The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) released a position statement in 2012 on the management of type 2 diabetes mellitus. This was deemed necessary because of the increasing number and variety of pharmacotherapies available to reduce hyperglycaemia, and uncertainty regarding their proper selection and sequence. There were also new uncertainties regarding the benefits of intensive glycaemic control on macrovascular complications. These treatment guidelines advocated a more individualised approach, and not as much a strict glycated haemoglobin (HbA1c) target, with an emphasis on patient-centred care and shared decision making.
Glycaemic targets
- Lowering HbA1c to <7.0% is recommended in most patients to reduce the onset and progression of microvascular complications.
- The impact of glucose control on cardiovascular complications remains uncertain; a more modest benefit is likely to be present, but probably emerges only after many years of improved control.
- Intensive glycaemic control to achieve near normal HbA1c targets, while essential in some patients, may not be applicable to every patient and may indeed present some risk.
- Therefore, instead of a one-size-fits-all approach, personalisation is necessary, balancing the benefits of glycaemic control with its potential risks, taking into account the adverse effects of glucose-lowering medications (particularly hypoglycaemia), and other factors including the patient’s age, life expectancy and comorbidities.
- More stringent HbA1c targets (e.g., 6.0– 6.5%) might be considered in selected patients (with short disease duration, long life expectancy, no significant CVD) if this can be achieved without significant hypoglycaemia or other adverse effects of treatment.
- Less stringent HbA1c goals (e.g., 7.5–8.0% or even slightly higher) may be appropriate for patients with a history of severe hypoglycaemia, limited life expectancy, advanced complications, extensive comorbid conditions and those in whom the target is difficult to attain despite intensive self-management education, repeated counselling, and effective doses of multiple glucose-lowering agents, including insulin.
Patient-centred care and shared decision making
- The guidelines advise adapting treatment to each patient’s situation, including history, wishes, and willingness to make lifestyle changes, since the achievement of any degree of glucose control requires active participation and commitment. Engaging patients in health care decisions may enhance adherence to therapy.
- Actual treatment targets which are now emphasised are patient-oriented outcomes, in general related to micro- and macrovascular events (e.g. stroke, cardiac infarction, blindness, nephropathy, neuropathy, amputation) rather than the surrogate HbA1c. Any target should reflect an agreement between patient and clinician.
Multiple agents needed for most people with diabetes
Initial therapy
- The first and most widely used medical treatment is metformin, a biguanide whose mechanism of action predominately involves reducing hepatic glucose production. Metformin helps nearly every facet of the type 2 diabetes syndrome. It lowers blood sugar levels and may help reduce cardiovascular risk without increased risk of hypoglycaemia and weight gain. However, metformin is associated with initial GI side effects, and caution is also advised to avoid its use in patients at risk for lactic acidosis (e.g. in advanced renal insufficiency, alcoholism). A slow increase of dose (oral solution may be used) may improve gastrointestinal tolerability.
Advancing to dual combination therapy
- If the HbA1c target is not achieved after ~3 months, there are six drug choices including a second oral agent (sulfonylurea, TZD, DPP-4 inhibitor, or SGLT2 inhibitor), a GLP-1 receptor agonist, or basal insulin (see FigA general algorithm). Notably, the higher the HbA1c, the more likely insulin will be required.
- Because there has been no good quality study comparing all available treatment strategies, there is no clear-cut decision tree as there was in the previous hyperglycaemia guidelines, and shared decision making with the patient is important to help in the selection of therapeutic option. The choice is based on patient and drug characteristics – including willingness to self-inject or need for weight loss – with the over-riding goal of improving glycaemic control while minimising side effects. An important consideration in most cases is to add an agent that does not cause weight gain and does not cause hypoglycaemia. Algorithms FigB and C are suggested treatment algorithms in case the treatment goal is avoiding hypoglycaemia or avoiding weight gain, respectively.
- On average, any second agent is typically associated with a further reduction in HbA1c of approximately 1%. If no clinically meaningful glycaemic reduction (i.e. “non-responder”) is observed, then, after adherence has been investigated, discontinue that agent, and replace it with another with a different mechanism of action.
Advancing to triple combination therapy
- Evidence suggests that there is some advantage in adding a third noninsulin agent to a two-drug combination not achieving the glycaemic target. Reconsider the approach promptly if it proves to be unsuccessful, as months of uncontrolled hyperglycaemia should specifically be avoided.
- Not surprisingly, however, the most robust response will usually be with insulin. Since diabetes is associated with progressive beta-cell loss, many patients, especially those with long-standing disease, will ultimately need to be transitioned to insulin. Insulin should be preferred in circumstances where the degree of hyperglycaemia (e.g. ≥8.5%) makes it unlikely that another drug will be sufficiently effective. Most patients are reluctant to start injectable therapy, but encouragement and education can usually overcome such reticence.
- In using triple combinations the essential consideration is obviously to use agents with complementary mechanisms of action.
Recommendations to Guide Treatment Selection in Combination Therapy
DPP-4 inhibitors
While still somewhat expensive, and modestly effective in HbA1c reduction, these once daily agents are convenient, weight neutral, with a very favourable adverse-effect profile, and they do not cause hypoglycaemia. Should be used with caution in patients with a prior history of pancreatitis or with pre-existing heart failure (HF).
GLP-1 receptor agonists
Despite issues with adverse effects and cost, GLP-1 RA demonstrate efficacy in lowering HbA1c and achieving weight loss. It is not clear whether the limited occurrence of pancreatitis observed with these agents is causative or associative. While GLP-1 RA are associated with GI adverse effects, these seem to decline dramatically with time.
SGLT2 inhibitors
This novel class of antidiabetics has shown efficacy in reduction of HbA1c comparable to other standard oral agents, with a low risk of hypoglycaemia. Their mechanism of action is independent of insulin, and therefore may be used at any stage of type 2 diabetes, even after insulin secretion has waned significantly. Other advantages of SGLT2 inhibitors include weight loss and blood pressure reduction. Associated with genital mycotic infections and UTIs. They also possess a diuretic effect. Depending on the agent, use is restricted or not recommended when the estimated GFR is <45 – 60ml/min.
Basal insulin
Insulin (especially, basal or basal +1 analogue therapy) continues to be a favoured candidate for early use, as an add-on shortly after metformin and/or an additional oral agent to establish control while minimising risk of hypoglycaemia or weight gain.
Sulfonylureas
Often favoured for their affordability, but pose a high risk for hypoglycaemia, contribute to weight gain, and lack durability related to glycaemic control (“beta-cell burnout”). Evidence also suggested poor cardiovascular outcomes in some trials. The low cost of medication must be weighed against the potential higher costs of morbid outcomes.
Thiazolidinediones (actually, only pioglitazone)
Do not cause hypoglycaemia, but were cited for concern about adverse effects, including the risk of weight gain, fluid retention, heart failure, and bone fractures in women. Pioglitazone appeared to have a modest impact on reducing cardiovascular events in one study. Earlier concerns about an association with bladder cancer have largely been allayed by subsequent evidence.
Pre-mixed and non-analogue insulins*
Concerns about weight gain or hypoglycaemia—both highly undesirable adverse effects as demonstrated by results from landmark diabetes treatment trials.
ADA-EASD Treatment Guidelines – main 2015 updates
The 2015 updates incorporate new data from recent clinical trials.
- The major change in treatment options since the publication of the 2012 position statement has been the availability of a new class of glucose-lowering drugs, the SGLT2 inhibitors.
- Updates to safety concerns relating to TZDs (bladder cancer), DPP-4 inhibitors (HF, pancreatitis) and GLP-1 RA (pancreatitis).
- In patients on basal insulin with one or more oral agents whose diabetes remains uncontrolled, the addition of a GLP-1 RA or mealtime insulin is now recommended (or in refractory patients, an SGLT2 inhibitor or TZD may be considered – see FigA).
- Includes proposed dosing instructions for the various insulin strategies, including the addition of rapid-acting insulin analogues before meals or the use of premixed insulin formulations.
DPP-4: Dipeptidyl peptidase-4; GLP-1 RA: Glucagon-like peptide-1 receptor agonist; SGLT2: Sodium glucose co-transporter 2; TZD: Thiazolidinedione; UTIs: Urinary tract infections *Regular human insulin and Neutral Protamine Hagedorn (NPH)
Key Recommendations
- Individualise glycaemic targets and glucose-lowering therapies.
- Diet, exercise, and education remain the foundation of all type 2 diabetes treatment programmes.
- Metformin is the optimal first-line drug in the absence of contraindications.
- After metformin, though data are more limited, it is reasonable to consider combination therapy with an additional 1-2 oral or injectable agents with the objective of minimising side effects where possible.
- For many patients insulin therapy alone or in combination with other agents will ultimately be required to maintain glucose control.
- All treatment decisions, where possible, should take into account the patient’s preferences, needs and values.
- A major focus of therapy must be comprehensive cardiovascular risk reduction.
References:
1. Inzucchi SE 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 [adapted].
2. Inzucchi SE et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2012;35:1364-1379 [adapted]
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Tables
Table 1: Antihyperglycaemic Therapy in Type 2 Diabetes – List of agents available in Ireland
Table 2: Antihyperglycaemic Therapy in Type 2 Diabetes – Pros and Cons
Algorithms
Figure A: Antihyperglycaemic Therapy in Type 2 Diabetes – General Recommendations