The increase in prevalence of type 2 diabetes mellitus underscores the importance of timely implementation of primary and secondary preventive measures.¹ The 2019 American Diabetes Association (ADA) guidelines highlight the role of clinical characteristics, such as age of onset, duration and complications of diabetes, as the risk-stratifying tools to define treatment goals for the management of patients with diabetes.² A disturbing trend is the increasing frequency of type 2 diabetes diagnosis in young adults with its attendant worse clinical outcomes.³ Findings from a recent paper by Sattar et al. place special emphasis on the role of age of diagnosis of diabetes with respect to the future cardiovascular disease (CVD) risk and life expectancy.³ Using the Swedish National Diabetes Registry, authors included 318,083 patients with diabetes matched with approximately 1.6 million controls. The primary analysis was conducted in a subset of patients with type 2 diabetes mellitus without previous CVD. Over a median follow up of 5.6 years, risk of all-cause mortality (HR = 2.05, 1.81-2.33), CVD mortality (HR = 2.72, 2.13-3.48), non-cardiovascular mortality (HR = 1.95, 1.68-2.25), coronary heart disease (HR = 4.33, 3.82-4.91), acute myocardial infection (HR = 3.41, 2.88-4.04), congestive heart failure (HR = 4.77, 3.86-5.89) and stroke (HR = 3.58, 2.97-4.32) were highest among diabetes patients with the age of diagnosis less than 40 years compared to controls. These risks all attenuated progressively with each decade increase in age of diagnosis, such that among patients older than 80 years old, adjusted hazard ratios for CVD and non-CVD death among patients with diabetes relative to controls were less than one. Therefore, late onset diabetes after 80 years of age did not shorten survival.³

These findings are important and should guide further attention to age-specific diabetes management, as current diabetes guidelines do not have strong recommendations for aggressive management of individuals younger than 40 with respect to more intensive lifestyle and pharmacological management.^2,4,5 For example, the 2019 ADA guidelines recommend moderate-intensity statin for patients with diabetes who have additional risk factors for atherosclerotic CVD (Class C recommendation).² The 2016 European guidelines recommend statin treatment for all patients with diabetes older than 40 years old (Class I recommendation), and selected patients younger than 40 years old with significantly elevated risk based on the presence of microvascular complications or presence of multiple CV risk factors (Class IIb recommendation).⁵

Worse prognosis and shorter life expectancy associated with earlier age for diagnosis of diabetes supports the importance of timely screening for risk factors associated with development of pre-diabetes and diabetes. The 2019 ADA guidelines place emphasis on the role of obesity and overweight by recommending to screen for pre-diabetes and diabetes among adults of any age with BMI ≥25 kg/m2, or BMI ≥23 kg/m2 for Asian Americans (Class B recommendation).² This is because obesity is a prevalent co-existing diagnosis among patient with diabetes. Since obesity is a mediator of CVD risk factors or events, such as dyslipidemia, hypertension, coronary heart disease, atrial fibrillation and obstructive sleep apnea, management of obesity is not only helpful for prevention of diabetes, but also improves CVD outcomes through other mechanisms. Therefore, obese patients will likely experience added benefit with regard to multiple risk factor control when they pursue weight control at an earlier age. Importantly, Sattar et al. demonstrated that earlier age of diagnosis is associated with higher rate of obesity, such that patients with diabetes younger than 40 years old had a mean BMI of 33.6 ± 7.5 while patients aged 81-90 and >91 had a BMI of 27.3 ± 4.4 and 25.8 ± 4.2, respectively.³ These individuals were more likely to have worse hyperglycemia compared to older individuals.⁶ Mean A_1c level for patients younger than 40 years old was 7.3 ± 3.9 compared to patients aged 81-90 and >91 with an A_1c of 6.9 ± 3.4 and 7.1 ± 3.5, respectively. Therefore, great emphasis should be placed on lifestyle modification regarding weight reduction. Current ADA guidelines suggest that 75 minutes per week of vigorous intensity or interval training may be sufficient for young patients who are physically fit. Otherwise, longer duration of physical activity is recommended in overweight or obese patients with engagement in 150 minutes/week of moderate-to-vigorous intensity aerobic exercise scattered over at least three days, without two consecutive days of having no exercise (Class B recommendation).² Also, in addition to emphasis on weight reduction coupled with a more aggressive exercise regimen, when indicated the options for surgical intervention among morbidly obese patients may be discussed at a younger age to achieve better long-term CVD and non-CVD outcomes.⁷

Patients with pre-diabetes should also be considered at increased risk of atherosclerotic CVD, as pre-diabetes (A_1c, 5.7-6.5) and diabetes (A_1c >6.5%) are within a spectrum of risk. While definition thresholds are useful for universal agreement on initiation of more aggressive lifestyle modification, and initiation of pharmacological treatment for overt diabetes, physicians should not neglect risk for complications among patient who are prone to diabetes but do not carry a formal diagnosis. There is growing evidence that patients with pre-diabetes may experience early forms of complications such as nephropathy, neuropathy, retinopathy and increased risk of macrovascular disease.⁸ This may justify initiation of pharmacological treatments, such as metformin or statin, at an earlier age, before the emergence of full-blown diabetes later in life.^8-9

Importantly, there is heterogeneity in coronary heart disease risk among patient with diabetes,¹⁰ so all patients with diabetes should not be treated equally aggressive with respect to preventive strategies.¹⁰ Subclinical markers of atherosclerosis may help identify patients younger than 40 who may benefit from slowing the process of atherosclerosis in order to prevent or postpone the occurrence of evident clinical CVD later in life. The 2018 American College of Cardiology/American Heart Association multi-society guideline for blood cholesterol management recommends diabetes-specific risk enhancers independent of other risk factors in diabetes. These risk enhancers may justify initiating moderate-intensity statins for patients with diabetes with age of 20-39 years old (Class IIb, Level of evidence C) (Table). Although there is extensive data suggesting the role of inflammation in type 2 diabetes, the role of inflammatory biomarkers for risk stratification or early identification of patients with diabetes remains to be further investigated.¹¹

Table

Long duration of diabetes ((≥10 years for type 2 diabetes) and ≥20 years for type 1 diabetes

Albuminuria ≥30 mcg of albumin/mg creatinine

eGFR <60 mL/min/1.73 m2

Retinopathy

Neuropathy

ABI <0.9

Coronary artery calcium (CAC) has already been shown to be promising for risk stratification of coronary heart disease in cohorts with age greater than 40 years old.¹² Data is limited on the utility of CAC scoring among young individuals due to the presence of non-calcified plaques that may not be visualized on cardiac-gated CT scans. One study including 3,723 asymptomatic individuals younger than 40 years old showed that CAC is almost two-fold more prevalent among those with diabetes than non-diabetic individuals (43% vs. 24%).¹³ High prevalence of CAC among patients with diabetes may provide opportunities for risk stratification, as it shows significant subclinical atherosclerosis. Young patients with CAC may benefit from initiation or intensification of statin treatment. On the other hand, absence of CAC has been associated with low risk of coronary heart disease after 5 years, but the risk of death increases significantly after this period. Therefore, aggressive lifestyle and pharmacologic strategies should be pursued following physician-patient risk discussion in the presence of risk enhancers among younger patient despite a CAC of zero.

In summary, age of diagnosis plays a critical role for risk stratification of patients with diabetes. This may have an important message for clinicians and policy makers. Optimal management of risk factors coupled with more strict treatment targets should be emphasized in younger patients with diabetes, especially with the presence of risk enhancers that suggest early microvascular disease or subclinical atherosclerosis. On the contrary, less aggressive preventive measures and potentially de-escalation of treatment should be recommended for older patients with diabetes.

References

1. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA 2015;314:1021-9.
2. American Diabetes Association. Obesity management for the treatment of type 2 diabetes: standards of medical care in diabetes-2019. Diabetes Care 2019;42:S81-9.
3. Sattar N, Rawshani A, Franzen S, et al. Age at diagnosis of type 2 diabetes mellitus and associations with cardiovascular and mortality risks. Circulation 2019;139:2228-37.
4. JBS3 Board. Joint British Societies' consensus recommendations for the prevention of cardiovascular disesase (JBS3). Heart 2014;100:ii1-67.
5. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clincial practice: the sixth joint task force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practcie (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Preventino & Rehabilityation (EACPR). Eur Heart J 2016;37:2315-81.
6. Steinarsson AO, Rawshani A, Gudbjornsdottir S, Franzen S, Svensson AM, Sattar N. Short-term progression of cardiometabolic risk factors in releation to age at type 2 diabetes diagnosis: a longitudinal observational study of 100,606 individuals from the Swedish National Diabetes Register. Diabetologia 2018;61:599-606.
7. Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683-93.
8. Tabak AG, Herder C, Rathmann W, Brunner EJ, Kivimaki M. Prediabetes: a high-risk state for diabetes development. Lancet 2012;379:2279-90.
9. Hostalek U, Gwilt M, Hildemann S. Therapeutic use of metformin in prediabetes and diabetes prevention. Drugs 2015;75:1071-94.
10. Bulugahapitiya U, Siyambalapitiya S, Sithole J, Idris I. Is diabetes a coronary risk equivalent? Systematic review and meta-analysis. Diabet Met 2009;26:142-8.
11. Tsalamandris S, Antonopoulos AS, Oikonomou E, et al. The role of inflammation in diabetes: current concepts and future perspectives. Eur Cardiol 2019;14:50-9.
12. Polonsky TS, McClelland RL, Jorgensen NW, et al. Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA 2010;303:1610-6.
13. Daga N, Nasir K, Hamirani Y, et al. Prevalence and severity of coronary artery calcium in young persons with diabetes. J Cardiovasc Computed Tomogr 2013;7:241-7.

Keywords: Diabetes Mellitus, Diabetes Mellitus, Type 2, Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Weight Loss, Albuminuria, Atrial Fibrillation, Creatinine, Hemoglobin A, Prevalence, American Heart Association, Diabetes Mellitus, Type 1, Ankle Brachial Index, Glomerular Filtration Rate, Metformin, Life Expectancy, Asian Americans, Coronary Vessels, Body Mass Index, Follow-Up Studies, Obesity, Morbid, Prediabetic State, Stroke, Coronary Disease, Life Style, Hyperglycemia, Dyslipidemias, Atherosclerosis, Hypertension, Sleep Apnea, Obstructive, Registries, Inflammation, Heart Failure, Diabetes Complications, Prognosis, Cholesterol, Albumins, Tomography, X-Ray Computed

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