TYPE 2 DIABETES ADA-EASD TREATMENT GUIDELINES AND 2015 NEW UPDATES 1,2

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1 TYPE 2 DIABETES ADA-EASD TREATMENT GUIDELINES AND 2015 NEW UPDATES 1,2 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 patientcentred 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., %) 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., % 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 glucoselowering 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 patientoriented 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. 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 hy- ii

2 perglycaemia (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, 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 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. s 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. s (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 (pancreatitis). In patients on basal insulin with one or more oral agents whose diabetes remains uncontrolled, the addition of a 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; : Glucagon-like peptide-1 receptor agonist; SGLT2: Sodium glucose co-transporter 2; TZD: ; 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. 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: [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: [adapted] MIMS Ireland Copyright iii

3 Table 1. Antihyperglycaemic Therapy in Type 2 Diabetes List of agents available in Ireland Antidiabetic drug type Active ingredient Trade name Frequency / form Competact* Eucreas* Glucophage 2-3 times daily tablet Janumet* Insulin sensitisers Biguanide metformin Jentadueto* Potentiate the effect of insulin Komboglyze* Aurobindo 2-3 times daily tablet Metophage 2-3 times daily tablet Xigduo* pioglitazone Actos Competact* Insulin secretagogues Traditional Trigger insulin release by direct action on the K ATP channel of β cells Sulphonylureas Prandial glucose regulators Short-acting glibenclamide Daonil Diabrezide once or gliclazide Diaglyc Diamicron MR glimepiride Amaryl daily tablet repaglinide Novonorm daily tablet with main meals GLP-1 agonists exenatide Byetta Bydureon twice daily injection (prefilled pen) once weekly injection (prefilled pen) liraglutide Victoza once daily injection (prefilled pen) linagliptin Jentadueto* Trajenta Incretin therapies Trigger insulin release & inhibit glucagon release saxagliptin Komboglyze* Onglyza DPP-4 inhibitors sitagliptin Janumet* Januvia Eucreas* vildagliptin Galvus (once daily with sulphonylurea) canaglifozin Invokana SGLT2 inhibitors Reduce renal glucose reabsorption (independent of b-cell function and insulin pathway) 5 a-glucosidase inhibitor Acts directly on glucose metabolism Forxiga dapaglifozin Xigduo* empagliflozin Jardiance acarbose Glucobay 3 times daily tablet *combination containing metformin and another active ingredient iv The above table was prepared from data available in June 2015 and lists products that are currently included in MIMS Ireland. Prescribers should refer to section 6.4 of MIMS Ireland and SPCs of each product for full up-to-date details of licensing. MIMS Ireland Copyright

4 Table 2. Antihyperglycaemic Therapy in Type 2 Diabetes - Pros and Cons 1 Antidiabetic drug type Active ingredient Pros Cons Insulin sensitisers Biguanide metformin pioglitazone No weight gain Extensive experience i CVD events (UKPDS) Low cost Durability h HDL-cholesterol i Triglycerides? i CVD events (ProACTIVE) Low cost GI side-effects (diarrhoea, abdominal cramping) Lactic acidosis risk (rare) Vitamin B 12 deficiency Multiple contraindications: CKD, acidosis, hypoxia, dehydration, etc. Weight gain Oedema/heart failure Bone fractures Sulphonylureas glibenclamide gliclazide glimepiride Extensive experience i Microvascular risk (UKPDS) Low cost Hypoglycaemia Weight gain? Blunts myocardial ischemic preconditioning Low durability Insulin secretagogues Prandial glucose regulators Short-acting GLP-1 agonists repaglinide exenatide liraglutide i Postprandial glucose excursions Dosing flexibility Moderate cost Weight loss i Post prandial glucose excursions i Cardiovascular risk factors Hypoglycaemia Weight gain? Blunts myocardial ischemic preconditioning Frequent dosing schedule GI side effects (nausea/vomiting/diarrhoea) h Heart rate? Acute pancreatitis C-cell hyperplasia/medullary thyroid tumours in animals Injectable Training requirements cost DPP-4 inhibitors linagliptin saxagliptin sitagliptin vildagliptin No weight gain Well tolerated Angioedema/urticaria and other immune-mediated dermatology effects? Acute pancreatitis h Heart failure hospitalisations cost SGLT2 inhibitors canaglifozin dapaglifozin empagliflozin Weight loss i Blood pressure Effective at all stages of T2DM Genitourinary infections Polyuria Volume depletion/hypotension/ dizziness h LDL-cholesterol h Creatinine (transient) cost 5 a-glucosidase inhibitor acarbose i Postprandial glucose excursions? i CVD events (STOP-NIDDM) Nonsystemic Moderate cost Generally modest HbA1c efficacy GI side effects (flatulence, diarrhoea) Frequent dosing schedule Reference: 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: [adapted] MIMS Ireland Copyright v

5 Monotherapy Efficacy ( HbA 1c ): Hypoglycaemia: Weight: Side effects: Cost: Dual therapy Efficacy ( HbA 1c ): Hypoglycaemia: Weight: Side effects: Cost: Triple therapy Combination injectable therapy Figure A: Antihyperglycaemic Therapy in Type 2 Diabetes General Recommendations 1 Begin with lifestyle changes healthy eating, weight control, increased physical activity, and diabetes education monotherapy is added at, or soon after, diagnosis (in patients intolerant, or with contraindications for, metformin, select initial drug from other classes depicted) Monotherapy Neutral/loss GI/lactic acidosis Low If HbA 1c target not achieved after ~3 months, proceed to two-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- and disease-specific factors) Consider beginning at this stage when HbA1c 9% Insulin (basal) Moderate risk Gain Hypoglycaemia Low Gain Oedema, HF, Fx s Low Intermediate Neutral Rare Intermediate Loss GU, dehydration Loss GI est risk Gain Hypoglycaemia Variable If HbA 1c target not achieved after ~3 months, proceed to three-drug combination (order not meant to denote any specific preference choice dependent on a variety of patient- and disease-specific factors) or or or or or or or or or or or Insulin (basal) or or or If HbA 1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on, add basal insulin; or (3) on optimally titrated basal insulin, add or mealtime insulin. In refractory patients consider adding thiazolidinedione or SGLT2 inhibitor. Consider beginning at this stage when blood glucose mmol/L and/or HbA1c 10-12%, especially if symptomatic or catabolic features present Basal insulin Mealtime insulin or GI: Gastrointestinal; HF: Heart failure; Fx s: Bone fractures; GU: Genitourinary; : GLP-1 receptor agonist; *usually basal insulin MIMS Ireland Copyright Reference: 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: [adapted]

6 Figure B: Antihyperglycaemic Therapy in Type 2 Diabetes Adapted Recommendations to Avoid Hypoglycaemia 1 Begin with lifestyle changes healthy eating, weight control, increased physical activity, and diabetes education monotherapy is added at, or soon after, diagnosis (in patients intolerant, or with contraindications for, metformin, select initial drug from other classes depicted) Monotherapy Efficacy ( HbA 1c ): Weight: Neutral/loss Side effects: GI/lactic acidosis Cost: Low If HbA 1c target not achieved after ~3 months, proceed to two-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- and disease-specific factors) Consider beginning at this stage when HbA1c 9% Efficacy ( HbA 1c ): Weight: Gain Side effects: Oedema, HF, Fx s Cost: Low Side effects: GU, dehydration Cost: Weight: Neutral Side effects: Rare Cost: Efficacy ( HbA 1c ): Side effects: GI Cost: If HbA 1c target not achieved after ~3 months, proceed to three-drug combination (order not meant to denote any specific preference choice dependent on a variety of patient- and disease-specific factors) or or or or Figure C: Antihyperglycaemic Therapy in Type 2 Diabetes Adapted Recommendations to Avoid Weight Gain or Facilitate Weight Loss 1 Begin with lifestyle changes healthy eating, weight control, increased physical activity, and diabetes education monotherapy is added at, or soon after, diagnosis (in patients intolerant, or with contraindications for, metformin, select initial drug from other classes depicted) Monotherapy Efficacy ( HbA 1c ): Weight: Neutral/loss Side effects: GI/lactic acidosis Cost: Low If HbA 1c target not achieved after ~3 months, proceed to two-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- and disease-specific factors) Consider beginning at this stage when HbA1c 9% Weight: Neutral Side effects: Rare Cost: Side effects: GU, dehydration Cost: Efficacy ( HbA 1c ): Side effects: GI Cost: If HbA 1c target not achieved after ~3 months, proceed to three-drug combination GI: Gastrointestinal; HF: Heart failure; Fx s: Bone fractures; GU: Genitourinary; : GLP-1 receptor agonist MIMS Ireland Copyright Reference: 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: [adapted]