Type 2 diabetes

Type 2 diabetes (T2D) is a progressive chronic metabolic disorder characterised by insulin deficiency and dysregulation of carbohydrate, lipid and protein metabolism. Both insulin resistance and insufficient insulin production are necessary for T2D to develop. Chronic hyperglycaemia, when combined with other metabolic abnormalities in people with T2D, can damage various organ systems, leading to the development of disabling and life-threatening health complications.

Long-term complications in T2D

Watch Professor Caroline Apovian discuss the burden and long-term complications of T2D in the following video.

Impact of T2D on long-term complications, mortality and burden

Prevalence of T2D

Over 537 million adults aged 20–79 years have type 1 or type 2 diabetes worldwide. With this number expected to rise to 783 million by the year 2045¹, there could be a significant increase in premature morbidity and mortality. The Global Burden of Disease Study identifies diabetes mellitus as the ninth major cause of reduced life expectancy²; about 12% of total global deaths under 60 ears are due to diabetes and its complications¹, making diabetes a global health emergency. Nearly one in two persons with diabetes do not have a formal diagnosis, further compounding the global burden of disease.

Paediatric T2D

Once thought to be exclusively a disease of adults, T2D in children has increased by over 35% since 2001³. Obesity is the most important risk factor for T2D, with 77% of children with T2D being obese at the time of diagnosis^3,4. Physical inactivity and poor diet also contribute to the disease burden among children⁵. Children with T2D experience higher rates of complications, more aggressive disease, and show less responsiveness to treatment than adults⁴.

Across all age groups, high body mass index (>25) is the most significant risk factor for developing T2D⁶

Long-term complications of T2D

T2D is routinely described as a metabolic disorder characterised by hyperglycaemia arising from defects in insulin secretion, insulin function, or both. People with T2D demonstrate insulin resistance (IR) and relative insulin deficiency. The pathologic hallmark of T2D involves damage and breakdown of the vasculature, leading to both microvascular and macrovascular complications. Chronic hyperglycaemia, as seen in T2D, is associated with long-term damage and failure of various organ systems, predominantly the eyes, nerves, kidneys and heart⁷. Microvascular complications include retinopathy, nephropathy and neuropathy, while macrovascular complications are associated with cardiovascular diseases (CVD) and stroke (Figure 1).

Figure 1. Summary of the incidence of microvascular and macrovascular complications observed in the A₁chieve, IMPROVE, IDMPS and DISCOVER studies^8-11.

Macrovascular complications of T2D

Diabetes and prediabetes are strongly associated with CVD. Adults with diabetes have a higher prevalence of CVD (32–35%)^12-14, indicating a significant unmet need for the management and reduction of CV risk factors (Figure 2). CVD is a leading cause of mortality among people with T2D and, on average, reduces life expectancy by 10 years¹³. In people with T2D, heart failure frequently presents as the first CV event. Individuals with prediabetes are 9–58% more likely to develop heart failure, and are also at a higher risk of all-cause mortality and cardiac outcomes than those with normoglycaemia¹⁵. Further, T2D increases the risk of long-term CV complications such as coronary artery disease (160% increase), ischemic heart disease (127% increase) and haemorrhagic stroke (56% increase)¹⁶.

Figure 2. Relative prevalence of cardiovascular disease with one or more risk factors¹⁴.
BMI, body mass index; CVD, cardiovascular disease; DBP, diastolic blood pressure; HbA1c, glycated haemoglobin; SBP, systolic blood pressure.

The relative risk of vascular events is proportionally higher in women, children, people with long-term diabetes and in the presence of microvascular complications, most notably renal disease or proteinuria¹⁷.

Microvascular complications of T2D

Long-term microvascular complications of T2D predominantly affect small blood vessels. These typically include retinopathy, nephropathy and neuropathy.

Diabetes nephropathy is the most common microvascular complication of T2D, affecting ~40% of patients

In T2D, hypertension frequently precedes chronic kidney disease, and contributes to nephropathy progression¹⁸. Diabetes or hypertension, or a combination of the two, are responsible for causing up to 80% of end-stage kidney disease, with considerable mortality and morbidity¹⁶. People with T2D and chronic kidney disease have a threefold increase in the risk of mortality from a heart attack or stroke when compared with those with T2D alone¹⁹.

Diabetic retinopathy annual incidence ranges from 2‒13% worldwide²⁰. It has historically been thought to be a primary vasculopathy; new evidence suggests that it may be the result of diabetic retinal neurodegeneration. If left untreated, retinopathy will evolve into serious complications, including blindness²¹.

Diabetic neuropathy affects about 41% of patients beyond 10 years of the disease's onset and 10–20% at the time of diagnosis²². However, nearly half of all patients are not diagnosed²³. If undiagnosed and untreated, the condition may lead to Charcot neuroarthropathy, foot ulceration and eventually foot amputation, all of which have significant negative effects on quality of life and lifespan²¹.

Erectile dysfunction is an often overlooked complication that appears to affect three times more T2D patients than non-T2D patients²¹. Erectile dysfunction appears 3‒5 years before the onset of coronary artery disease. The primary prevention of coronary artery disease may therefore benefit from patient screening for the existence of erectile dysfunction, particularly in younger patients with T2D²⁴.

Common risk factors for the emergence of microvascular complications include the duration of T2D as well as glycaemic, blood pressure and cholesterol management²¹

Economic burden of T2D

T2D can have a significant economic impact on both individuals and society as a whole. The cost of managing diabetes includes the cost of medications, medical appointments and hospitalisations. Direct costs were up to nine times higher in patients with T2D-related complications compared with those without²⁵.

Additionally, individuals with diabetes may have increased absenteeism from work, reduced productivity while at work and a higher risk of disability^17,26. The total global healthcare expenditure for people with diabetes aged 18–99 years was estimated at US $850 billion in 2017 and is expected to increase by 7% by 2045²⁷. In addition, T2D disproportionately affects certain populations, such as low-income individuals and minority groups, which can exacerbate existing health disparities.

Age, complications and comorbidities are the major cost drivers of T2D (Figure 3 and Figure 4)²⁵.

Figure 3. Mean total annual direct costs per patient in patients with or without complications (Adapted)²⁵.

Figure 4. Mean total annual direct costs per patient in patients with different types of complications (Adapted)²⁵.
CARD, coronary artery disease; CeVD, cerebrovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; MAC, macrovascular events; MIC, microvascular events; NEPH, nephropathy; PVD, peripheral vascular disease; RETI, retinopathy.

The increasing prevalence of T2D implies a significant increase in CV and renal diseases and, consequently, a high burden on healthcare providers and the economy

T2D treatment

Treatment options for T2D

The foundation of treatment for type 2 diabetes (T2D) is dietary adjustment and increased physical activity to facilitate weight loss, which have been demonstrated in clinical trials to be more beneficial than medication at preventing diabetes²⁸.

The selection of drugs should focus on reducing the treatment burden, establishing glucose control, and lowering the risk of microvascular and macrovascular complications. Individualising treatment goals is critical, and a collaborative decision-making process with the patient may aid in the selection of therapeutic options and treatment compliance^29-33. Table 1 lists the characteristics of commonly used antidiabetic medications.

Table 1. Characteristics of commonly used antihyperglycaemic medication classes^32,34,35.

Newer drugs with proven cardiovascular (CV) benefits may also help some people who are at high risk for CV disease (Table 2 and Table 3).

Table 2. Summary of GLP-1 analogues in cardiovascular outcomes trials (CVOT).

Table 3. Outcomes of sodium–glucose cotransporter 2 inhibitors in cardiovascular outcomes trials (CVOT).

New drugs for T2D management

Professor Caroline Apovian discusses some of the new additions to treatment options for T2D in the video below.

Additions to treatment options for type 2 diabetes

Tirzepatide is novel first-in-class drug used to treat T2D. It is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist³⁹. The SURPASS-5 clinical trial found that 5 mg per week dosing reduced HbA1c levels by -2.11% vs -0.86% with placebo. Tirzepatide resulted in a -2.34% reduction in HbA1c at the highest dose of 15 mg per week over a period of 40 weeks. With 5 mg of tirzepatide, a weight loss of 5.4 kg was observed, and a weight loss of 10.5 kg was observed with 15 mg dosing. This dose-dependent relationship with weight loss is similar to semaglutide^40,41.

The U.S. Food and Drug Administration (FDA) has recently approved bexagliflozin, a sodium–glucose cotransporter-2 (SGLT2) inhibitor, for the treatment of adults with T2D. In the BEST trial, the drop in HbA1c from baseline at Week 24 was 0.48% lower in the bexagliflozin group than in the placebo group. Overweight or obese patients in the bexagliflozin group lost 3 kg on average versus 0.38 kg in the placebo group (a difference of 2.65 kg)⁴².

Treatment sequencing for T2D

Unless it is contraindicated or not tolerated, metformin is usually the first oral medication used to treat T2D after diagnosis, coupled with lifestyle changes. Specific GLP-1 analogues or SGLT2 inhibitors with established CV benefits are advised for patients with established atherosclerotic CV disease, heart failure or chronic kidney disease (Figure 5)⁴³.

Figure 5. Glycaemic control algorithm (Adapted)⁴⁴.
*Order of medications represents a suggested hierarchy of usage; length of line reflects strength of recommendation. †If not at goal in 3 months, proceed to next level therapy. ‡CKD 3: canagliflozin; HFrEF: dapagliflozin. AGi, alpha-glucosidase inhibitor; ASCVD, atherosclerotic cardiovascular disease; CGM, continuous glucose monitoring; CKD 3, stage 3 chronic kidney disease; DPP4i, dipeptidyl peptidase 4 inhibitor; GLN, glinide; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HFrEF, heart failure with reduced ejection fraction; LA, long-acting (≥ 24 hour duration); MET, metformin; QR, quick release; SGLT2i, sodium–glucose cotransporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinediones.

References

1. International Diabetes Federation. IDF Diabetes Atlas 10th Edition 2021. Available at https://diabetesatlas.org/idfawp/resource-files/2021/07/IDF_Atlas_10th_Edition_2021.pdf. Accessed 16 Jan 2023.
2. Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al Kaabi J. Epidemiology of type 2 diabetes - global burden of disease and forecasted trends. J Epidemiol Glob Health. 2020;10(1):107–111.
3. Todd JN, Srinivasan S, Pollin TI. Advances in the genetics of youth-onset type 2 diabetes. Curr Diab Rep. 2018;18(8):57.
4. Cioana M, Deng J, Nadarajah A, Hou M, Qiu Y, Chen SSJ, et al. The prevalence of obesity among children with type 2 diabetes: a systematic review and meta-analysis. JAMA Netw Open. 2022;5(12):e2247186.
5. International Diabetes Federation. Type 2 diabetes. Available at https://www.idf.org/aboutdiabetes/type-2-diabetes.html. Accessed on 16 Jan 2023.
6. Safiri S, Karamzad N, Kaufman JS, Bell AW, Nejadghaderi SA, Sullman MJM, et al. Prevalence, deaths and disability-adjusted-life-years (DALYs) due to type 2 diabetes and its attributable risk factors in 204 countries and territories, 1990-2019: results from the Global Burden of Disease Study 2019. Front Endocrinol (Lausanne). 2022;13:838027.
7. Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: distinct or continuum? Indian J Endocrinol Metab. 2016;20(4):546–51.
8. Litwak L, Goh SY, Hussein Z, Malek R, Prusty V, Khamseh ME. Prevalence of diabetes complications in people with type 2 diabetes mellitus and its association with baseline characteristics in the multinational A1chieve study. Diabetol Metab Syndr. 2013;5(1):57.
9. Valensi P, Benroubi M, Borzi V, Gumprecht J, Kawamori R, Shaban J, et al. The IMPROVE study—a multinational, observational study in type 2 diabetes: baseline characteristics from eight national cohorts. Int J Clin Pract. 2008;62:1809–19.
10. Chan JC, Gagliardino JJ, Baik SH, Chantelot JM, Ferreira SR, Hancu N, et al. Multifaceted determinants for achieving glycemic control: the international diabetes management practice study (IDMPS). Diabetes Care. 2009;32:227–33.
11. Kosiborod M, Gomes MB, Nicolucci A, Pocock S, Rathmann W, Shestakova MV, et al. Vascular complications in patients with type 2 diabetes: prevalence and associated factors in 38 countries (the DISCOVER study program). Cardiovasc Diabetol. 2018;17(1):150.
12. Mosenzon O, Alguwaihes A, Leon JLA, Bayram F, Darmon P, Davis TME, et al. CAPTURE: a multinational, cross-sectional study of cardiovascular disease prevalence in adults with type 2 diabetes across 13 countries. Cardiovasc Diabetol. 2021;20(1):154.
13. Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovasc Diabetol. 2018;17(1):83.
14. McGurnaghan S, Blackbourn LAK, Mocevic E, Haagen Panton U, McCrimmon RJ, Sattar N, et al. Cardiovascular disease prevalence and risk factor prevalence in type 2 diabetes: a contemporary analysis. Diabet Med. 2019;36(6):718–725.
15. Ceriello A, Catrinoiu D, Chandramouli C, Cosentino F, Dombrowsky AC, Itzhak B, et al. Heart failure in type 2 diabetes: current perspectives on screening, diagnosis and management. Cardiovasc Diabetol. 2021;20(1):218.
16. International Diabetes Federation. IDF Diabetes Atlas Ninth Edition 2019. Available at https://diabetesatlas.org/upload/resources/material/20200302_133351_IDFATLAS9e-final-web.pdf. Accessed 16 Jan 2023.
17. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). European Heart Journal, 2020;41(2):255–323.
18. Umanath K, Lewis JB. Update on diabetic nephropathy: Core Curriculum 2018. Am J Kidney Dis. 2018;71(6):884–895
19. American Heart Association. Heart Health: The link between type 2. Available at https://www.knowdiabetesbyheart.org/wpcontent/uploads/2022/12/89159_KDBH_Kidney_HeartHealth.pdf. Accessed 17 Jan 2023.
20. Sabanayagam C, Banu R, Chee ML, Lee R, Wang YX, Tan G, et al. Incidence and progression of diabetic retinopathy: A systematic review. Lancet Diabetes Endocrinol 2018;8587:1–10.
21. Faselis C, Katsimardou A, Imprialos K, Deligkaris P, Kallistratos M, Dimitriadis K. Microvascular complications of type 2 diabetes mellitus. Curr Vasc Pharmacol. 2020;18(2):117–124.
22. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993;43(4):817-24.
23. Pop-Busui R, Boulton AJ, Feldman EL, Bril V, Freeman R, Malik RA, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-154.
24. Vlachopoulos CV, Terentes-Printzios DG, Ioakeimidis NK, Aznaouridis KA, Stefanadis CI. Prediction of cardiovascular events and all-cause mortality with erectile dysfunction: a systematic review and meta-analysis of cohort studies. Circ Cardiovasc Qual Outcomes. 2013;6(1):99–109.
25. Alzaid A, Ladrón de Guevara P, Beillat M, Lehner Martin V, Atanasov P. Burden of disease and costs associated with type 2 diabetes in emerging and established markets: systematic review analyses. Expert Rev Pharmacoecon Outcomes Res. 2021(4):785–798.
26. American Diabetes Association. The cost of diabetes. Available at https://diabetes.org/about-us/statistics/cost-diabetes. Accessed 17 Jan 2023.
27. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271–281.
28. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.
29. Garber AJ, Handelsman Y, Grunberger G, Einhorn D, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2020 executive summary. Endocr Pract. 2020;26(1):107–39.
30. Handelsman Y, Bloomgarden ZT, Grunberger G, Umpierrez G, Zimmerman RS, Bailey TS, et al. American Association of Clinical Endocrinologists and American College of Endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015. Endocr Pract. 2015;21 Suppl 1:1–87.
31. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 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):140–9.
32. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S125–S43.
33. American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S144–S74.
34. Sherifali D, Nerenberg K, Pullenayegum E, Cheng JE, Gerstein HC. The effect of oral antidiabetic agents on A1C levels: a systematic review and meta-analysis. Diabetes Care. 2010;33(8):1859–64.
35. Chaudhury A, Duvoor C, Reddy Dendi VS, Kraleti S, Chada A, Ravilla R, et al. Clinical review of antidiabetic drugs: implications for type 2 diabetes mellitus management. Front Endocrinol (Lausanne). 2017;8:6.
36. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–57.
37. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22.
38. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–1844.
39. Tirzepatide (Mounjaro) for type 2 diabetes. Med Lett Drugs Ther. 2022;64(1654):105–107.
40. Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: The SURPASS-5 randomized clinical trial. JAMA. 2022;327(6):534–545.
41. Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503–515
42. McMurray JJ, Freeman MW, Solomon S, Massaro J, Solomon S, Lock JP, et al. 32-OR: The bexagliflozin efficacy and safety trial (BEST): a randomized, double-blind, placebo-controlled, phase IIII, clinical trial. Diabetes. 2020;69(Supplement_1):32-OR.
43. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121–130.
44. American Association of Clinical Endocrinology. AACE comprehensive type 2 diabetes management algorithm 2020. Available at https://pro.aace.com/pdfs/diabetes/AACE_2019_Diabetes_Algorithm_03.2021.pdf. Accessed 18 Jan 2023.