Epidemiology, pathophysiological aspects and treatment options

Diabetes mellitus is a growing disease with a very high morbidity and mortality. It affects the micro- and macrovasculature in different ways and can thus lead to various forms of cardiovascular disease in the human body. Lifestyle change remains one of the important therapy strategies but several new drugs that emerged over the last years also demonstrate improvement in cardiovascular outcome.

Epidemiology

Worldwide about 415 million people have diabetes mellitus (DM) and this number is expected to increase to 642 million in 2040 [1]. This means that about one out of eleven adults worldwide is concerned. Every six seconds a person dies from DM. More than half of the mortality rates and a rising amount of morbidity rates in DM patients are related to cardiovascular disease [2]. The lifetime risk of developing DM in the European population is about 30–40% and rises with age.

Cardiovascular (CV) event rates in type 2 DM patients correlate well with the degree of hyperglycaemia [3]. Every 1-mmol/l increase in fasting plasma glucose predicts a 17% increase in the risk of future CV events or death [4]. An increase of 1% in glycated haemoglobin (HbA_1c) is associated with an increased risk of 18% in CV events and 12–14% in all-cause mortality [5]. Correlation between hyperglycaemia and microvascular events is much stronger than that for macrovascular disease. An increase of 1% of HbA_1c is associated with a 37% increase in the risk of developing retinopathy or renal failure [6].

Pathophysiology of diabetes mellitus

There are several types of DM. The most important are type 1 and type 2 DM. Type 1 DM defines a condition induced by autoimmune destruction of pancreatic beta-cells that typically starts in young patients and leads to absolute insulin deficiency. In a small part of patients, disease arises at advanced age or progression is prolonged resulting in the latent autoimmune diabetes mellitus in adults (LADA) form of type 1 DM. Type 2 DM describes a condition characterized by insulin resistance, compensatory hyperinsulinemia and finally beta-cell failure. Type 2 DM is mostly enhanced by a sedentary lifestyle and high-calorie diet leading particularly to the abdominal form of obesity. There are also some other infrequent forms of DM including gestational DM, maturity-onset DM of the young or DM induced by surgery or drug-intoxication.

DM leads to microvascular disorders, including retinopathy and nephropathy and autonomic neuropathy as well as to macrovascular disease especially coronary artery disease (CAD), peripheral vascular disease and cerebrovascular artery disease. Also, a direct impact on cardiac myocyte function leading to systolic and diastolic left ventricular dysfunction and heart failure has been described [7,8].

The hallmark of DM is hyperglycaemia. However, hyperglycaemia alone is apparently not the only factor responsible for cardiovascular harm. Prediabetes and the presence of metabolic syndrome in normoglycaemic patients are associated with increased rates of CAD and excessive mortality [9]. Also, intensive glycaemic control alone in patients with DM does not necessarily lower CV mortality [10,11]. Aetiology of cardiovascular damage in patients with DM is consequently multifactorial and more complex and is nowadays not yet fully understood.

Impact of Diabetes mellitus on macrovascular disease

DM impacts macro- and microvasculature in different ways. Macrovasculature is generally affected by atherosclerosis induced by dyslipidaemia. Indeed, a vast majority of patients with DM has dyslipidaemia [12,13]. The characteristic pattern of increased triglycerides and decreased high-density lipoprotein (HDL) found in patients with DM is accompanied by abnormalities of the structure of the lipoprotein particles [14]. The predominant form of low-density lipoprotein (LDL) in type 2 DM is the small, dense form called very low-density lipoprotein (VLDL). VLDL production is promoted by increased free fatty acid release from insulin-resistant fat cells in adipose tissue to the liver impairing insulin sensitivity as well as by increased lipogenesis. Small LDL particles can more easily penetrate the arterial wall and form arterial plaques. Additionally, they are more disposed to oxidation. The oxidized form of LDL leads to an inflammatory response by attracting leucocytes to the intima of the vessel, forming foam cells by lipid ingestion and proliferation of leucocytes, endothelial cells and smooth muscle cells resulting in atherosclerotic plaque formation [15]. High levels of circulating free fatty acids and triglycerides promote furthermore secretion of apolipoprotein B (ApoB) that was demonstrated to be associated with increased risk of CV disease [16]. Protective HDL properties may be concomitantly impaired in type 2 DM due to alteration of the protein structure [17].

Additionally, decreased release of the vasodilator nitric oxide (NO) due to oxidative stress and vascular inflammation promotes endothelial dysfunction, an accepted risk factor for CV disease [18]. The decreased NO bioavailability induced by insulin deficiency is accompanied by increased endothelin-1 secretion, a potent vasoconstrictor, leading to a hyper-constrictive state of the vasculature in patients with metabolic syndrome and DM [19].

A vast majority of CV events in diabetic patients is related to thromboembolic events, mostly myocardial infarction [20]. Undeniably, diabetic patients experience a hypercoagulable state induced by enhanced platelet activation and increased clotting factors in blood. Concomitantly, anticoagulant properties are diminished in diabetic patients, mostly by inhibition of the fibrinolytic system through abnormal clot structures that are more resistant to degradation [21].

Impact of Diabetes mellitus on microvascular disease

Microvascular disease in DM patients impacts small vessels throughout the whole body, even if retinopathy, autonomic neuropathy or nephropathy, are the most endemic effects. While atherosclerosis is mainly causal for macrovascular disease, microvascular disease is affected by a variety of molecular and cellular mechanisms. The autonomous nervous system is mainly responsible for the central vascular autoregulation of blood flow also of the cardiovascular bed. Vasoconstrictive and vasodilatative molecules produced by the endothelial cells control the local vascular regulation assuring the current metabolic requirements of the respective tissue. DM leads to diabetic autonomic neuropathy (DAN) impairing autoregulation of cardiac microvascular blood flow. Cardiac flow reserve, necessary for temporary augmentation of blood flow in case of increased demand was demonstrated to be dysfunctional in DM patients presenting DAN [22]. This may, in part also be responsible for an excess in cardiovascular mortality seen in patients with DAN [23]. Another hallmark of microvascular dysfunction in type 2 DM is basement membrane thickening induced by prolonged hyperglycaemia. The thickened membrane results in decreased exchange of metabolic products between blood circulation and tissue and increased microvascular permeability for larger molecules like albumin in the kidney. In fact, increased microalbuminuria reflects very well the degree of microvascular damage throughout the whole vasculature of the body [24].

Systolic and diastolic heart failure in patients with diabetes

In the UK prospective diabetes study (UKPDS), every 1% increase in HbA_1c was associated with 12% rise in heart failure (HF) [6]. The most suggestive aetiology for systolic HF in patients with diabetes would be ischemic cardiomyopathy induced by thromboembolic events due to endothelial dysfunction, oxidation of atherogenic lipids and a hypercoagulable state. Diabetic cardiomyopathy (DCM), a condition associated with systolic and diastolic dysfunction, has however been demonstrated in diabetic patients without any macrovascular prove of CAD. DCM, is probably mainly provoked by microvascular disease and is associated with myocardial injury and fibrosis and myocellular hyperpertrophy [25]. In fact, DCM patients with impaired coronary flow reserve and DAN demonstrate typical patterns of diastolic dysfunction like early diastolic filling time or elevated left atrial pressure [26].

Therapeutic aspects of diabetes mellitus and CV outcome

Glycaemic control: Considering the previously shown data regarding the strong association between hyperglycaemia and CV outcome in diabetic patients, a rigorous glycaemic control is considered to be an option to improve prognosis. A couple of studies have investigated the effect of intensive versus conventional glycaemic control on CV outcome with mostly conflicting results [27–29]. While the majority of these trials demonstrated a decrease of microvascular complications in patients randomized to intensive glycaemic control (in particularly reduction of nephropathy and retinopathy), there was no impact on macrovascular events. On the contrary, patients randomised to intensive treatment demonstrated increased hospitalisation rates for severe hypoglycaemia [30]. One trial had to be stopped prematurely due to excess all-cause and CV mortality after 3,7 years in the intensive treatment group [29]. A possible revelation of these inconsistent results may be found in concomitant CV risk factors in DM patients including arterial hypertension (AHT), dyslipidaemia and obesity that overcome the benefit of optimal glycaemic control. The degree of relevant CV comorbidities existing at the beginning of intensive glycaemic control may have an important impact on success of this treatment. Diabetic patients who achieve a strict glycaemic control early enough during their disease course and before developing concomitant CV risk factors may have the most benefit of an intensive treatment.

While intensive glycaemic control in type 2 DM patients seems to increase the risk of hypoglycaemia, weight gain and CV mortality, the same is not true for type 1 DM patients. Some studies demonstrated a benefit regarding microvascular and macrovascular outcome in type 1 diabetic patients randomized to intensive glycaemic therapy (goal HbA_1c ≤7,0%) [31,32].

A tailored HbA_1c goal depending on age, disease history, concomitant CV risk factors as well as other co-morbidities as proposed for example by the ACC/AHA guidelines may be a good approach in order to improve CV prognosis in diabetic patients without exposing them to harm induced by hypoglycaemia, weight gain or increase CV mortality [33].

Non-medical treatment (lifestyle change): The corner­stone of a successful management of patients with type 2 DM is optimal control of typical co-morbidity including obesity, dyslipidaemia and AHT by lifestyle changes and medical treatment.

Obesity is a common co-morbidity especially in type 2 diabetic patients and is associated with a compromised CV outcome. Current guidelines recommend a weight loss of 5% in obese patients with diabetes or pre-diabetes [34]. This amount of weight loss is associated with a decrease in triglycerides and increase in the vasoprotective HDL. While a more consequent weight loss was proved to reduce the risk of developing DM in pre-diabetic individuals, current evidence shows conflicting results regarding CV outcome in patients with already established DM [35]. One study demonstrated improved CV outcome in type 2 diabetic patients with moderate weight loss, while another study lacked to prove an impact of weight loss on a composite endpoint including CV mortality, myocardial infarction and hospitalizations for angina pectoris [36,37].

Lifestyle intervention in type 2 diabetic patients in order to lose weight include dietary change focused on caloric restriction, augmented energy expenditure through appropriate daily physical activity and regular aerobic activity three to five days a week [33]. Indeed, an intensive exercise intervention strategy in subjects with type 2 DM demonstrated beside improvements in physical fitness, a decrease in HbA_1c, systolic and diastolic blood pressure, LDL, waist circumference, body mass index, insulin resistance, inflammation, and CAD risk scores [38]. Regular physical acti­vity by a structured aerobic and resistance exercise program has not only the ability to decrease HbA_1c values but also to improve CV prognosis [6,39]. A meta-analysis revealed that a structured exercise program of >150 minutes/week was able to decrease HbA_1c levels by 0,9% [40]. This decrease is in the range observed by treatment with currently used oral antidiabetic drugs, i.e. DPP-4-inhibitors or GLP-1-agonist. In order to achieve long-term persistent results, reinforcement by healthcare workers is however recommended [41,42].

In very obese individuals, bariatric surgery may be the only option to achieve long-term persistent weight-loss. However, a cautious selection of suitable patients is necessary to outweigh peri-interventional risk vs. long-term benefit of weight loss [43].

Medical nutrition therapy (MNT) is recommended in order to prevent DM, manage existing DM, and prevent, or at least delay rate of DM complications. MNT is an integral component of diabetes self-management education and is therefore suggested at all levels of diabetes prevention [44]. Dietary advice includes an appropriate intake of total calories, thereby giving preference of fruits, vegetables, wholegrain cereals and low-fat protein sources [45]. Adherence to exact proportions of total energy intake provided by major macronutrients like carbohydrates, proteins seems less important [2,45]. However a Mediterranean-type diet seems acceptable, as long as monounsaturated oils are used as fat source like demonstrated in a study using virgin olive oil [2,46].

Medical treatment: Antidiabetic drugs can be attri­but­ed to three main mechanisms of action: insulin providers, insulin sensitizers or glucose absorption inhibi­tors [2]. The first group includes human insulin or insulin analogues, sulphonylureas, meglitinides, glucagon-like-peptide-1 (GLP-1) receptor agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors. Metfor­min and pioglitazone are the main actors of the second group. The third group consists of alpha-gluco­­sidase inhibitors and sodium-glucose-co-transporter-2 (SGLT-2) inhibitors. The estimated decrease in HbA_1c with every one of these agents is about 0,5–1% with considerable individual variations depending on ­disease duration and pharmacogenomics [2]. Usually a combination of up to three agents may be necessary in order to achieve satisfactory blood glucose levels.

Metformin is recommended as first-line treatment in type 2 DM patients, especially in obese patients [47]. Caution is advocated to patients with impaired renal function (especially when GFR <50 mL/min) because of increased risk for developing lactic acidosis [48]. Incretin mimetic drugs (GLP-1 receptor antagonists and DDP-4 inhibitors) act mainly by stimulating endogenous pancreatic insulin secretion. Concomitantly, they increase satiety by dedicated actions on gastro-intestinal (GI) tract and brain, which makes them indispensable in the treatment of obese diabetic patients, despite a relatively high rate of GI side-effects like nausea. Another new class of recently discovered antidiabetic drugs are the SGLT-2 inhibitors. By increasing urinary glucose excretion, these agents improve glycaemic control independently of insulin secretion with a low risk of hypoglycaemia [49]. They also reduce body weight and blood pressure without compensatory increases in heart rate and have some effects on plasma lipids (increase in HDL-C and LDL-C, with no change in HDL-C/LDL-C) [50]. The recently published «Cardiovascular Outcome Event Trial» in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) demonstrated that in type 2 DM patients with high CV disease risk empagliflozin (SGLT-2 inhibitor) reduced the primary cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14%, mostly by a 38% reduction in CV mortality. Empagliflozin also reduced HF hospitalizations by 35% without affecting hospitalization for unstable angina [51]. These properties make this agent class an interesting treatment option, especially for type 2 DM patients with concomitant HF and/or AHT. A recently published study, demonstrated improved glycaemic control with the SGLT-1 and 2 inhibitor sotagliflozin when added to standard insulin therapy in type 1 DM patients, suggesting a larger therapeutic potential of this new agent group [52].

Medical treatment for important common co-morbidities: AHT is a common co-morbidity encountered in patients particularly with type 2 DM, mostly triggered by increased renal sodium reabsorption due to hyperinsulinaemia, augmented sympathetic tone as well as increased renin-angiotensin-aldosterone system (RAAS) activity [53]. Prognosis of diabetic patients with AHT is dismal with a 4-fold increase in cardiovascular event rates [54]. Thus, screening for and treatment of AHT in DM patients is mandatory with a treatment target of <140/85 mmHg [2]. Despite lifestyle changes, pharmacologic treatment in diabetic patients with AHT should target the blockade of the RAAS activity, preferably by an angiotensin converting enzyme inhibitor (ACE-I) or an angiotensin-receptor-blocker (ARB) [55]. When combination therapy is necessary, there is some evidence favouring addition of amlodipine rather than a diuretic to an ACE-I [55].

Another typical finding associated with impaired outcome in DM patients are lipid abnormalities. There is a solid evidence supporting statins as a first-line therapy of typical DM associated lipid disorders. Each 1-mmol/l reduction in serum LDL by statin therapy decreases major CV events by 21% [56]. If LDL target values are not achieved by statin therapy alone, ezetimibe can be added in order to improve CV outcome [57]. Newer evidence confirms benefit of cholesterol lowering by PCSK-9 inhibitors in DM patients [58].

Conclusions

Diabetes mellitus is a rapidly spreading, potentially lethal disease boosted by a sedentary lifestyle and high-calorie diet. Diabetes affects micro- and macrovasculature at different levels and by different mechanisms. A systematic screening for with DM associated cardiovascular disease and co-morbidities is essential. Lifestyle modification, in particular regular physical activity and dietary advice, if necessary together with medical treatment has the virtue to mitigate the dismal outcome induced by DM. Several innovative treatment options that could prove to decrease CV mortality emerged over the last few years. However, comprehensive information campaigns for a broad population in order to prevent DM remains crucial.

Take-Home-Messages

• Diabetes mellitus is a growing disease with a very high morbidity and mortality.
• Diabetes affects the micro- and macrovasculature in different ways.
• Diabetes can lead to systolic and diastolic left ventricular dysfunction independently of the occurrence of coronary artery disease.
• Tight glycaemic control is indicated only in selected patient groups.
• Lifestyle change including regular physical activity and dietary advice is the fundament of diabetes treatment.
• Several new agents demonstrating improvement in cardiovascular outcome emerged over the last years.

Bibliography:

1. IDF Diabetes Atlas – 7^th edition. www.diabetesatlas.org, 2017 (Key messages).
2. Authors/Task Force Members, et al.: 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.
3. Emerging Risk Factors Collaboration, et al.: Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010; 375(9733): 2215–2222.
4. Anand SS, et al.: Glucose levels are associated with cardiovascular disease and death in an international cohort of normal glycaemic and dysglycaemic men and women: the EpiDREAM cohort study. Eur J Prev Cardiol 2012; 19(4): 755–764.
5. Selvin E, et al.: Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004; 141(6): 421–431.
6. Stratton IM, et al.: Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321(7258): 405–412.
7. Marwick TH: Diabetic heart disease. Heart 2006; 92(3): 296–300.
8. Schannwell CM, et al.: Left ventricular diastolic dysfunction as an early manifestation of diabetic cardiomyopathy. Cardiology 2002; 98(1-2): 33–39.
9. Muhlestein JB, et al.: Effect of fasting glucose levels on mortality rate in patients with and without diabetes mellitus and coronary artery disease undergoing percutaneous coronary intervention. Am Heart J 2003; 146(2): 351–358.
10. Action to Control Cardiovascular Risk in Diabetes Study Group, et al.: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358(24): 2545–2559.
11. Hemmingsen B, et al.: Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ 2011; 343: d6898.
12. Kannel WB: Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. Am Heart J 1985; 110(5): 1100–1107.
13. Taskinen MR: Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 2003; 46(6): 733–749.
14. Cannon CP: Mixed dyslipidemia, metabolic syndrome, diabetes mellitus, and cardiovascular disease: clinical implications. Am J Cardiol 2008; 102(12A): 5L–9L.
15. Chan AC: Vitamin E and atherosclerosis. J Nutr 1998; 128(10): 1593–1596.
16. Chahil TJ, Ginsberg HN: Diabetic dyslipidemia. Endocrinol Metab Clin North Am 2006; 35(3): 491–510, vii–viii.
17. Sorrentino SA, et al.: Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation 2010; 121(1): 110–122.
18. Zeng G, Quon MJ: Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest 1996; 98(4): 894–898.
19. Koh KK, Han SH, Quon MJ: Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions. J Am Coll Cardiol 2005; 46(11): 1978–1985.
20. Gu K, Cowie CC, Harris MI: Mortality in adults with and without diabetes in a national cohort of the U.S. population, 1971-1993. Diabetes Care 1998; 21(7): 1138–1145.
21. Carr ME: Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001; 15(1): 44–54.
22. Di Carli MF, et al.: Effects of autonomic neuropathy on coronary blood flow in patients with diabetes mellitus. Circulation 1999; 100(8): 813–819.
23. Astrup AS, et al.: Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy. Diabetes Care 2006; 29(2): 334–339.
24. Weir MR: Microalbuminuria and cardiovascular disease. Clin J Am Soc Nephrol 2007; 2(3): 581–590.
25. Kawaguchi M, et al.: A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with diabetes mellitus with and without hypertension. Heart Vessels 1997; 12(6): 267–274.
26. Pop-Busui R, et al.: Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial blood flow reserve and diastolic dysfunction. J Am Coll Cardiol 2004; 44(12): 2368–2374.
27. King P, Peacock I, Donnelly R: The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol 1999; 48(5): 643–648.
28. Duckworth WC, et al.: Glucose control and cardiovascular complications: the VA Diabetes Trial. Diabetes Care 2001; 24(5): 942–945.
29. Riddle MC: Effects of intensive glucose lowering in the management of patients with type 2 diabetes mellitus in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Circulation 2010; 122(8): 844–846.
30. Group AC, et al.: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358(24): 2560–2572.
31. Diabetes Control and Complications Trial Research Group, et al.: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329(14): 977–986.
32. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group: Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 2003; 290(16): 2159–2167.
33. Fox CS, et al.: Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association. Circulation 2015; 132(8): 691–718.
34. Jensen MD, et al.: 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 2014; 129(25 Suppl 2): S102–138.
35. Tuomilehto J, et al.: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344(18): 1343–1350.
36. James WP, et al.: Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010; 363(10): 905–917.
37. Look ARG, et al.: Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013; 369(2): 145–154.
38. Balducci S, et al.: Effect of an intensive exercise intervention strategy on modifiable cardiovascular risk factors in subjects with type 2 diabetes mellitus: a randomized controlled trial: the Italian Diabetes and Exercise Study (IDES). Arch Intern Med 2010: 170(20): 1794–1803.
39. Sigal RJ, et al.: Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial. Ann Intern Med 2007; 147(6): 357–369.
40. Snowling NJ, Hopkins WG: Effects of different modes of exercise training on glucose control and risk factors for complications in type 2 diabetic patients: a meta-analysis. Diabetes Care 2006; 29(11): 2518–2527.
41. Umpierre D, et al.: Physical activity advice only or structured exercise training and association with HbA_1c levels in type 2 diabetes: a systematic review and meta-analysis. JAMA 2011; 305(17): 1790–1799.
42. Kirk AF, Barnett J, Mutrie N: Physical activity consultation for people with Type 2 diabetes: evidence and guidelines. Diabet Med 2007; 24(8): 809–816.
43. Adams TD, et al.: Weight and Metabolic Outcomes 12 Years after Gastric Bypass. N Engl J Med 2017; 377(12): 1143–1155.
44. American Diabetes Association, et al.: Nutrition recommendations and interventions for diabetes: a position statement of the American Diabetes Association. Diabetes Care 2008; 31 Suppl 1: S61–78.
45. Mann JI, et al.: Evidence-based nutritional approaches to the treatment and prevention of diabetes mellitus. Nutr Metab Cardiovasc Dis 2004: 14(6): 373–394.
46. Estruch R, et al.: Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013; 368(14): 1279–1290.
47. Inzucchi SE, et al.: 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.
48. Salpeter S, et al.: Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2006; (1): CD002967.
49. Inzucchi SE, et al.: SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 2015; 12(2): 90–100.
50. Vasilakou D, et al.: Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013; 159(4): 262–274.
51. Zinman B, et al.: Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373(22): 2117–2128.
52. Garg SK, et al.: Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. N Engl J Med 2017. doi: 10.1056/NEJMoa1708337. [Epub ahead of print]
53. Redon J, et al.: Mechanisms of hypertension in the cardiometabolic syndrome. J Hypertens 2009; 27(3): 441–451.
54. Haffner SM, et al.: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339(4): 229–234.
55. Weber MA, et al.: Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol 2010; 56(1): 77–85.
56. Cholesterol Treatment Trialists’ (CTT) Collaborators, et al.: Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371(9607): 117–125.
57. Giugliano R: Ezetimibe reduces cardiovascular events in diabetics with recent acute coronary syndrome. Oral presentation at the European Society of Cardiology Congress, Barcelona 2015, 2015.
58. Sabatine MS, et al.: Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol 2017. pii: S2213-8587(17)30313-3. doi: 10.1016/S2213-8587(17)30313-3. [Epub ahead of print]

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