Communities Study, Multi-Ethnic Study of Atherosclerosis, and Jackson Heart Study. Diabetes Care 2016;39:668-76.
17. Montvida O, Shaw J, Atherton JJ, Stringer F, Paul SK. Long-term trends in antidiabetes drug usage in the US: real-world evidence in patients newly diagnosed with type 2 diabetes. Diabetes Care 2018;41:69-78.
18. Matthews DR, Paldánius PM, Proot P, et al. Glycemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicenter, randomized, double-blind trial. Lancet 2019;394:1519-29.
19. Scheen AJ. Cardiovascular outcome studies in type 2 diabetes: comparison between SGLT2 inhibitors and GLP-1 receptor agonists. Diabetes Res Clin Pract 2018;143:88-100.
20. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2021. Diabetes Care 2021;44:S111-24.

Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Diet

Keywords: Sodium-Glucose Transporter 2 Inhibitors, Glycated Hemoglobin A, Cholesterol, LDL, Liraglutide, Incretins, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Nutrition Surveys, Glucagon-Like Peptide-1 Receptor, Diabetes Mellitus, Type 2, Insulin, Incidence, Metformin, Secondary Prevention, Albuminuria, Prevalence, Blood Pressure, Cardiovascular Diseases, Cross-Sectional Studies, Glucose, Mesangial Cells, Endothelial Cells, Macular Edema, Diabetic Foot, Glycemic Control, Fasting, Sample Size, Standard of Care, Hyperglycemia, Dyslipidemias, Risk Factors, Heart Failure, Obesity, Pharmaceutical Preparations, Stroke, Risk Reduction Behavior, Myocardial Infarction, Hospitalization, Renal Insufficiency, Chronic, Schwann Cells, Peripheral Nerves, Prescriptions, Lower Extremity, Neurons, Retina, Albumins

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