Karen Blackwood discusses considerations when individualising care and setting glycaemic targets for adult patients with type 2 diabetes, with a focus around decision making when escalating treatment.

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Read this article to learn more about:

  • individualising care and treatment for adult patients with type 2 diabetes
  • glycaemic targets, and situations when these should be relaxed
  • treatment options for type 2 diabetes.

One of the key messages of the updated NICE guideline Type 2 diabetes in adults: management is individualised care.1 However, with so many drugs available for the treatment of type 2 diabetes—and without a greater understanding of diabetes and the available treatment options—tailoring care to the individual can be both challenging and somewhat confusing. This article will discuss considerations when individualising care and setting glycaemic targets, with a focus around decision making when escalating treatment for adult patients with type 2 diabetes.

Individualised care

NICE recommend that consideration is given to an individual's needs and circumstances, including any disabilities or sensory impairment, plus personal preference, when individualising care.1 Also, to be mindful of co-morbidities; the risk of poly pharmacy; and due to the reduced life expectancy associated with type 2 diabetes, the potential gain from long-term interventions.1 Remember to review medication and stop medications that are not effective or are no longer required.1

Individualising glycaemic target

The glycated haemoglobin (HbA1c) level recommended by NICE for adult patients with type 2 diabetes that is managed by lifestyle and diet, or by lifestyle and diet combined with a single drug not associated with hypoglycaemia, is 48 mmol/mol (6.5%).1 Adult patients with type 2 diabetes on a drug associated with hypoglycaemia should be supported to aim for an HbA1c level of 53 mmol/mol (7.0%).1 If HbA1c levels are not controlled in adult patients with type 2 diabetes and rise to 58 mmol/mol (7.5%) or higher the following steps should be taken:1

  • reinforce advice about diet, lifestyle, and adherence to drug treatment
  • support the person to aim for an HbA1c level of 53 mmol/mol (7.0%)
  • intensify drug treatment.

In the UK Prospective Diabetes Study (UKPDS), there was a lower risk of micro vascular complications in patients that received intensive glucose therapy (either sulfonylurea or insulin or in overweight patients, metformin) compared with those receiving conventional dietary therapy.2 In a large post-trial study, involving more than 66,000 person-years of follow-up, the benefits of an intensive strategy to control blood-glucose levels in patients with type 2 diabetes were sustained after randomised interventions had ceased for up to 10 years.2 In the metformin group (patients with type 2 diabetes that were overweight), there was a significant reduction in risk for myocardial infarction and death from any cause during the trial.2 This risk reduction was sustained during the 10-year follow-up period.2 This emphasises the need to reach the targets set by NICE following a diagnosis of type 2 diabetes, and to continue to reassess glycaemic control and escalate treatment to reach the agreed glycaemic target providing it is considered safe to do so.1

NICE recommends considering relaxing target HbA1c levels on a case by case basis (with particular consideration for people who are older or frail) for adults with type 2 diabetes:1

  • who are unlikely to achieve longer-term risk-reduction benefits, for example, people with a reduced life expectancy
  • for whom tight blood glucose control poses a high risk of the consequences of hypoglycaemia, for example, people who are at risk of falling, people who have impaired awareness of hypoglycaemia, and people who drive or operate machinery as part of their job
  • for whom intensive management would not be appropriate, for example, people with significant comorbidities.

The American Diabetes Association has developed a useful guide of factors to consider when setting glycaemic targets with patients—for instance, proposing a tighter glycaemic target for those patients who are newly diagnosed with diabetes relative to that set for patients with a longer duration of diabetes.3

When relaxing glycaemic targets because of frailty or declining health be honest with patients and family members—it is simply a question of changing priorities; 20 years ago the priority was to reduce their risk of long-term complications and now the consequences of hypoglycaemia may provide a greater risk.

A patient decision aid has been developed by NICE, which is designed to help patients participate along with their healthcare professional, in the decision making process of setting a glycaemic target. (see Figure 1, below). This patient decision aid may also be a useful starting point for the less experienced clinician.

Figure 1: HbA1c target level decision guide4

HbA1c target level decision guide

By encouraging patients to consider the factors that are pertinent to them it should provide some direction towards treatment options, as well as engaging and empowering the patient. For example, fear of hypoglycaemia due to age or frailty may steer a patient to consider treatment options with low risk of hypoglycaemia; concerns about weight gain may lead another patient towards treatment options that are weight neutral or cause weight loss.

Individualising treatment for type 2 diabetes

The benefits of tight glycaemic control are well documented.5 Type 2 diabetes is a multi-organ disease (see Table 1, below), characterised by declining beta-cell function. Pharmaceutical interventions used to improve and/or maintain glycaemic control include oral hypoglycaemic agents, glucagon-like peptide-1 (GLP-1) mimetics, and insulin— these may be used separately or in combination.6

Table 1: Hyperglycaemia in diabetes7

Organ affected Pathophysiologic disturbance
Brain Neurotransmitter dysfunction
Fat Accelerated lipolysis
Gastrointestinal tract Incretin deficiency/resistance
Kidneys Increased reabsorption
Liver Increased glucose production
Muscle Decreased glucose uptake
Pancreatic islet alpha-cell Increased glucagon secretion
Pancreatic islet beta-cell Impaired insulin secretion

In order to offer an individualised treatment regimen for adults with type 2 diabetes, there needs to be an understanding of the mechanism of action of individual drugs, individual treatment benefits, potential adverse effects and contraindications, and licensed indications for individual drugs; acquisition cost, and the individual's circumstances and preference must also be a consideration.1

An algorithm for blood glucose lowering therapy in adults with type 2 diabetes has been developed by NICE, which outlines available treatments and combinations (see Figure 2, below).8 The clinician must still make an individualised treatment choice as the algorithm makes no distinction as to why one drug may be selected in preference to another.

Figure 2: Algorithm for blood glucose lowering therapy in adults with type 2 diabetes8

Algorithm for blood glucose lowering therapy in adults with type 2 diabetes

Treatment options for type 2 diabetes

We will now consider the different treatment options for type 2 diabetes, including dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, glucagon-like peptide 1 (GLP-1) mimetics, and sodium–glucose co-transporter-2 (SGLT-2) inhibitors, in more detail. For more information regarding a particular drug, refer to the relevant summary of product characteristics. For patients with symptoms of hyperglycaemia, the use of insulin or sulfonylureas is recommended at any stage of the disease process.1

Table 2: Comparison between treatment options for people with type 2 diabetes (developed by the author with information from the following sources: American Diabetes Association,3 NICE,4 Electronic Medicines Compendium,9 and British National Formulary,10)

Medicine4Regimen4*Mechanism of actionRisk of Hypoglycaemia?4Effect on weight4Specific renal or hepatic considerationsPotential adverse effects
DPP-4 inhibitors: alogliptin
linagliptin
saxagliptin
sitagliptin
vildagliptin
1 tablet usually taken daily
  • Inhibits the enzyme DPP-4 from degrading and inactivating GLP-1 and GIP uncertain hormones, which regulate insulin production and secretion3
  • Lowers glucagon secretion from pancreatic alpha cells9
Low Neutral
  • Dose reduction in renal impairment (eGFR below 50 ml/min/1.73m2)10*
  • Digestive problems; diarrhoea, abdominal pain and heartburn, rashes/itching, and urine infections have been seen in 10 to 100 people in every 10004
  • Inflammation of the pancreas has been seen in 1 to 10 people in every 10004
  • Upper respiratory tract infections9,10
Metformin 1 tablet usually taken 2 or 3 times daily
  • Decreases output of glucose from the liver
  • Increases insulin sensitivity in the liver, fat and skeletal muscle9,10
Low Neutral or small loss
  • Renal function should be monitored:10
    • contraindicated with eGFR below 30 ml/min/1.73m²
    • review dose if eGFR below 45 ml/min/1.73m²
  • Digestive problems such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite are common, seen in >100 people in every 1000 who take metformin. These problems are usually temporary and most commonly occur at the beginning of treatment4
  • Changes in the sense of taste have been seen in 10 to 100 people in every 1000 who take it4
  • Rarely, metformin can cause lactic acidosis.3 The risk is higher for those with liver or kidney disease, uncontrolled diabetes, prolonged fasting, or dehydration due to diarrhoea or vomiting4
  • Association with Vitamin B12 deficiency3,9,10
Pioglitazone 1 tablet taken once daily
  • Reduces insulin resistance by improving insulin sensitivity in the liver, fat, and skeletal muscle9
  • Reduces glucose output from the liver and increases uptake of peripheral glucose9
Low Average gain; 2–3 kg over 12 months
  • Liver blood tests must be monitored
  • Avoid use in liver disease4,10
  • Bone fractures have been seen in 10 to 100 women in every 1000 who take pioglitazone4
  • Bladder cancer has been seen in 1 to 10 people in every 1000 who take pioglitazone4
  • Fluid retention can occur in some people who take pioglitazone, which could worsen heart failure in people who already have it or might get it4
  • Dose may need to be reduced when used in conjunction with sulfonylurea or insulin9
  • Contraindicated in heart failure9,10
SGLT-2 inhibitors:
canagliflozin
dapagliflozin
empagliflozin
1 tablet taken once daily
  • Reduces the reabsorption of glucose in the proximal convoluted tubule, in the kidney, facilitating glucose excretion in the urine10
  • Independent of insulin secretion9
Low Average loss; 2–3 kg over 6–12 months
  • Monitor renal function
    • if eGFR below 60ml/min/1.73m² do not initiate10*
  • Digestive problems such as nausea and constipation, and also thirst, increased passing of urine, urine infections, and thrush (in men and women) seen in 10 to 100 people in every 1000 who take SGLT-2 inhibitors4
  • Low blood/ volume depletion has been seen in 1 to 10 people in every 1000 who take SGLT-2 inhibitors. Increased risk in older people and in people with heart or circulation problems, or dehydration due to diarrhoea or vomiting4
  • DKA is a rare side-effect of SGLT-2 inhibitors10
Sulfonylureas:
glibenclamide
gliclazide
glimepiride
glipizide
tolbutamide
1–3 tablets, usually taken daily
  • Insulin secretion is stimulated from the beta cells in the pancreas, resulting in lowered blood glucose10
Moderate Possible gain
  • Caution in renal impairment due to risk of hypoglycaemia10
  • Avoid or reduce dose in severe hepatic impairment due to risk of hypoglycaemia; may result in jaundice10
  • Digestive problems such as nausea, diarrhoea, and abdominal pain have been seen in 10 to 100 people in every 1000 who take sulfonylureas4
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide 1; GIP=gastric inhibitory polypeptide; eGFR=estimated glomular filtration rate; SGLT-2—sodium-glucose co-transporter-2; DKA=diabetic ketoacidosis
* Please refer to the summary of product characteristics for information regarding specific drugs.

Metformin

Standard-release metformin remains the initial drug of choice for adults with type 2 diabetes; offering modified-release (MR) metformin to those suffering gastrointestinal (GI) side-effects from the standard-release preparation.1

Metformin remains the initial drug of choice as it has been shown to offer long-term protection; in the UKPDS 10-year follow up, for patients in the metformin group the risk reduction for any diabetes-related end point, for diabetes-related death, for myocardial infarction, and for death from any cause was 21, 30, 33, and 27%, respectively, compared with that for patients receiving conventional therapy (dietary restriction)—all of these risk reductions were significant.2 The long-term benefits should be explained to patients who are reluctant to start or continue treatment. Patients should also be counselled about adverse effects—gradual titration of the dose will help lessen potential GI effects.

Sulfonylureas

Sulfonylureas, especially shorter acting ones, are particularly useful if a patient is experiencing symptoms of elevated blood glucose and requires rapid improvement, for example, alongside courses of steroid treatment.11 Due to the risk of hypoglycaemia, patients may need to monitor their blood glucose; blood glucose monitoring will increase acquisition cost.

DPP-4 inhibitors

For more information on DPP-4 inhibitors refer to individual summaries of product characteristics. Although DPP-4 inhibitors are generally well tolerated, the dose may need to be reduced depending on renal function.

Pioglitazone

NICE recommends not to offer or continue pioglitazone in adults with type 2 diabetes if they have any of the following:1

  • heart failure or history of heart failure
  • hepatic impairment
  • diabetic ketoacidosis
  • current, or a history of, bladder cancer
  • uninvestigated haematuria.

Pioglitazone is particularly useful for those patients with type 2 diabetes who are extremely resistant to insulin.

SGLT-2 inhibitors

The use of SGLT-2 inhibitors is recommended by NICE if a sulfonylurea is contraindicated or not tolerated, or the individual is at significant risk of hypoglycaemia or the consequences of hypoglycaemia.12–14

Diabetic ketoacidosis (DKA) is a potential rare adverse effect following treatment with SGLT-2 inhibitors.10 The European Medical Agency (EMA) recommends patients are made aware of the symptoms of DKA—rapid weight loss, nausea or vomiting, stomach pain, excessive thirst, fast and deep breathing, confusion, unusual sleepiness or tiredness, a sweet smell to the breath, a sweet or metallic taste in the mouth, or a different odour to urine or sweat—and seek advice if the symptoms present.15 Healthcare professionals should consider the possibility of atypical DKA presenting, where patients have symptoms consistent with the condition even if blood sugar levels are not high.15 Treatment with SGLT-2 inhibitors should be stopped immediately if DKA is suspected or confirmed and it should not be restarted unless another cause for the ketoacidosis is identified and resolved.15 Treatment with SGLT-2 inhibitors should be stopped temporarily in patients undergoing major surgery or are hospitalised due to serious illness.15

In the EMPA-REG OUTCOME trial, the effects of the SGLT-2 inhibitor empagiflozin were compared with placebo on cardiovascular morbidity and mortality in patients with type 2 diabetes at high risk for cardiovascular events who were receiving standard care.16 Significantly lower rates of death from cardiovascular causes, hospitalisation for heart failure, and death from any cause, were seen in the empagiflozin group compared with the placebo group.16 There were no significant between-group differences for rates of myocardial infarction or stroke.16 Cardiovascular outcomes data are awaited from ongoing trials for other SGLT-2 inhibitors.

Due to the SGLT-2 inhibitor mode of action, potential additional benefits include a reduction in blood pressure and weight loss. Counsel patients regarding the need to increase sugar-free fluid intake—as well as the potential adverse effects of thrush or urinary tract infections, and the need to seek treatment for these.

GLP-1 mimetics

Where triple therapy with metformin and two other oral drugs—either a DPP-4 inhibitor and a sulfonylurea or pioglitazone and a sulfonylurea—is not effective, not tolerated, or contraindicated, NICE recommends the use of GLP-1 mimetics in combination with metformin and a sulfonylurea for adults with type 2 diabetes who:1

  • have a BMI of 35 kg/m2 or higher (adjust accordingly for people from black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity or
  • have a BMI lower than 35 kg/m2 and:
    • for whom insulin therapy would have significant occupational implications or
    • weight loss would benefit other significant obesity-related comorbidities.

NICE also recommends that GLP-1 mimetic therapy should only be continued if the person with type 2 diabetes has had a beneficial metabolic response—a reduction of at least 11 mmol/mol (1.0%) in HbA1c and a weight loss of at least 3% of initial body weight in 6 months.1

GLP-1 mimetics activate GLP-1 receptors resulting in an increase in glucose-dependent insulin secretion; a reduction in glucose-dependent glucagon secretion; a reduction in the rate of gastric emptying; and increased satiety.3 Benefits include weight loss and a decrease in some cardiovascular risk factors; gastrointestinal side effects (including nausea, vomiting, and diarrhea) may occur and there is a risk of acute pancreatitis.3 Refer to individual summaries of product characteristics for specific information on licensed indications.

Insulin

In an adult with type 2 diabetes who is symptomatically hyperglycaemic—NICE recommends considering treatment with insulin, or a sulfonylurea, where rescue therapy is required at any phase of treatment; and reviewing treatment when blood glucose control has been achieved.1 Treatment with insulin should only be initiated by an appropriately trained healthcare professional.1 The Royal College of Nursing has issued comprehensive guidance on the initiation of insulin treatment entitled Starting injectable treatment in adults with Type 2 diabetes.17

Conclusion

Individualised patient care in type 2 diabetes can only occur when we consider the individual patient, their personal circumstances, and preferences. Healthcare professionals must strive to include our patients in decision making; utilisation of tools such as the NICE decision aid can support this.4 Once a glycaemic target has been agreed, treatment can then be tailored to the individual. Healthcare professionals need to increase their knowledge and understanding of available treatment options to allow them to individualise treatment care, selecting the most appropriate treatment option in agreement with the patient, dependent on individual drug licenses, and within the remit of national and local guidance. 

References

  1. NICE. Type 2 diabetes in adults: management. NICE Guideline 28. NICE, 2015 (last updated 2016). Available at: www.nice.org.uk/guidance/ng28
  2. Holman R, Paul S, Bethel A, et al.10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359 (15): 1577–1589.
  3. American Diabetes Association. Standards of medical care in diabetes—2016. Diabetes Care 2016; 39 (1): suppl 1.
  4. NICE. Type 2 diabetes in adults: management. NICE Guideline 28—Type 2 diabetes in adults: controlling your blood glucose by taking a second medicine—what are your options? NICE, 2015. Available at: www.nice.org.uk/guidance/ng28/resources/patient-decision-aid-2187281197 (accessed 17 January 2017).
  5. Stratton I, Adler A, Neil A, et al. Association of glycaemia with macro vascular and microv ascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405–412.
  6. International Diabetes Federation.Global guideline for type 2 diabetes. Available at: www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-Diabetes.pdf
  7. De Fronzo R. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009; 58 (4): 773–795.
  8. NICE. Type 2 diabetes in adults: management. NICE Guideline 28—Algorithm for blood glucose lowering therapy in adults with type 2 diabetes. NICE, 2015. Available at: www.nice.org.uk/guidance/ng28/resources/algorithm-for-blood-glucose-lowering-therapy-in-adults-with-type-2-diabetes-2185604173
  9. Datapharm Communications Limited. Electronic medicines compendium. www.medicines.org.uk/emc/ (accessed 17 January 2017).
  10. British National Formulary. 6.1 Drugs used in diabetes. www.evidence.nhs.uk/formulary/bnf/current/6-endocrine-system/61-drugs-used-in-diabetes (accessed17 January 2017).
  11. Joint British Diabetes Societies for Inpatient Care. Management of hyperglycaemia and steroid (glucocorticoid) therapy—October 2014. Available at: www.diabetologists-abcd.org.uk/JBDS/JBDS_IP_Steroids.pdf (accessed 17 January 2017).
  12. NICE. Empagliflozin in combination therapy for treating type 2 diabetes. Technology Appraisal 336. NICE, 2015. Available at: www.nice.org.uk/ta336 (accessed 17 January 2017).
  13. NICE. Canagliflozin in combination therapy for treating type 2 diabetes. Technology Appraisal 315. NICE, 2014. Available at: www.nice.org.uk/ta315 (accessed 17 January 2017).
  14. NICE. Dapagliflozin in combination therapy for treating type 2 diabetes. Technology Appraisal 288. NICE, 2013 (last updated 2016). Available at: www.nice.org.uk/ta288 (accessed 17 January 2017).
  15. European Medicines Agency. SGLT2 inhibitors. www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/SGLT2_inhibitors/human_referral_prac_000052.jsp&mid=WC0b01ac05805c516f (accessed 17 January 2017).
  16. Zinman B, Wanner C, Lachin J, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373 (22), 2117–2128.
  17. Royal College of Nursing. Starting injectable treatment in adults with type 2 diabetes. Available at: www2.rcn.org.uk/__data/assets/pdf_file/0009/78606/002254.pdf

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