ADA/EASD 2022: Consensus report aims to simplify clinical decision-making

The latest iteration of the highly respected consensus report from the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) calls for a holistic person-centred approach to the management of type 2 diabetes, and prioritises organ protection

Type 2 diabetes is a chronic complex disease, and management requires multifactorial behavioural and pharmacological treatments to prevent or delay complications and maintain quality of life. This includes management of blood glucose levels, weight, cardiovascular risk factors, comorbidities, and complications.

A systematic review of studies published since 2018 has informed the new recommendations, which cover social determinants of health, physical behaviours including sleep, and a greater emphasis on weight management.

In addition, the results of recent cardiovascular and renal outcomes trials for SGLT2 inhibitors and GLP-1 receptor agonists underpin recommendations for cardiorenal protection in people at high risk of cardiovascular and renal disease.

As in previous consensus reports, the overall goal of management of type 2 diabetes (T2D) is to maintain quality of life and avoid complications. The approach must be holistic and multifactorial and take the lifelong nature of T2D into account.

Holistic care means promoting healthy behaviours through medical nutrition therapy, physical activity and psychological support, as well as weight management, smoking cessation and substance abuse counselling as needed by the individual, often provided by diabetes self-management education and support (DSMES).

The growing number of glucose-lowering medications, and growing information about their benefits and risks, provide more options for people with diabetes but making decision-making more complex. The proven benefits for high-risk individuals with atherosclerotic cardiovascular disease (CVD), heart failure (HF), or chronic kidney disease (CKD) provided by GLP-1 RAs and SGLT2i’s represent significant progress in the progression and burden of diabetes and its complications. These treatments were initially introduced as glucose-lowering agents but are now also prescribed for organ protection. This consensus report aims to simplifying clinical decision-making, enabling more attention to be paid to providing holistic person-centred care.

TARGETS

The benefits of intensive glucose control emerge slowly while harms can be immediate. This means that people with longer life expectancy have more to gain from early intensive glycaemic management.

A sensible target for adults who are likely to live long enough to see microvascular benefits (generally approximately 10 years) is ≥53 mmol/mol. A lower target may be reasonable if it can be achieved safely, without significant adverse effects, by using agents that are not associated with hypoglycaemia. Higher targets are more appropriate in people with limited life expectancy, advanced complications or frailty.

This target should be tailored to the individual’s characteristics, such as age, risk of complications, frailty and comorbid conditions.

AN INDIVIDUALISED APPROACH

T2D is a diverse disease with variable age at onset, degree of obesity, insulin resistance and the tendency to develop complications.

Shared decision-making, using decision aids that show the absolute benefits and risk of the available treatment options, is essential.

Clinicians should evaluate the impact of treatment options in the context of cognitive impairment, limited literacy, cultural beliefs and individual fears or worries. In addition, the social determinants of health, which are outside the individual’s control, can have an important impact on outcomes.

The five identified social determinants of health are:

• Socioeconomic status – education, income and occupation
• Living and working conditions
• Multi-sector factors – housing, education and criminal justice system
• Sociocultural context – shared cultural values, practices and experiences
• Sociopolitical context – policies underlying health disparities.

Person-centred care includes the assessment of key characteristics and preferences to determine individualised treatment goals and strategies, including:

• The individual’s priorities
• Current lifestyle and health behaviours
• Comorbidities
• Clinical characteristics – age, HbA1c, weight
• Issues such as motivation, depression and cognition

WEIGHT REDUCTION AND PHSYCIAL BEHAVIOURS

The new report places much greater emphasis on the role of weight reduction in the management of T2D. Weight loss of:

• 5-10% of overall body weight results in metabolic improvement
• 10-15% or more can have a disease modifying effect and can lead to remission.

Weight loss may have benefits beyond the management of glycaemia, and improve both risk factors for cardiovascular disease and quality of life.

Weight loss medications are effective additions to lifestyle advice in helping patients to lose weight. For example, in the STEP 2 trial, semaglutide 2.4mg once a week as an adjunct to lifestyle intervention resulted in weight loss of 9.6%. Conversely, withdrawing treatment with semaglutide leads in weight gain.

Tirzepatide

Although not currently licensed for weight management, tirzepatide, a novel glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA, at weekly doses of 5mg, 10mg, and 15mg reduced body weight by 15%, 19.5%, and 20.9%, respectively compared with 3.1% with placebo at 72 weeks in people with obesity but not with diabetes.

Physical activity

Increased physical activity can improve cardiometabolic health in people with T2D. Regular aerobic exercise can reduce HbA1c by ~7 mmol/mol, and resistance exercise can counter the increased risk of impaired physical function at an earlier age in T2D.

Even small, regular changes can make a difference to long-term health: an increase of only 500 steps/day can decrease cardiovascular morbidity by between 2% and 9%.

Sleep

Sleep disorders are common in T2D and are associated with increased risk of obesity, and impairments of glucose metabolism as well as daytime functioning. Extending the duration of sleep in ‘short’ sleepers can increase insulin sensitivity and reduce energy intake – but catching up on sleep at the weekend is not enough to reverse the effect of insufficient sleep.

ORGAN PROTECTION

Traditionally, the primary focus of the management of T2D has been to lower blood glucose. While this is still crucial, a new priority is organ protection, arising from the ‘compelling’ evidence that some agents protect the heart and kidneys independently of their glucose lowering effect, as this protection also occurs in people without T2D.

Therefore, the ADA/EASD recommends that regardless of HbA1c level or the use of other glucose-lowering drugs, all patients with diabetes and established or sub-clinical cardiovascular disease should be prescribed either a GLP-1 RA or SGLT2i with proven cardiovascular benefit.

All patients with diabetes and CKD should be prescribed an SGLT2i (or GLP-1 RA if SGLT2i is contraindicated or not preferred) with proven kidney benefit.

Patients with T2D and heart failure (HF), (HF with reduced ejection fraction or HF with preserved ejection fraction) should be offered an SGLT2i with proven benefit in HF.

The goal of organ protection with SGLT2i or GLP-1 RA should be independent of background glucose-lowering treatments, or current or target HbA1c levels.

ADHERENCE

Almost half of people with T2D have low rates of continued medication use or less than optimal medication-taking behaviour. This leads to suboptimal blood glucose management and control of CVD risk factors. Rates of adherence and persistence vary between medication classes and agents, and careful consideration of these may improve outcomes. Even when clinical characteristics suggest the use of a particular medication, the individual’s preferences for route of administration (oral or injectable), devices, or side effects may prevent them from using it.

THERAPEUTIC INERTIA

Therapeutic inertia is the term used to describe failure to intensify treatment when targets are not met, and can also include failure to de-intensify treatment when people are over-treated. The causes may lie with the clinician or the person with diabetes, but involving prescribing nurses in diabetes management has been shown to reduce this phenomenon. Individual glycaemic targets and their achievement should be re-assessed at regular intervals. When targets are not met, treatment should be intensified by combining drugs with complementary mechanisms of action.

SPECIFIC FACTORS IMPACTING CHOICE OF TREATMENT

• Individualised glycaemic and weight goals
• Impact on weight, hypoglycaemia and cardiorenal protection
• Underlying physiological factors
• Side effect profiles of medications
• Complexity of regimen – frequency, mode of administration
• Regimen choice to optimise medication use and reduce treatment discontinuation.

GLUCOSE LOWERING DRUGS

Metformin

For most patients, for the treatment of hypoglycaemia, metformin remains the treatment of choice, based on its effective glucose-lowering, low risk of hypoglycaemia, weight neutrality and affordability. However, monotherapy with metformin is often insufficient to maintain glucose levels at target. As recommended in previous consensus reports, other agents can be useful, in combination with metformin, or instead if metformin in contraindicated or not tolerated. The choice of agent should be based on the balance between its glucose-lowering efficacy and side effect profile. In populations for whom hypoglycaemia is most dangerous, e.g. people with frailty, choose an agent that is not associated with hypoglycaemia risk.

Metformin should not be used in people with an eGFR of <30ml/min/1.73m2, and the dose should be reduced in people with an eGFR of <45ml/min/1.73m2. Metformin use may result in lower vitamin B levels so patients should be monitored and offered vitamin B supplements where levels are deficient.

DPP-4 inhibitors

Treatment with DPP-4 inhibitors results in glucose-dependent insulin release and a decrease in glucagon secretion. They have a more modest glucose-lowering effect, a neutral effect on weight, are well tolerated and have a minimal risk of hypoglycaemia. While CVOTs have established the cardiovascular safety of four drugs in this class – saxagliptin, alogliptin, sitagliptin, and linagliptin – cardiovascular risk reduction has not been demonstrated. Reductions in the risk of progression of albuminuria have been shown with linagliptin. Saxagliptin is associated with an increased risk of hospitalisation for heart failure.

The tolerability and modest efficacy of the DPP-4s mean they are suitable for specific populations, for example, older and frail individuals. DPP-4s in combination with basal insulin results in similar average daily blood glucose levels with lower glycaemic variability and less hypoglycaemia than with basal-bolus insulin regimens.

Sulfonylureas

Second-generation sulfonylureas have a high glucose-lowering effect, are inexpensive and accessible, but are associated with an increased risk of hypoglycaemia and weight gain, and their efficacy is not long lasting. Both glyburide and glipizide should be used with caution in people at risk of hypoglycaemia, and initiated cautiously. They have a neutral impact on cardiovascular disease/risk, heart failure, and kidney disease, but glyburide is not generally recommended in chronic kidney disease.

Thiazolidinedione (TZDs)

TZDs increase insulin sensitivity and are effective glucose-lowering agents. Their efficacy is durable, through their powerful effect on preserving β-cell function. They have potential benefits in major cardiovascular events (MACE) but an increased risk in heart failure (HF) and a neutral effect on progression of diabetic kidney disease. Pioglitazone has been shown to have beneficial effects on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) but these should be balanced against possible side effects of fluid retention and congestive HF, weight gain and bone fracture.

SGLT2i’s

SGLT2i’s work by increasing the excretion of glucose in the urine. Their efficacy is described as intermediate-to-high, with reduced efficacy in patients with impaired renal function (lower eGFR). The scope of use for this class of drugs has expanded significantly, as a result of CVOTs that have shown them to be effective in reducing the risk of MACE, cardiovascular death, hospitalisation for heart failure (hHF), and also for improving renal outcomes. Dapaglifozin has been shown to improve progression to renal replacement therapy, cardiovascular death and hospitalisation for heart failure in people with or without type 2 diabetes. Empaglifozin has also recently been demonstrated to reduce cardiovascular mortality and hHF in people with HF with reduced ejection fraction, and with preserved ejection fraction, irrespective of their diabetes status.

The main side effect of SGLT2i’s is an increased risk of mycotic genital infections, but these are generally mild and treatable. SGKT2i use can increase the risk of diabetic ketoacidosis but the incidence is low. Early studies raised a number of possible safety issues with SGLT2i’s, such as acute kidney injury, dehydration, orthostatic hypotension, amputation and fractures. More recently, longer-term studies have prospectively monitored for these events and have not confirmed a significant increase in risks. In post hoc analyses, SGLT2i use has been associated with reduced incidence of serious and nonserious kidney-related adverse events in people with type 2 diabetes and CKD and greater full recovery from acute kidney injury.

GLP-1 RAs

GLP-1 RAs increase glucose-dependent insulin secretion and suppress glucagon, slow gastric emptying and reduce appetite, energy intake and body weight. Beyond glucose control, drugs in this class have been approved for reducing the risk of MACE in adults with established CVD or multiple cardiovascular risk factors. Note, however, that NICE does not endorse GLP-1 RAs for cardiovascular risk management, and has imposed restrictions on their use in UK NHS practice.

The most common side effects of GLP-1 RAs are nausea, vomiting and diarrhoea during initiation and dose escalation, but these effects lessen over time. Gradual dose increases can help reduce gastrointestinal effects. It is also important to help people tell the difference between nausea, a negative sensation, and satiety, a positive sensation that helps with weight loss.

This is important in the light of recent GLP-1 RA studies, which have shown incremental benefits for glucose control and weight loss at higher doses.

GLP-1 RAs should be considered ahead of insulin for people with type 2 diabetes, and should be continued where possible once insulin has been initiated, preferably as a single combination injection with basal insulin to reduce the complexity of treatment.

GIP and GLP-1 RA

Tirzepatide, a first-in-class combination glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA, was approved by UK regulators in October 2022 and in the US earlier in 2022, as a once-weekly subcutaneous injection to improve glucose control in adults with type 2 diabetes as an addition to healthy eating and exercise. It has been shown to be more effective at reducing glycaemia than semaglutide 1mg weekly, insulin degludec and insulin glargine, with reductions in HbA1c of between 21 mmol/mol and 23 mmol/mol. In addition, weight loss of 7–9.5 kg was achieved. Tirzepatide also improved liver fat content, and reduced visceral fat. While superior to other long-acting GLP-1 RAs, it is associated with a greater risk of gastrointestinal side effects. Its impact on MACE will be available when the current CVOT is completed.

Combination therapy

A stepwise approach has formerly been accepted practice but there is growing evidence to support a more proactive approach by combining glucose-lowering agents from diagnosis. Early use of combination therapy allows tighter glucose control that monotherapy with individual agents, and avoids delaying access to drugs that protect against cardiovascular and kidney disease. Given the benefits of GLP-1 RAs and SGLT2i’s for cardiovascular and renal outcomes, these agents should be considered for people with established or high risk of cardiovascular disease, heart failure or chronic kidney disease, independent of metformin use. Early initiation of combination therapy provides greater glucose-lowering efficacy and cardiovascular and renal protection.

This approach is recommended for patients who have HbA1c levels more than >16.3 mmol/mol above target at diagnosis (e.g. ≥70 mmol/mol) and particularly for young adults, to avoid complications across their lifespan.

PRACTICAL TIPS FOR CLINICIANS

• Avoid therapeutic inertia and re-evaluate health behaviours, individuals’ medication-taking behaviours, and side effects of agents at every clinic visit
• Review response to all therapies at regular intervals, to include impact on efficacy (HbA1c and weight), safety and organ protection
• When additional glycaemic control is needed, incorporate, rather than substitute, glucose-lowering therapies with complementary mechanisms of action
• Consider fixed-dose combinations to reduce prescription burden
• Consider de-intensification of therapy, for example, in frail older adults and in the setting of hypoglycaemia-causing medications, in those with glycaemic values substantially better than target.

Reference

Davies MJ, Aroda VR, Collins BS, et al. Management of hypoglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care November 2022;45(11): https://diabetesjournals.org/care/article/45/11/2753/147671/Management-of-Hyperglycemia-in-Type-2-Diabetes