Diabetes and CVD module 1: epidemiology

Prevalence of type 2 diabetes

In 2019 approximately 463 million adults (20-79 years) were living with diabetes; by 2045 this will rise to 700 million.¹ The proportion of people with type 2 diabetes is increasing in most countries. In 2019, 79% of adults with diabetes were living in low- and middle-income countries (figure 1).

• One in five of the people who are above 65 years old have diabetes
• One in two (232 million) people with diabetes were undiagnosed
• 374 million people are at increased risk of developing type 2 diabetes
• Diabetes caused 4.2 million deaths
• Diabetes in adults uses at least 10% of the total health budget

In the UK the latest figures show that there are 3,919,505 people living with diabetes, 90% with type 2 diabetes (T2D) and perhaps as many as 1 million undiagnosed.²

Risk factors for developing type 2 diabetes

Type 2 diabetes is a heterogenous disease with the contribution of genetic and environmental factors. Unlike monogenic diabetes (less than 1% of diabetes), there is a complex array of polygenic loci (>50 known) that contribute to the risk of developing type 2 diabetes. It is therefore not surprising that approximately 40% of patients have at least one parent with type 2 diabetes.

There is a large environmental contribution and type 2 diabetes is associated with obesity mainly as a consequence of dietary excess and sedentary lifestyle. A healthy diet, regular physical activity and maintaining a normal body weight are ways to prevent or delay the onset of type 2 diabetes. Indeed, the DiRECT study, an open label, cluster-randomised, controlled trial done in primary care practices in the UK with the intervention consisting of withdrawal of diabetes and antihypertensive drugs, total diet replacement (825–853 kcal per day formula diet for 12–20 weeks), stepped food reintroduction (2–8 weeks), and then structured support for weight-loss maintenance achieved sustained remissions at 24 months for more than a third of people with type 2 diabetes.³ Sustained remission was linked to the extent of sustained weight loss. However, despite a clear understanding of the link to diet and public health messages, the prevalence of type 2 diabetes continues to increase.

Although, historically, type 2 diabetes was considered to be an illness that comes on in older age, it is increasingly seen in younger patients usually in the context of morbid obesity.

Ethnicity has an influence with those with Asian, Pacific Islander and Afro-Caribbean ethnicity at higher risk interacting with excess calories and high energy diets of a developed and developing world. The risk of developing type 2 diabetes in some ethnic backgrounds can be seen with a body mass index (BMI) that would be considered to be normal.

You are more likely to develop type 2 diabetes if you:

• are overweight or obese
• are age 45 or older
• have a family history of diabetes
• are Asian, Afro-Caribbean or Pacific Islander
• have high blood pressure
• have a low level of high-density liprotein (‘good’) cholesterol (HDL-C), or a high level of triglycerides
• have a history of gestational diabetes or gave birth to a baby weighing nine pounds or more
• are not physically active
• have a history of heart disease or stroke
• have depression
• have polycystic ovary syndrome
• have acanthosis nigricans.

Diagnostic criteria for diabetes including the use of HbA1c

Unlike type 1 diabetes, type 2 diabetes often has a slow progression, perhaps with few symptoms, that may take years to manifest, all the while cardiovascular risk accruing. It is a biochemical diagnosis based on fasting blood glucose, random blood glucose (with symptoms), two-hour plasma glucose post-75 g-oral glucose challenge and, more recently, haemoglobin A1c (HbA1c) (see table 1). If HBA1c is normal, but there is strong clinical suspicion of type 2 diabetes, then fasting blood glucose and/or an oral glucose tolerance test is needed. HbA1c should not be used in diagnosing gestational diabetes where the diagnostic criteria are different.

There is a disease spectrum including those with glucose tolerance (IGT) and impaired fasting glucose (IFG) which reflect the natural history of type 2 diabetes and are associated with an increased risk of going on to have a diagnosis of the condition (figure 2). Those on the pre-diabetes spectrum are an interesting group as they share with those with established type 2 diabetes increased risk of cardiovascular disease.

Pathophysiology

Type 2 diabetes develops initially as insulin resistance initially in muscle in the context of obesity. Insulin has a catabolic function promoting storage of excess calories as fat. As obesity develops, beta cells make more insulin in response, but after time begin to fail leading to raised blood glucose. The interplay between insulin resistance and beta cell failure varies on the individual, with hyperglycaemia itself having a considerable impact on beta cell function although the precise mechanisms of the neuro-hormonal mechanisms between beta cells and insulin sensitive tissues (heart, skeletal muscle and adipose tissue) are not fully understood (figure 3).

Role of type 2 diabetes along with comorbidities in defining an individual’s cardiovascular risk

Chronic hyperglycaemia contributes to the development of cardiovascular disease. In the Emerging Risk Factors Collaboration meta-analysis of data for 698,782 people (52,765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies:

• Adjusted hazard ratios (HRs) with diabetes were: 2.00 (95% CI 1·83 – 2.19) for coronary heart disease; 2.27 (1.95 – 2.65) for ischaemic stroke; 1.56 (1.19 – 2.05) for haemorrhagic stroke; 1.84 (1.59 – 2.13) for unclassified stroke; and 1.73 (1.51 – 1.98) for the aggregate of other vascular deaths.⁷
• HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers.

Therefore, type 2 diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10–12%) of vascular deaths.

Treating to glycaemic targets

UKPDS

In the UK Prospective Diabetes Study (UKPDS)*, 3,867 newly diagnosed patients with type 2 diabetes, median age 54 years, were randomly assigned to intensive treatment with a sulfonylurea or insulin versus diet alone and followed up 10 years.⁸ In UKPDS:

• The median HbA1c was 7.0% (53 mmol/mol) in the intensive group compared with 7.9% (63 mmol/mol) in the conventional group.
• The risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related end point; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality.
• Most of the risk reduction in the any diabetes-related aggregate end point was due to a 25% risk reduction (7-40, p=0.0099) in microvascular end points.
• The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin.
• Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001).

The UKPDS included a secondary analysis comparing 342 patients’ allocated metformin with 951 overweight patients allocated intensive blood-glucose control with sulfonylurea or insulin.⁹ The primary outcome measures were aggregates of any diabetes-related clinical end point, diabetes-related death, and all-cause mortality. In the metformin sub-study:

• The median HbA1c was 7.4% (57 mmol/mol) in the metformin group compared with 8.0% (64 mmol/mol) in the conventional group.
• Patients allocated metformin, compared with the conventional group, had risk reductions of 32% (95% CI 13-47, p=0.002) for any diabetes-related end point, 42% for diabetes-related death (9-63, p=0.017), and 36% for all-cause mortality (9-55, p=0.011).
• Among patients allocated intensive blood-glucose control, metformin showed a greater effect than sulfonylurea or insulin for any diabetes-related end point (p=0.0034), all-cause mortality (p=0.021), and stroke (p=0.032).

Learning point
It is this study that has resulted in metformin being considered the first line oral glucose lowering agent in most guidelines.

ADVANCE

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial randomised 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, based on initial use of modified release gliclazide plus any additional treatment with target HbA1c 6.5% (48 mmol/mol) or less.¹⁰ Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy). Follow-up was for a median of five years. In ADVANCE:

• HbA1c was lower in the intensive-control group at 6.5% (48 mmol/mol) than in the standard-control group at 7.3% (56 mmol/mol).
• Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; HR, 0.90; 95% confidence interval [CI], 0.82 to 0.98; p=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; HR, 0.86; 95% CI, 0.77 to 0.97; p=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; HR, 0.79; 95% CI, 0.66 to 0.93; p=0.006), with no significant effect on retinopathy (p=0.50).
• There were no significant effects of the type of glucose control on major macrovascular events (HR with intensive control, 0.94; 95% CI, 0.84 to 1.06; p=0.32), death from cardiovascular causes (HR with intensive control, 0.88; 95% CI, 0.74 to 1.04; p=0.12), or death from any cause (HR with intensive control, 0.93; 95% CI, 0.83 to 1.06; p=0.28).
• Severe hypoglycaemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; HR, 1.86; 95% CI, 1.42 to 2.40; p<0.001).

ACCORD

The Action to Control Cardiovascular Risk in Diabetes (ACCORD)* study used the standard range of available therapies at the time including sulfonylureas, metformin, thiazolidinediones, insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors and exenatide to intensify therapy.¹¹ 10,251 patients (mean age, 62.2 years) with a median HbA1c 8.1% were assigned to receive intensive therapy (targeting a HbA1c <6.0% (42 mmol/mol)) or standard therapy (targeting a level from 7.0 to 7.9% (53 – 63 mmol/mol)). Median follow up was for 3.5 years. In ACCORD:

• At one year, HbA1c of 6.4% (46 mmol/mol) and 7.5% (58 mmol/mol) were achieved in the intensive-therapy group and the standard-therapy group, respectively.
• The primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (HR, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16).
• 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (HR, 1.22; 95% CI, 1.01 to 1.46; p=0.04)
• Hypoglycaemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (p<0.001).

Learning point
This study identified a potential concern about rapidly intensifying glucose lowering in high-risk patients with type 2 diabetes.

VADT

In the Veteran Affairs Diabetes Trial (VADT), 791 military veterans (mean age 60.4 years) who had a suboptimal response to therapy for T2D, received either intensive (targeting an absolute reduction of 1.5% (7 mmol/mol) or standard glucose control.¹² Other cardiovascular risk factors were treated uniformly in both groups. The primary outcome was the time from randomisation to the first occurrence of a major cardiovascular event. This was a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischaemic gangrene. The median follow-up was for 5.6 years. In VADT:

• Median HbA1c were 8.4% (68 mmol/mol) in the standard-therapy group and 6.9% (52 mmol/mol) in the intensive-therapy group.
• The primary outcome occurred in 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group (HR in the intensive-therapy group, 0.88; 95% CI, 0.74 to 1.05; p=0.14).
• There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause (HR, 1.07; 95% CI, 0.81 to 1.42; p=0.62).
• No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycaemia, were 17.6% in the standard-therapy group and 24.1% in the intensive-therapy group.

There was a considerable amount of debate at the time as to what targets were appropriate for patients with type 2 diabetes and whether or not treating glucose in itself was likely to accrue benefit. Diabetes guidelines were generally advising first line use of metformin with glycaemic targets and time to achieve them influenced by ADVANCE, ACCORD and VADT, but embedded within a multi-factorial approach best illustrated by the STENO-2 study.¹³

STENO-2

The Steno-2 Study randomly assigned 160 patients with type 2 diabetes and persistent microalbuminuria to receive either intensive therapy or conventional therapy. The primary end point at 13.3 years of follow-up was the time to death from any cause. In Steno-2:

• 24 patients in the intensive-therapy group died, as compared with 40 in the conventional-therapy group (HR, 0.54; 95% CI, 0.32 to 0.89; p=0.02).
• Intensive therapy was associated with a lower risk of death from cardiovascular causes (HR, 0.43; 95% CI, 0.19 to 0.94; p=0.04) and of cardiovascular events (hazard ratio, 0.41; 95% CI, 0.25 to 0.67; p<0.001).
• One patient in the intensive-therapy group had progression to end-stage renal disease, as compared with six patients in the conventional-therapy group (p=0.04).
• Fewer patients in the intensive-therapy group required retinal photocoagulation (relative risk, 0.45; 95% CI, 0.23 to 0.86; p=0.02). Few major side effects were reported.

Problem of heart failure in people with type 2 diabetes

Type 2 diabetes is highly prevalent in those patients with heart failure and the prevalence is increasing. It is now more common for those with type 2 diabetes to present with heart failure as the initial presentation of cardiovascular disease rather than acute myocardial infarction. It is particularly common in the elderly, perhaps up to 30%, especially if obese. The combination of type 2 diabetes and heart failure with preserved ejection fraction (HFpEF) is associated with a higher risk of mortality. Part of this increase in mortality is that it is often unrecognised compounded by lack of evidence as to best treatment. Indeed as the number of hospitalisations for heart failure with reduced ejection fraction (HFrEF) falls, hospitalisation for HFpEF will become the bigger challenge.

The high prevalence of heart failure in people with type 2 diabetes suggests that it has a pathophysiological role in its development. The pathophysiology of heart failure in type 2 diabetes includes abnormal cardiac handling of glucose and free fatty acids. There are various phenotypes for HFpEF including metabolic syndrome, obesity, renal dysfunction, hypertension and coronary artery disease, all features seen in type 2 diabetes.

CHARM

In the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme a post-hoc analysis was done to assess the impact of diabetes on outcomes.¹⁴ The CHARM programme randomised 7,599 patients with symptomatic heart failure and a broad range of ejection fractions. In CHARM:

• The prevalence of diabetes was 28.3% in patients with preserved ejection fraction (>40%) and 28.5% in those with low ejection fraction (>or=40%).
• Diabetes was associated with an increase in the incidence of hospitalisation or cardiovascular mortality in HFrEF (adjusted HR = 1.6; 95% CI, 1.44 to 1.77).
• Diabetes was associated with an increase in the incidence of hospitalisation or cardiovascular mortality in HFpEF (adjusted HR = 2; 95% CI, 1.7 to 2.36) compared with those without diabetes.

Independent risk factors for developing heart failure in type 2 diabetes are:

• advanced age
• duration of disease
• insulin use
• presence of coronary artery disease
• elevated serum creatinine.

Rationale for cardiovascular outcome trials (CVOTs) and approaches to modern management of type 2 diabetes

Following concerns about an increased risk of cardiovascular morbidity and mortality with the PPARɣ agonist, rosiglitazone, resulting in it losing its marketing authorisation, since 2008 the Food and Drug Administration (FDA) in the US and the European Medicines Agency (EMA) have mandated that all treatments in development for type 2 diabetes should undergo cardiac safety testing.^15,16 This has meant that all type 2 diabetes drugs in development have to have clinical study evidence to confirm cardiovascular safety. Given that the safety signal of concern was relating to atherosclerotic outcomes, the primary end point for these safety studies was to use a composite end point of major adverse cardiovascular events (MACE). This was usually a three-point MACE including death, non-fatal MI and non-fatal stroke, but occasionally MACE plus which also includes hospitalisation for unstable angina (figure 4).

These safety trials in people with type 2 diabetes have recruited participants with either established atherosclerotic cardiovascular disease or at increased risk of cardiovascular disease due to the presence of other risk factors, including chronic kidney disease, microalbuminuria or proteinuria. They have been designed to meet the FDA/EMA requirement of non-inferiority over a short period (two-years duration). Baseline heart failure and renal function was recorded by local investigators and, although at times poorly recorded, secondary end points including heart failure and renal outcomes have been included.

Trials have reported for DPP4 inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors, and these are described in detail in modules 3 and 4. Some have been shown to be superior to standard treatment for the primary outcome, but clinical investigators have modified trial designs to explore secondary outcomes including heart failure and progression of renal disease. As of 2016, approximately 200,000 patients had been recruited into CVOTs.

The CVOTs have had a significant impact on clinical guidelines with selection of agent largely recommended on the basis of patient characteristics, including the presence of cardiovascular and renal disease, with the aim of improving prognosis with anti-diabetes drugs that have benefit beyond reducing HbA1c.

Key learning messages

• The prevalence of type 2 diabetes is increasing
• Managing hyperglycaemia is part of a multifactorial approach to risk factor management aimed at reducing the risk of cardiovascular events
• CVOTs have provided evidence for preferential use of newer anti-diabetic drugs in managing type 2 diabetes because of improved prognosis
• Heart failure (especially HFpEF) is increasing in prevalence with challenges in diagnosis and treatment strategies

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References

1. International Diabetes Federation. IDF Diabetes Atlas, 9th edn. Brussels, Belgium: International Diabetes Federation, 2019. http://www.diabetesatlas.org [last accessed 8th December 2020]

2. Diabetes UK. Position statement reports. https://www.diabetes.org.uk/professionals/position-statements-reports/statistics/diabetes-prevalence-2019 [last accessed 8th December 2020]

3. Lean MEJ, Leslie WS, Barnes AC et al. Durability of primary care lead weight management intervention for the remission of type 2 diabetes: 2-year results of the DiRECT open labelled, cluster- randomised study. Lancet Diabet Endocrinol 2019;7:344–55. https://doi.org/10.1016/S2213-8587(19)30068-3.

4. Bailey CJ. Antidiabetic drugs. Br J Cardiol 2000;7:350-60.

5. DeFronzo RA and Ferraninni E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173-94. https://doi.org/10.2337/diacare.14.3.173

6. DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773-95. https://doi.org/10.2337/db09-9028

7. The Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2000;375:2215–22

8. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53

9. 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;352:854–65. https://doi.org/10.1016/S0140-6736(98)07037-8

10. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–72. https://doi.org/10.1056/NEJMoa0802987

11. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–59. https://doi.org/10.1056/NEJMoa0802743

12. Duckworth W, Abraira C, Moritz T et al. for the VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129–39. https://doi.org/10.1056/NEJMoa0808431

13. Gaede P, Lund-Anderson H, Parving H-H, Pedersen O et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580–91. https://doi.org/10.1056/NEJMoa0706245

14. MacDonald MR, Petrie MC, Varyani F et al. on behalf of the CHARM investigators. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J 2008;29:1377–85. https://doi.org/10.1093/eurheartj/ehn153

15. Food and Drug Administration. Draft Guidance. Guidance for Industry. Diabetes mellitus: evaluating the safety of new drugs for glycemic control. Silver Spring, MS: US Department of Health and Human Services, Food and Drug Administration, Center for Evaluation and Research, 2020. Available from: https://www.fda.gov/media/135936/download

16. European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. London: EMA, 2012. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf [last accessed 8th December 2020]

17. Hirschberg B and Katz A. Cardiovascular outcome studies with novel anti diabetes agents: scientific and operational considerations. Diabetes Care 2013;36:S253-S258. https://doi.org/10.2337/dcS13-2041