Abstract
Context
Identification of CV risk factors from T2DM diagnosis allows optimization of treatment to prevent CV complications and death.
Objective
The primary objective of the study was to describe the CV risk factors in patients with T2DM at the time of diagnosis and/or therapeutic specific measures taken.
Design
This was a non-interventional, multicenter, retrospective chart review of newly diagnosed patients with T2DM in 49 study centers in Romania.
Subjects and Methods
Adults with a diagnosis of T2DM between January - December 2014. Statistical analysis used appropriate descriptive methods.
Results
1218 patients were included, mean age (SD) at diagnosis was 59.16 (10.87) years. Half of the patients (54%) presented obesity and 47.7% of patients had arterial hypertension. Overall, 76.2% of subjects had LDL-cholesterol ≥ 100 mg/dL, and 59.1% had triglycerides ≥ 150 mg/dL. The mean glycemia was 198.8 mg/dL (78.3) and 50.2% of patients had HbA1c ≥7%. Sedentary lifestyle in 73.8% of the cases, and 91.3% unhealthy eating habits reported. In addition to diet, 82.2% of patients received anti-diabetes treatment, 62.6% lipid-lowering, and 66.6% anti-hypertensive medication.
Conclusion
This retrospective study showed a high prevalence of CV risk factors and/or established CV disease at the time of T2DM diagnosis in Romania.
Keywords: Type 2 Diabetes, cardiovascular risk factors, obesity, arterial hypertension, dyslipidemia, HbA1c, insulin resistance
Introduction
Over the last 20 years, basic and translational studies have unraveled a strong biological relation between high glucose levels, impaired insulin signaling and vascular disease in the context of type 2 diabetes mellitus (T2DM) (1). The risk of cardiovascular (CV) complications has been related to chronic hyperglycemia, abnormal lipid profiles, alterations in inflammatory mediators and coagulation parameters, as well as other ‘nontraditional’ risk factors, such as low serum albumin and high plasma fibrinogen, many of which may be closely associated with insulin resistance (2). The combination of multiple CV risk factors and insulin resistance is collectively known as the ‘metabolic syndrome’ (3). The patients with T2DM and increased insulin resistance have a proatherogenic cardiovascular risk profile which includes impaired glucose regulation, abdominal obesity, hypertension, atherogenic dyslipidemia (characterized by increased small low-density lipoprotein particles, elevated levels of triglycerides and low levels of high-density lipoprotein cholesterol), microalbuminuria, and specific changes of endothelial cell and vascular functions (3-5). In addition to atherosclerosis, other complex molecular mechanisms are involved in diabetic microvascular disease, thus contributing to myocardial injury early in the course of diabetes (6). Evidence from a large cohort with T2DM (7) show that heart failure (HF) is one of the most common first CV presentations in this patient population.
T2DM has long been considered a coronary risk equivalent (8). Although this topic is a subject of debate, there is unanimous agreement that strict control of cardiovascular risk factors in such patients reduces the incidence of cardiovascular disease. To prevent or diminish the progression of microvascular and macrovascular complications, diabetes management necessarily encompasses both glycemic control and control of cardiovascular risk factors. Current therapeutic guidelines (9-11) indicate the cardio- and reno-protective medications, sodium-glucose co-transporters 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1 RA), as preferred options in T2DM patients with high CV and/or renal risk, irrespective of glycemic control.
In Romania, the cardiovascular disease is the leading cause of mortality (12), placing it among the European regions with the highest CV risk (13). Prevalence of diabetes and obesity is also increasing, data collected at national level indicating an overall prevalence of 12.41% for diabetes in adult population (14). These evidence combined, it is imperative to emphasize the major goal of preventing and delaying T2DM complications, including CV morbidity and mortality.
Limited data about CV risk in newly diagnosed T2DM patients from Romania are currently available. The purpose of this retrospective study (RISK) was to investigate the overall assessment and treatment of CV risk factors in newly diagnosed T2DM patients in Romania.
Materials and methods
This non-interventional, multicenter, retrospective chart review was carried out in 49 sites throughout Romania. Data were collected from the medical records of newly diagnosed patients with T2DM. Eligible patients were male or female aged at least 18 years with a diagnosis of T2DM made between January 2014 and December 2014. Patients with a diagnosis of type 1 diabetes or gestational diabetes were not included. Also, patients with a diagnosis of T2DM made before the limit set or patients participating in a clinical trial at the time of T2DM diagnosis were excluded.
The primary objective of the study was to describe the CV risk factors in patients with T2DM at the time of diagnosis and/or therapeutic measures taken to specifically address these risk factors. For this purpose, numerous variables have been defined as primary: blood glucose value that prompted the diabetes diagnosis and/or HbA1c value, blood pressure levels, smoking status, cholesterol and/or triglycerides levels, BMI, age, gender, lifestyle, family history of CV disease, presence of CV disease at the time of T2DM diagnosis (either reported by the patients or resulted from their medical records), and management strategies (primary and secondary prevention) to address CV risk factors and/or associated CV disease. Two study populations have been defined: Full Analysis Set (FAS), which included all enrolled and eligible subjects, and Per Protocol Set (PP), which included all enrolled and eligible subjects with non-missing data for primary variables. Descriptive analyses have been performed for all study data, with two-sided, 95% confidence intervals provided for binomial variables (via Wilson score interval for proportion), for multinomial variables (via Glaz-Sison simultaneous confidence interval for proportions) and for continuous variables (via normal approximation for mean or Hahn-Meeker distribution-free confidence interval for median). Statistical tests performed in the analysis were based on Spearman’s rank correlation.
Results
A total of 1218 patients were included in the Full Analysis Set, out of which 572 (47.0%) had no primary variables missing and defined the Per-Protocol population (PP). No major differences were seen between the 2 sets of data. Overall, in the PP population, the mean age (SD) was 59.16 (10.87) years, with 43.7% of patients aged between 45 – 60 years, 39.3% aged 61 – 75 years, 10% < 45 years and 7% > 75 years. A similar distribution of age was observed in FAS population. The gender distribution was almost equal, with 52.4% male subjects in PP population, respectively 51.1 % male subjects in FAS.
Most subjects included in RISK study lived in urban areas (71%), and over half of the patients (58.1%) were retired at the time of T2DM diagnosis, while 34% of patients were employed. Within the whole study population, the diagnosis of T2DM was made following incident laboratory measurements in 65.1% of patients, 32.9% of patients presented with signs and symptoms, and 1.9% with diabetes complications. Other diabetes and cardiovascular disease characteristics within the study population are included in Table 1.
Table 1.
Distribution of patients by family history of diabetes and confirmed diagnosis of hypertension and cardiovascular disease
| Characteristics | |
|---|---|
| Diabetes | 1218 (100) |
| Family history of diabetes, n (%) | |
| Yes | 398 (32.7) |
| Mother | 203 (16.7) |
| Father | 112 (9.2) |
| Sister/brother | 165 (13.5) |
| Other | 8 (0.7) |
| No | 710 (58.3) |
| Unknown | 110 (9.0) |
| Hypertension | 848 (69.6) |
| Angina | 186 (15.3) |
| Myocardial infarction | 53 (4.4) |
| Peripheral artery disease | 47 (3.9) |
| Arrhythmias | 75 (6.2) |
| Heart failure | 84 (6.9) |
| Stroke | 57 (4.7) |
| TIA | 10 (0.8) |
* some patients have associated comorbidities.
Primary objective
We will report the results for the primary objective in the PP population, with all primary variables included.
The average BMI of subjects was 31.23 kg/m2 and half of the patients (54%) had BMI ≥ 30 kg/m2.
The mean systolic blood pressure (SD) was 142.48 (19.43) mmHg, and the mean diastolic blood pressure (SD) was 83.09 (11.13) mmHg. Systolic blood pressure (SBP) >140 mmHg was present in 45.3% of subjects and diastolic blood pressure (DBP) > 90 mmHg in 18.7% of subjects, with 47.7% of patients having a high blood pressure overall (high SBP or high DBP or both).
The majority (61.9%) of patients were non-smokers, but 187 (32.7%) of patients within PP population were either active or former smokers, 17.8% patients were active smokers at the time of T2DM diagnosis, with a mean number of cigarettes per day (SD) of 17.4 (9.7). Formers smokers had a slightly higher mean number of cigarettes per day (SD) of 21.3 (12.6).
For the lipids levels, the mean values (SD) found at the time of T2DM diagnosis in PP population were the following: LDL-cholesterol was 132.87 (43.80) mg/dL, HDL cholesterol was 47.52 (20.44) mg/dL, total cholesterol was 218.51 (56.08) mg/dL, and triglycerides 196.71 (129.58) mg/dL. When the optimal thresholds for moderate or high CV risk have been taken into account (10), the results showed that 94.6% of subjects had LDL-cholesterol ≥ 70 mg/dL at the time of T2DM diagnosis, with 76.2% of subjects having LDL-cholesterol ≥ 100 mg/dL, 40.4% of the subjects had HDL-cholesterol < 40 mg/dL (men), respectively <45 mg/dL (women), and 59.1% of subjects had triglycerides ≥ 150 mg/dL.
In terms of blood glucose value and HbA1c level at the time of the diagnosis, the mean glycemia (SD) that prompted diagnosis was 198.8 mg/dL (78.3), 83.4% of patients had a mean glycemia ≥140 mg/dL. For 366 patients within PP set, a second glycemia value was determined, with a mean value (SD) of 173.6 (63.5) mg/dL. For 407 patients within PP set, HbA1c level was available at the time of T2DM diagnosis, with a mean level of 8.31% (1.94). Half of the patients (50.2%) had HbA1c ≥7% at the time of T2M diagnosis.
The family history of CVD was positive in 170 patients (29.7%), the illness being presented by patients’ mother in most of these cases (for 118 patients [20.6%]), followed by father (for 74 patients [12.9%]) and siblings (for 27 patients [4.7%]). For almost half of the patients (47.7%) the family CVD history was negative, and for 22.6% was not known.
The rate of subjects having sedentary lifestyle at the time of T2DM diagnosis was 73.8%, and for the vast majority (91.3%), the eating habits were considered unhealthy.
Several correlations between the number of cardiovascular risk factors and various parameters have been analyzed and a weak Spearman’s rank correlation was identified, as following: for age, the correlation coefficient was -0.087 (p = 0.0438); for blood glucose level, the correlation coefficient was 0.009 (p = 0.8338, not significant); for HbA1c level, the correlation coefficient was 0.090 (p = 0.0751); for BMI, the correlation coefficient was 0.143 (p = 0.0012). When correlations with the presence of CV disease (CVD), diabetic complications or both were analyzed, only for age was identified a significant, positive correlation, and the correlation coefficients with the presence of CVD, diabetic complications and both were 0.274 (p <.0001), 0.192 (p <.0001) and 0.220 (p <.0001), respectively. For the other parameters, such as blood glucose, HbA1c and BMI, the correlation with the presence of CVD and diabetic complications were weak and/or not significant.
Specific measures taken for diabetes and CVD at the time of T2DM diagnosis
As specific measures taken at the time of T2DM diagnosis within the whole study population (FAS), a diabetes diet was recommended for almost every subject (99.8%). In total, 82.2% of patients received anti-diabetes treatment, and the most common treatments recommended for newly diagnosed T2DM patients were metformin (71.8%), and sulphonylureas (21.8%). Monotherapy was recommended for the vast majority of patients at the time of T2DM diagnosis (774 patients, [63.5%]). Of patients receiving treatment, 75 (6.2%) patients received insulin.
Lipid-lowering treatment was present at the time of T2DM in 763 patients (62.6%), with 403 (33.1%) of patients already receiving this type of treatment before the diagnosis of T2DM. Of them, 348 patients (28.6%) received lipid lowering treatment recommendations at the time of T2DM diagnosis, and 12 (1%) patients were referred to a cardiologist at the moment of T2DM diagnosis. The most common lipid lowering treatments were based on statins (55.7%) and fibrates (14.5%) within the whole study population.
Antihypertensive medication was recommended in 811 patients (66.6%) at the time of T2DM diagnosis, with 708 (58.1%) of patients already receiving antihypertensive treatment before the diagnosis of T2DM. At the time of T2DM diagnosis, 77 patients (6.3%) received antihypertensive treatment recommendations, and 26 (2.1%) patients were referred to a cardiologist in this regard. The most common antihypertensive treatments were based on ACE inhibitors (40.3%), diuretics (37.9%), and calcium-channel blockers (14.4%) within the whole study population. Also, 450 (36.9%) patients had aspirin recommendations at the time of T2DM diagnosis.
The lifestyle changes recommendations included healthy diet (98.5%), exercises at least 30 min/day (89.3%), weight control (86%), reduced alcohol consumption (25.6%) and smoking cessation (17.2%).
When correlations with recommended treatment and the various parameters have been analyzed, all had a very weak Spearman’s rank correlation, except for the following: correlation coefficients of blood glucose and HbA1c with anti-diabetes treatment were 0.193 and 0.481, respectively (p <.0001), and the correlation coefficient of high blood pressure with blood pressure treatment was 0.385 (p <.0001).
Discussion
Due to the heterogeneous nature of the disease, prevalence and pattern of CV risk factors vary among individuals with T2DM and therefore the risk of developing CV events such as coronary artery disease and stroke is also different (15-17). In our study, the mean values of glycemia and HbA1c are high at the moment of diagnosis, suggesting that deterioration of glycemic control occurred long before the moment of diagnosis. Almost all patients diagnosed (90%) were overweight and obese, with a sedentary lifestyle (74.4%) and unhealthy eating (90%). The majority of patients had indicators for increased CV risk (10), with high blood pressure being the most prevalent condition. These results are consistent with other recently published reports from Romania (18,19) showing a high prevalence of overweight and obesity, as well as other CV risk factors not only in T2DM population, but also in overall adult Romanian population.
The complex interaction of risk factors in T2DM carries the need to apply a holistic approach to the management of this chronic disorder, and a comprehensive care that includes treatment of all cardiovascular risk factors. Our results show that at the time of diabetes diagnosis, 31.9% of patients had already at least one diabetic complication, as assessed and indicated by the study investigators. Metformin was the preferred option to initiate pharmacologic treatment for diabetes, as specified by current guidelines. The treatment pattern observed in our study, with metformin in first line followed by add-on of a sulphonylurea should be interpreted in the context of therapeutic recommendations available at the time of data collection (20). In the recent years, results of several cardiovascular outcome trials (CVOTs) in T2D patients have been published (21-25), providing the needed evidence that novel anti-diabetes therapies have an overall favorable effect on CV risk. These results were also proven in large real-world evidence studies, such as CVD-REAL (26), confirming the change of treatment paradigm, with an estimated significant impact in clinical practice. The current ADA/EASD Consensus (9) considers the impact of CV risk factors on T2DM outcomes, as well as the beneficial effects of SGLT2 inhibitors and GLP-1 RA in reducing the risk of CV and/or renal events.
In total, 66.6% of patients had at least 1 antihypertensive medication recommended and a similar percent had at least 1 lipid lowering treatment recommended. These results indicate that the treatment approach of patients with diabetes was very much aligned with the guidelines in use at the time of study (20, 27, 28), with early identification of the potential risk factors, and choosing the necessary therapeutic regimen for their management. These strategies include targeted lifestyle advice, advice to increased physical activity, healthy dietary regimen and early use of statins and antihypertensive drugs as primary prevention drugs in addition to diabetes medication.
A significant, positive correlation was found between the age and the presence of CVD, diabetes complications or both. In a 10-year model based on data from ADDITION-Europe study (29), CV risk estimated declined during time, despite increasing of age and diabetes duration. Therefore, a treatment strategy addressing multiple CV risk factors, early in diabetes evolution might slow CVD progression and improve outcomes.
The present study was a retrospective chart review of newly diagnosed T2DM patients in clinical practice in 2014. Although the study included a high number of patients (n=1218) and given the retrospective design of data collection, all primary variables were available only for half of the patients (47%). This indicates that in clinical practice more attention should be paid when collecting and registering patients’ CV risk data.
In conclusion, this retrospective study aiming at assessing the CV risk factors at the time of T2DM diagnosis in Romania showed a high prevalence of CV risk factors and/or overt CV disease. We would like to raise a signal for a more comprehensive screening of CV and renal risk factors at T2DM diagnosis and an early treatment strategy appropriately addressing these risk factors. Our results in a contemporary patient population with T2DM remind clinicians the importance of continuous adjustment of the individualized care, as we continue to learn more about the complexity of links between diabetes and other chronic diseases.
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgements
The following investigators contributed equally to study data collection: Adamescu E (Bucharest), Aganencei M (Tecuci), Alexandru C (Brasov), Andreescu G (Curtea de Arges), Anghel V (Galati), Avram R (Deva), Barbu R (Bacau), Balan D (Ramnicu Valcea), Boboc D (Bucharest), Bratu D (Bucharest), Cerghizan A (Cluj-Napoca), Ciomos D (Targu Mures), Carstoiu E (Bucharest), Colda A (Bucharest), Coman A (Bucharest), Constantinescu S (Buzau), Cosma D (Oradea), Cristescu J (Bucharest), Crisan C (Targu Mures), Doros R (Bucharest), Ene D (Bucharest), Fantana D (Satu-Mare), Fulop E (Miercurea Ciuc), Sutu O (Iasi), Halmagy I (Sfantu Gheorghe), Hogea C (Timisoara), Kicsi-Matyus I (Sfantu Gheorghe), Mateescu AM (Constanta), Mandrescu N (Bucharest), Morosanu M (Galati), Munteanu L (Timisoara), Muresan C (Pitesti), Nagy Bodo A (Targu Mures), Nicodim S (Constanta), Onaca A (Oradea), Paun C (Bucharest), Penciu C (Reghin), Popa D (Ploiesti), Porojnicu C (Ploiesti), Protasiewicz D (Craiova), Reghina A (Bucharest), Roman G (Cluj-Napoca), Szabo M (Targu Mures), Serban G (Bucharest), Tutescu A (Pitesti), Vacaru G (Bucharest), Vanghelie L (Craiova), Verde I (Bucharest).
The study was sponsored by AstraZeneca. Medical writing support was provided by Raluca Voicu, MD of MedInteractiv Plus with the financial support from AstraZeneca Romania.
References
- 1.Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J. 2013;34(31):2436–2443. doi: 10.1093/eurheartj/eht149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Kalofoutis C, Piperi C, Kalofoutis A, Harris F, Phoenix D, Singh J. Type II diabetes mellitus and cardiovascular risk factors: Current therapeutic approaches. Exp Clin Cardiol. 2007;12(1):17–28. [PMC free article] [PubMed] [Google Scholar]
- 3.National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143–3421. [PubMed] [Google Scholar]
- 4.Laakso M. Insulin resistance and cardiovascular disease. Br J Diabetes Vasc Dis. 2002;2(Suppl 1):S9–S11. [Google Scholar]
- 5.Kendall DM, Sobel BE, Coulston AM, Peters Harmel AL, McLean BK, Peragallo-Dittko V, Buse JB, Fonseca VA, Hill JO, Nesto RW, Sunyer FX, Partners Against Insulin Resistance Advisory Panel The insulin resistance syndrome and coronary artery disease. Coron Artery Dis. 2003;14(4):335–348. doi: 10.1097/01.mca.0000076512.29238.2a. [DOI] [PubMed] [Google Scholar]
- 6.Dokken BB. The pathophysiology of cardiovascular disease and diabetes: beyond blood pressure and lipids. Diabetes Spectrum. 2008;21(3):160–165. [Google Scholar]
- 7.Shah AD, Langenberg C, Rapsomaniki E, Denaxas S, Pujades-Rodriguez M, Gale CP, Deanfield J, Smeeth L, Timmis A, Hemingway H. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol. 2015;3(2):105–113. doi: 10.1016/S2213-8587(14)70219-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Authors/Task Force Members. Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C, Escaned J, Hammes HP, Huikuri H, Marre M, Marx N, Mellbin L, Ostergren J, Patrono C, Seferovic P, Uva MS, Taskinen MR, Tendera M, Tuomilehto J, Valensi P, Zamorano JL; ESC Committee for Practice Guidelines (CPG), Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S; Document Reviewers, De Backer G, Sirnes PA, Ezquerra EA, Avogaro A, Badimon L, Baranova E, Baumgartner H, Betteridge J, Ceriello A, Fagard R, Funck-Brentano C, Gulba DC, Hasdai D, Hoes AW, Kjekshus JK, Knuuti J, Kolh P, Lev E, Mueller C, Neyses L, Nilsson PM, Perk J, Ponikowski P, Reiner Z, Sattar N, Schächinger V, Scheen A, Schirmer H, Strömberg A, Sudzhaeva S, Tamargo JL, Viigimaa M, Vlachopoulos C, Xuereb RG. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. 2013;34(39):3035–3087. doi: 10.1093/eurheartj/eht108. [DOI] [PubMed] [Google Scholar]
- 9.Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, D’Alessio DA, Davies MJ. 2019 Update to: 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. 2020;43(2):487–493. doi: 10.2337/dci19-0066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Jüni P, Lettino M, Marx N, Mellbin LG, Östgren CJ, Rocca B, Roffi M, Sattar N, Seferović PM, Sousa-Uva M, Valensi P, Wheeler DC, ESC Scientific Document Group 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular disease developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255–323. doi: 10.1093/eurheartj/ehz486. [DOI] [PubMed] [Google Scholar]
- 11.Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Dennison Himmelfarb C, Khera A, Lloyd-Jones D, McEvoy JW, Michos ED, Miedema MD, Muñoz D, Smith SC, Jr, Virani SS, Williams KA, Sr, Yeboah J, Ziaeian B. 2019 ACC/AHA Guidelines on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2019;140(11):e596–e646. doi: 10.1161/CIR.0000000000000678. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Cinteza M, Pana B, Cochino E, Florescu M, Margulescu A, Florian A, Vinereanu D. Prevalence and control of cardiovascular risk factors in Romania cardio-zone national study. Maedica. 2007;2(4):277–288. [Google Scholar]
- 13.Kulcsar I, Gaita D. Country Report Romania – April 2016. 2020 September; Available on < www.escardio.org>, last accessed on. [Google Scholar]
- 14.International Diabete Federation (IDF) Atlas. 2019 Available on < http://www.idf.org/diabetesatlas>, last accessed September 2020. [Google Scholar]
- 15.Coccheri S. Approaches to prevention of cardiovascular complications and events in diabetes mellitus. Drugs. 2007;67(6):997–1026. doi: 10.2165/00003495-200767070-00005. [DOI] [PubMed] [Google Scholar]
- 16.Barr EL, Zimmet PZ, Welborn TA, Jolley D, Magliano DJ, Dunstan DW, Cameron AJ, Dwyer T, Taylor HR, Tonkin AM, Wong TY, McNeil J, Shaw JE. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation. 2007;116(2):151–157. doi: 10.1161/CIRCULATIONAHA.106.685628. [DOI] [PubMed] [Google Scholar]
- 17.Smith SC., Jr Multiple risk factors for cardiovascular disease and diabetes mellitus. Am J Med. 2007;120((3Suppl 1)):S3–S11. doi: 10.1016/j.amjmed.2007.01.002. [DOI] [PubMed] [Google Scholar]
- 18.Popa S, Mota M, Popa A, Mota E, Serafinceanu C, Guja C, Catrinoiu D, Hâncu N, Lichiardopol R, Bala C, Popa A, Roman G, Radulian G, Timar R, Mihai B. Prevalence of overweight/obesity, abdominal obesity, and metabolic syndrome and atypical cardiometabolic phenotypes in adult Romanian population: PREDATORR Study. J Endocrinol Invest. 2016;39(9):1045–1053. doi: 10.1007/s40618-016-0470-4. [DOI] [PubMed] [Google Scholar]
- 19.Serafinceanu C, Timar R, Catrinoiu D, Zaharia A. Choice of the add-on therapy to metformin in type 2 diabetes patients in clinical practice. Initial results from a non-interventional multicenter study in Romania (REALITY). Acta Endo (Buc). 2016;12(4):455–460. doi: 10.4183/aeb.2016.455. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Inzucchi SE, Bergenstal RM, Buse JB, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR, American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD) Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364–1379. doi: 10.2337/dc12-0413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR, CANVAS Program Collaborative Group Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644–657. doi: 10.1056/NEJMoa1611925. [DOI] [PubMed] [Google Scholar]
- 22.Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117–2128. doi: 10.1056/NEJMoa1504720. [DOI] [PubMed] [Google Scholar]
- 23.Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB, LEADER Steering Committee; LEADER Trial Investigators Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311–322. doi: 10.1056/NEJMoa1603827. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, Chan JC, Choi J, Gustavson SM, Iqbal N, Maggioni AP, Marso SP, Öhman P, Pagidipati NJ, Poulter N, Ramachandran A, Zinman B, Hernandez AF, EXSCEL Study Group Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2017;377(13):1228–1239. doi: 10.1056/NEJMoa1612917. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS, DECLARE–TIMI 58 Investigators Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–357. doi: 10.1056/NEJMoa1812389. [DOI] [PubMed] [Google Scholar]
- 26.Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, Norhammar A, Birkeland KI, Jørgensen ME, Thuresson M, Arya N, Bodegård J, Hammar N, Fenici P CVD-REAL Investigators and Study Group. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs. The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136(3):249–259. doi: 10.1161/CIRCULATIONAHA.117.029190. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, DeFronzo RA, Einhorn D, Fonseca VA, Garber JR, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez GE. Consensus Statement by the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) on the Comprehenisve Type 2 Diabetes Management Algorithm – 2018 Executive Summary. Endocrine Practice. 2018;24(1):91–120. doi: 10.4158/CS-2017-0153. [DOI] [PubMed] [Google Scholar]
- 28.Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140–149. doi: 10.2337/dc14-2441. [DOI] [PubMed] [Google Scholar]
- 29.Black JA, Sharp SA, Wareham NJ, Sandbæk A, Rutten GEHM, Lauritzen T, Khunti K, Davies MJ, Borch-Johnsen K, Griffin SJ, Simmons RK. Does early intensive multifactorial therapy reduce modelled cardiovascular risk in individuals with screen-detected diabetes? Results from the ADDITION-Europe cluster randomized trial. Diabet. Med. 2014;31(6):647–656. doi: 10.1111/dme.12410. [DOI] [PMC free article] [PubMed] [Google Scholar]