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What the studies say about targets for glycaemic control (including hypoglycaemia)

Comment by Kamlesh Khunti, Leicester General Hospital, UK For the EAPC Diabetes and CVD Educational Programme

Risk Factors and Prevention


Clinical trials in both type 1 and type 2 diabetes have demonstrated the connection between hyperglycaemia and the complications of diabetes (1,2,3) To reduce long-term microvascular complications trials have supported reducing glycaemia levels (4, 16). The evidence on reduction of macrovascular complications is not clear (5). A singular blood glucose target for people with diabetes has not been robustly studied due to the nature of our individuality; what target is right for one person might not be right for another (4,5). There is also the difficulties and risks associated with obtaining and then maintaining tight glycaemic control (6-15).

The large cohort studies DCCT and the UKPDS could not maintain HbA1c levels in the normal (non-diabetic) range for the people enrolled into their intensive-treatment arms (2, 12, 13). However, the intensively managed UKPDS participants did demonstrate the later termed “legacy effect” gained by attaining good glycaemic control early in their diabetes journey (12, 13). The “legacy effect” describes the long-term microvascular risk reduction that continues to benefit the initially intensively managed person with diabetes for many years (16). Such people were also shown to benefit from cardiovascular (CV) relative risk reduction that can emerge later in their life (11). It stands to reason that those with longer life expectancy will benefit the most from early tight control of their glucose levels (5).

Trying to achieve near normal HbA1c levels can create risk, including hypoglycaemia. Hypoglycaemia is a prognostic marker for mortality risk (16, 17). The ACCORD study linked tight glycaemic control to CV harm (18). However, one of the issues with ACCORD was that it enrolled people with high CV risk and multi co-morbidities; such people are not representative of the large numbers of newly diagnosed patients with low CV risk who would benefit from tight control (4).

The biggest cause of mortality in people with type 2 diabetes is atherosclerotic cardiovascular disease (ASCVD) (20). We know from the UKPDS, a lowing of HbA1c by 11mmol/mol (1%) was estimated to equate to a 37% lower risk for microvascular complications (1). Studies support the view that the lower the HbA1c without hypoglycaemia, the lower the long-term risks of microvascular and CV events (1, 6).

The balance of risks to benefits should be assessed for the individual person with diabetes. The European ASD and the ADA recently updated their guidelines (2018) to reflect the options available to treat individuals with a tailored person-centred approach (5). The guidelines reflect the development of advanced treatments for diabetes that have demonstrated their CV and or renal benefits in addition to glycaemic control without causing hypoglycaemia (20-24). The guidelines also reflect other characteristics/needs that make us individuals. For example, if weight is an issue then there is a recommended treatment course, using therapies that have been shown to reduce weight. Whereas if the person is self-funding and cost is an issue then there is a different lower-cost treatment course is recommended (5).

A good example of the need to treat people with diabetes as individuals, are elderly people or those with reduced life expectancy. In these people treatment targets should be to improve quality of life and reduce symptomatic hyperglycaemia, ketoacidosis or hypoglycaemia (25, 26). The International Diabetes Federation (IDF) published a useful guide to help clinicians adjust targets to such individuals (27).

Therefore setting glycaemic targets should be done at an individual level. Trials have found the benefits of tight control, especially early on in the individual’s diabetes journey, but the benefits of this compared to the risks have to be assessed for the individual.

Davies MJ et al. Diabetes Care 2018. Sep; dci180033. https://doi.org/10.2337/dci18-0033;

 

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The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology

 

References

1. Stratton IM, Adler AI, Neil HA et al. (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. British Medical Journal 321(7258):405–412. 1. Stratton IM, Adler AI, Neil HA et al. (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. British Medical Journal 321(7258):405–412.

2. Diabetes Control and Complications Trial Research Group (1993) The effect of intensive diabetes treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus: the Diabetes Control and Complications Trial. New England Journal of Medicine 329:978–986

3. Morgan CL, Currie CJ, Peters JR. (2000) Relationship between diabetes and mortality: a population study using record linkage. Diabetes Care 23(8):1103–1107.
4. Riddle MC, Gerstein HC, Holman RR et al (2018) A1c targets should be personalised to maximise benefits while limiting risks. Diabetes Care 41:1121-1124

5. Davies MJ, D’Alessio DA, Fradkin J et al. (2018) Management of Hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetologia 61: 2461-2498

6. White NH, Sun W, Cleary PA, et al. (2008) Diabetes Control and Complications/Epidemiology of Diabetes Interventions and Complications Research Group. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial. (EDIC)Arch Ophthalmol 126:1707–1715pmid:19064853

7. Hemmingsen B, Lund SS, Gluud C et al. (2011) Intensive glycaemic control for patients with type 2 diabetes: Systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. British Medical Journal (Online).343 (7834) (pp 1136), 

8. Reichard P, Nilsson B-Y, Rosenqvist U (1993) The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. New England Journal of Medicine 329:304–309

9. Eastman RC, Javitt JC, Herman WH et al. (1997) Model of complications of NIDDM. II. Analysis of the health benefits and cost-effectiveness of treating NIDDM with the goal of normoglycemia. Diabetes Care 20: 735-44

10. Clarke PM, Gray AM, Briggs A et al. (2005) Cost-utility analyses of intensive blood glucose and tight blood pressure control in type 2 diabetes (UKPDS 72). Diabetologia 48: 868-77

11. Holman RR, Paul SK, Bethel MA et al. (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. New England Journal of Medicine 359:1577–1589

12. UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complication in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853

13. UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood glucose control with metformin on complication in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865

14. Turnbull FM, Abraira C, Anderson RJ, et al. (2009) Control Group. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 52:2288–2298pmid:19655124

15. Ohkubo Y, Kishikawa H, Araki E et al (1995) Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with NIDDM: a randomized prospective 6-year study. Diabetes Research Clinical Practice 28:103–117

16. Mellbin LG, Rydén L, Riddle MC, et al.; ORIGIN Trial Investigators. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. European Heart Journal 2013;34:3137–3144pmid:23999452

17. Standl E, Stevens SR, Armstrong PW, et al.; TECOS Study Group. Increased risk of severe hypoglycemic events before and after cardiovascular outcomes in TECOS suggests an at-risk type 2 diabetes frail patient phenotype. Diabetes Care 2018;41:596–603pmid:29311155

18. Gerstein HC, Miller ME, Byington RP, et al.; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes (ACCORD). New England Journal of Medicine 2008;358:2545–2559pmid:18539917

19. ADA (2018) 9. Cardiovascular disease and risk management: standards of medical care in diabetes- 2018 Diabetes Care 41:S86-S104

20. Marso SP, Daniels GH, Brown-Frandsen K, et al.; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–322pmid:27295427

21. Marso SP, Bain SC, Consoli A, et al.; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–1844pmid:27633186

22. Zinman B, Wanner C, Lachin JM, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–2128pmid:26378978

23. Neal B, Perkovic V, Mahaffey KW, et al.; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–657pmid:28605608

24. Wiviott SD, Raz I, Bonaca MP et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes (DECLARE-TIMI) N Engl J Med 2019; 380:347-357

25. Testa MA, Simonson DC. Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled, double-blind trial. JAMA 1998;280:1490–1496pmid:9809729

26. Kitabchi AE, Umpierrez GE, Miles JM et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009;32:1335–1343pmid:19564476

27. International Diabetes Federation (IDF) Managing Older People With Type 2 Diabetes: Global Guideline 2013 available at: https://www.idf.org/component/attachments/attachments.html?id=985&task=download accessed January 2019

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