Achieving “optimal” glycemic control: individualization of target





Stephen COLAGIURI, Stephen COLAGIURI, MD
Boden Institute
University of Sydney
Sydney, New South Wales
AUSTRALIA

Achieving “optimal”
glycemic control:
individualization of target

 

by S. Colagiuri, Australia

Although improved glycemic control has been shown to prevent or reduce complications in patients with type 2 diabetes, intensive glycemic control may not benefit every patient, and may in some cases be harmful. In particular, the occurrence of serious hypoglycemia is of concern, especially since it may increase the risk of adverse cardiovascular outcomes. Setting glycemic targets therefore requires careful balancing of potential benefits and harms, and should take into account an individual’s phenotypic characteristics. Consequently, a patient-centered approach to the medical management of diabetes is now increasingly emphasized in diabetes management guidelines, and the HbA1c target of 7.0% suggested by most guidelines should be considered as a starting point from which to set patient-specific targets according to individual patient factors. The main factors that are usually considered include age, hypoglycemia risk, diabetes duration, and presence of complications, comorbidities, and impaired renal function. Patient preferences are also important, and the target should be agreed between patient and health professional. HbA1c targets will also be influenced by previous attempts to optimize glycemic control: a lower target may be set if it can be easily and safely achieved, and conversely, a higher target should be considered when previous attempts to optimize glycemic control have been associated with unacceptable adverse effects. Once set, the chosen HbA1c target should be reviewed regularly, taking into account benefits, safety, and tolerability, and adjusted when clinical circumstances change.

Medicographia. 2016;38:14-19 (see French abstract on page 14)

Improved glycemic control prevents or reduces diabetes-related complications.1,2 However, intensive glycemic control may not benefit every person and may sometimes be harmful.3 Phenotypic characteristics of individuals with type 2 diabetes are important determinants in balancing the benefits and harms of more intensive glycemic control. Consequently, individualizing diabetes care plans, including patient- specific targets, is increasingly emphasized in diabetes guidelines.4,5 In focusing on glycemic control it should be noted that it is only one element of multifactorial treatment which should also consider healthy lifestyle changes, blood pressure and lipid control, and possibly, antiplatelet therapy.

While glycemic control targets include fasting and postprandial glucose levels, the main focus remains the glycated hemoglobin (HbA1c) level. Guidance on general HbA1c targets is informed by intervention studies and from epidemiological analyses of randomized controlled trials (RCTs). Tables I and II summarize the major RCTs that have examined the effects of intensive glycemic control, with or without prespecified HbA1c targets. The majority of studies reported microvascular benefits with an achieved HbA1c of around7.0%, while the ACCORD study (Action to Control CardiOvascular Risk in Diabetes) reported adverse mortality outcomes with an achieved HbA1c in the intensive group of 6.4%.3 All studies reported an increase risk of hypoglycemia with lower HbA1c levels.

Table I
Table I. Outcome studies with prespecified HbA1c targets.

Abbreviations: ACCORD, Action to Control CardiOvascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR
Controlled Evaluation; HbA1c, glycated hemoglobin; MR, modified release; VADT, Veterans Affairs Diabetes Trial.

Table II
Table II. Outcome studies comparing intensive and conventional therapy without prespecified HbA1c targets.

Abbreviations: DCCT, Diabetes Control and Complications Trial; HbA1c, glycated hemoglobin; MDI, multiple daily injections; UKPDS, United Kingdom Prospective
Diabetes Study.

Most guidelines recommend an HbA1c target below 7.0% measured by a DCCT (Diabetes Control and Complications Trial)-aligned assay in order to minimize the risk of developing diabetes-related complications and minimize the risk of adverse events, especially hypoglycemia.

Individualizing targets

A general HbA1c target is useful for assessing quality of care at a population level. At an individual level it is also useful as a starting point for individualizing a treatment goal and guiding and changing interventions if the target is not attained.

Setting and adjusting HbA1c treatment targets should balance potential benefits and possible harms, and a number of publications have suggested ways in which targets can be personalized.5,9-12

Personalizing an HbA1c target is based on an individual’s phenotypic characteristics. The main factors that are usually considered include age, hypoglycemia risk, diabetes duration, complications, comorbidities, and renal function. In addition, there are a number of relevant practical considerations.

Patient preferences are important, and the target should be agreed between patient and health professional. HbA1c targets will also be influenced by experience of previous attempts to optimize glycemic control: a lower target may be considered if it is easily and safely achieved, and conversely, a higher target should be considered when previous attempts to optimize control have been associated with unacceptable consequences. The target should be regularly reviewed taking into account benefits, safety, and tolerability, and adjusted according to the clinical course of the individual.

Considerations in individualizing HBA1c treatment targets.

Age
Age is an important consideration with younger people having a greater potential than older people to benefit from lower HbA1c targets, which is related primarily to longer life expectancy and the potential harm of a longer exposure to hyperglycemia.

HbA1c targets frequently require modifying in older people with diabetes. The International Diabetes Federation (IDF) guidance for the management of older people with diabetes is based not on age per se but on functional categorization of older people with diabetes, taking into consideration comorbidities and functional status. Significant for diabetes and setting HbA1c targets is an increased vulnerability to hypoglycemia, diminishing life expectancy, and cognitive dysfunction and frailty.13

The IDF guidelines describe three main categories for older individuals with diabetes as a basis for clinical decision-making, including setting glycemic targets and treatment intensification (Table III).

Category 1: Functionally independent
This category includes people who are living independently, have no important impairments of activities of daily living (ADL), and who are receiving none or minimal caregiver support. The usual HbA1c target is 7.0%-7.5% and the full range of therapeutic options can be considered in this category.

Category 2: Functionally dependent
This category includes individuals who, due to loss of function, have impairments of ADL such as bathing, dressing, or personal care and are at particular risk of requiring admission to a care (nursing) home. The usual HbA1c target is 7.0%- 8.0%. There should be an emphasis on choosing medications with a low potential for hypoglycemia and simplified insulin regimens with a low hypoglycemic risk.

Table III
Table III. General glycemic targets according to functional category

After reference 13: International Diabetes Federation. IDF global guideline for
managing older people with type 2 diabetes. 2013. http://www.idf.org/guidelines/
managing-older-people-type-2-diabetes. © 2013, International Diabetes
Federation.

This category includes two particular subgroups requiring special consideration:
Frailty, which is characterized by a combination of significant fatigue, recent weight loss, severe restriction in mobility and strength, increased propensity to falls, and increased risk of institutionalization. Frailty affects up to 25% of older people with diabetes. An HbA1c target up to 8.5% may be appropriate. Medications that might cause nausea or gastrointestinal disturbance or excess weight loss (eg, metformin, glucagonlike peptide-1 [GLP-1] receptor agonists, sodium-glucose transport protein 2 [SGLT2] inhibitors) should be avoided or discontinued.

Dementia, which is characterized by cognitive impairment with significant memory problems, a degree of disorientation or a change in personality, and an inability to self-care. Many will be relatively physically well. An HbA1c target up to 8.5% may be appropriate and caregivers and/or family should be educated to recognize the subtle indicators of hypoglycemia. The emphasis of treatment is on patient safety, avoiding hypoglycemia and unacceptable hyperglycemia, using simplified regimens and providing family/patient education and support.

Category 3: End of life care
This category includes individuals with a significant medical illness or malignancy and whose life expectancy has been reduced to less than1 year. The glycemic target is to avoid symptomatic hyperglycemia, minimize the risk of hypoglycemia, and consider appropriate withdrawal of therapy, including insulin, during the terminal stage.

Hypoglycemia
Occurrence of or potential risk of severe hypoglycemia is a major consideration in setting glycemic targets. Hypoglycemia is the most common adverse effect of blood glucose–lowering therapy and its occurrence is influenced by treatment modality and complexity, factors which affect metabolism of the medication, particularly renal impairment,14,15 and patient factors including adherence to treatment regimen, mental function, and hypoglycemia awareness.16 Severe hypoglycemia impacts the quality of life, increases the risk of falls and injuries, and may increase the risk of adverse cardiovascular outcomes. The ADVANCE study (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) reported an association between severe hypoglycemia and increased risk of cardiovascular death.17 However, the annual death rate was actually lower in the group receiving intensive treatment (3.6% vs 5.1%). Despite the higher rate of severe hypoglycemia, intensive glucose control was not associated with excess mortality. While the reason for the increased all-cause mortality in the ACCORD study remains unexplained, intensive treatment tripled the frequency of severe hypoglycemia and speculation continues that this may have contributed to the increased mortality. Simultaneous 24-h ECG and continuous glucose monitoring have reported an association between nocturnal hypoglycemia and prolonged corrected QT interval, and disturbing changes in cardiac rate and rhythm.18

People who experience recurrent severe hypoglycemia or in whom there is a high risk associated with possible severe hypoglycemia (eg, with certain occupations or the elderly who live alone), should have their HbA1c target increased by about 0.5%.

Duration of diabetes
Interventions in the earlier stages of type 2 diabetes are generally considered to be associated with better outcomes, but the evidence is limited. This has been interpreted to support setting lower HbA1c targets with shorter diabetes duration. The UKPDS (United Kingdom Prospective Diabetes Study) is the only outcome study in people with newly diagnosed diabetes and showed benefits on microvascular outcomes of more intensive control compared with conventional treatment. 2 With longer-term follow up, benefits emerged in relation to risk reductions in myocardial infarction and death from any cause.19 The evidence in relation to the long-term effects of intensive glycemic control in people with type 2 diabetes with longer diabetes duration has been mixed. The ADVANCE-ON study of subjects with diabetes duration of 8 years at the time of recruitment did not find emerging benefits of more intensive vs conventional treatment.20 The VADT study (Veterans Affairs Diabetes Trial) in people with type 2 diabetes duration of 11.5 years at recruitment, recently reported emerging long-term benefits of intensive glycemic control in time to the first major cardiovascular event.21 In addition to potential outcome benefits, more aggressive treatment in people with shorter duration of diabetes may be associated with less potential harm from hypoglycemia.

Diabetes complications
The presence of complications is another consideration when setting HbA1c targets. All studies of intensive blood glucose– lowering interventions have shown that lower HbA1c levels reduce the development or progression of microvascular complications.1,2,6-8 Therefore, people with no or early signs of microvascular complications could potentially benefit from tighter control, provided there are no other modifying considerations. There is limited evidence of the benefits of tight glycemic control per se on macrovascular disease in the short term, but there is accumulating evidence that benefits may accrue in the longer term.19,21 Multifactorial treatment including more intensive glycemic control has been shown to be beneficial both in the short and longer term in reducing premature mortality and a range of macrovascular and microvascular outcomes.22,23

A group of particular interest is people with diabetes with established cardiovascular disease, a common occurrence in type 2 diabetes. There is no convincing evidence that tight glycemic control has particular benefits in this group as evidenced from a number of outcome studies including ACCORD,3 ADVANCE,6 and ORIGIN (Outcome Reduction with an Initial Glargine Intervention).24 As noted in the hypoglycemia section, caution is warranted in setting low HbA1c targets in people with established cardiovascular disease because of the potential risk associated with the occurrence of severe hypoglycemia related to the increased risk of adverse outcomes and predisposition to induce arrhythmias. Consequently, the presence of established cardiovascular disease warrants a more cautious approach and adopting a less stringent HbA1c target.

Comorbidities
Comorbidities are common in people with type 2 diabetes, especially with increasing age and diabetes duration. Concomitant treatment of significant comorbidities increases the number of medications and the overall burden of disease, and increases the risks associated with complex management regimens, including poor adherence due to errors, confusion, and side effects. Higher HbA1c targets should be considered in these patients.

Impaired renal function
Renal insufficiency is an important consideration in choosing blood glucose–lowering therapy due to the potential effect of impaired renal function in altering drug metabolism. This may result in an increase in the medication’s blood glucose– lowering effect, thereby increasing the risk of hypoglycemia (eg, certain sulfonylureas), or it may diminish its efficacy (eg, SGLT2 inhibitors), or may result in the accumulation of potentially harmful metabolites (eg, metformin).

In addition, in patients with diabetes and chronic kidney disease, HbA1c may not accurately reflect glycemic control. Factors which may contribute to this effect include increased levels of urea directly interacting with HbA1c assays, reduced erythropoiesis, shortened red blood cell half-life, the use of iron and erythropoiesis stimulating agents (ESAs), and blood transfusions. A recent study reported that in people with type 2 diabetes and chronic kidney disease, the usual linear rela tionship observed between HbA1c and average glucose is attenuated by use of ESAs and results in a systematic underestimation of the average glucose level derived from HbA1c.25

Consequently, there are a number of competing considerations when setting HbA1c targets in people with type 2 diabetes and renal insufficiency. It is therefore important when setting and reviewing HbA1c targets to monitor renal function closely— especially in older people—by measuring creatinine and calculating the estimated glomerular filtration rate (eGFR).

Conclusion

Glycemic control is closely related to diabetes-specific complications, and more intensive glycemic control has been shown unequivocally to prevent or reduce these complications. However, overly aggressive blood glucose–lowering can be associated with harms, particularly the occurrence of serious hypoglycemia. Consequently, setting glycemic targets requires careful balancing of potential benefits and harms. Although most guidelines suggest a general HbA1c target of 7.0%, this should be considered only as a starting point from which individual patient factors should be taken into consideration in setting a specific target for an individual. There are several factors that influence an individual’s risk-to-benefit ratio and which need to be considered, including age, duration of diabetes, risk of hypoglycemia, and presence of complications, comorbidities, and impaired renal function. Once set, the appropriateness of the chosen HbA1c target should be frequently reviewed and modified if necessary, especially when individual patient circumstances change. ■

References
1. DCCT Study Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986.
2. 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;352:854-865.
3. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.
4. International Diabetes Federation: Global Guideline for Type 2 Diabetes. Diabetes Res Clin Pract. 2014;104:1-52
5. Inzucchi SE, Bergenstal RM, Buse JB, 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;38:140-149.
6. ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
7. Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139.
8. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103-117.
9. Cheung WN, Conn JJ, D’Emden MC, et al. Position statement of the Australian diabetes society: Individualisation of glycated haemoglobin targets for adults with diabetes mellitus. Med J Aust. 2009;191:339-344.
10. Eldor R, Raz I. The Individualized Target HbA1c: A New Method for Improving Macrovascular Risk and Glycemia Without Hypoglycemia and Weight Gain. Rev Diabet Stud. 2009;6:6-12.
11. Buse JB. Type 2 diabetes mellitus in 2010: individualizing treatment targets in diabetes care. Nat Rev Endocrinol. 2011;7:67-68.
12. Ismail-Beigi F, Moghissi E, Tiktin M, Hirsch IB, Inzucchi SE, Genuth S. Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med. 2011;154:554-559.
13. International Diabetes Federation. IDF global guideline for managing older people with type 2 diabetes. 2013. http://www.idf.org/guidelines/managing-olderpeople- type-2-diabetes. Accessed October 12, 2015.
14. Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities. Diabetes Care. 2005;28: 2948-2961.
15. Schernthaner G, Ritz E, Schernthaner GH. Strict glycaemic control in diabetic patients with CKD or ESRD: beneficial or deadly? Nephrol Dial Transplant. 2010; 25:2044-2047.
16. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007;50: 1140-1147.
17. Zoungas S, Patel A, Chalmers J, et al; ADVANCE Collaborative Group. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010; 363:1410-1418.
18. Gill GV, Woodward A, Casson IF, Weston PJ. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes – the ‘dead in bed’ syndrome revisited. Diabetologia. 2009;52:42-45.
19. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589.
20. Zoungas S, Chalmers J, Neal B, et al; ADVANCE-ON Collaborative Group. Follow-up of Blood-Pressure Lowering and Glucose Control in Type 2 Diabetes. N Engl J Med. 2014;371:1392-1406.
21. Hayward RA, Reaven PD, Wiitala WL, et al; VADT Investigators. Follow-up of Glycemic Control and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;372:2197-2206.
22. Gæde P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393.
23. Gæde P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes – STENO 2. N Engl J Med. 2008; 358:580-591.
24. The ORIGIN Trial Investigators. Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia. N Engl J Med. 2012;367:319-328.
25. Lo C, Lui M, Ranasinha S, Teede HJ, et al. Defining the relationship between average glucose and HbA1c in patients with type 2 diabetes and chronic kidney disease. Diabetes Res Clin Pract. 2014;104:84-91.

Keywords: diabetes; glycemic control; HbA1c target; individualized care