Summary

This AACE and ACE consensus statement includes up-to-date sections on lifestyle therapy and all classes of obesity, antihyperglycaemic, lipid-lowering, and antihypertensive medications approved by the U.S. Food and Drug Administration (FDA) until December 2018.

The American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) have recently released a consensus statement outlining the comprehensive management algorithm for Type 2 diabetes. The updated 2019 document has been published in the journal Endocrine Practice.

This algorithm supplements the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) 2015 Clinical Practice Guidelines and organized into discrete sections that address the following topics: the founding principles of the algorithm, lifestyle therapy, obesity, prediabetes, management of hypertension and dyslipidemia, and glucose control with noninsulin antihyperglycemic agents and insulin.

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What has changed?

Since originally drafted in 2013, the algorithm has been updated as new therapies, management approaches, and important clinical data have emerged.

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Pharmacotherapy in Type 2 Diabetes

The key takeaways in this section of the guidance document are:-

1. According to AACE an A1C level of ≤6.5% (48 mmol/mol) is considered optimal if it can be achieved in a safe and affordable manner. A broader A1C range may be suitable for older patients and those at risk for hypoglycaemia and may change for a given individual over time.
2. A less stringent A1C >6.5% is appropriate for patients with a h/o severe hypoglycemia, limited life expectancy, advanced renal disease or macrovascular complications, extensive comorbid conditions, or long-standing T2D in which the A1C goal has been difficult to attain despite intensive efforts, so long as the patient remains free of polydipsia, polyuria, polyphagia, or other hyperglycemia-associated symptoms.
3. The choice of diabetes therapies must be individualized based on attributes specific to both patients and the medications themselves. Medication attributes that affect this choice include initial A1C, duration of T2D, and obesity status. Other considerations include:

• antihyperglycaemic efficacy
• mechanism of action
• risk of inducing hypoglycaemia
• risk of weight gain
• other adverse effects, tolerability, ease of use, likely adherence, cost and
• safety or risk reduction in heart, kidney, or liver disease

4. Regardless of the treatment selected, patients must be followed regularly and closely to ensure that glycemic goals are met and maintained.

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Metformin

• Metformin has a low risk of hypoglycaemia, can promote modest weight loss, and has good antihyperglycaemic efficacy at doses of 1,000 to 2,000 mg/day
• The FDA has recently uplifted previous contra-indication in males with serum creatinine >1.5 mg/dL and females with serum creatinine >1.4 mg/dL. Newer CKD guidelines are now based on eGFR, not on serum creatinine.
• Metformin can be used in patients with stable eGFR >30 mL/min/1.73 m²; however, it should not be started in patients with an eGFR <45 mL/min/1.73 m².
• Reduction in total daily dose is judicious in patients with eGFR between 30 and 45 mL/min/1.73 m², and due to risk of lactic acidosis, it should not be used in patients with eGFR <30 mL/ min/1.73 m²
• In patients taking metformin who develop neuropathy, B12 should be monitored and if required supplements should be given to affected patients.

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GLP1 receptor agonists

• These drugs have strong A1C-lowering properties, are usually associated with weight loss and lipid and BP reductions
• The risk of hypoglycaemia with GLP1 receptor agonists is low and they reduce fluctuations in both fasting and postprandial glucose levels by stimulating glucose-dependent insulin secretion and suppressing glucagon secretion
• GLP1 receptor agonists should not be used in patients with a personal or family history of medullary thyroid carcinoma or those with multiple endocrine neoplasia (MEN) syndrome type 2
• Exenatide should not be used if creatinine clearance is <30 mL/min. No dose adjustment is required for liraglutide, semaglutide, and dulaglutide in CKD, although renal function should be monitored in patients reporting severe adverse gastrointestinal reactions
• Cautious use of GLP1 receptor agonists required in patients with a history of pancreatitis and discontinued if pancreatitis develops
• Furthermore, it’s use in patients with gastroparesis or severe gastro-esophageal reflux disease requires careful monitoring and dose adjustment owing to the fact that some GLP1 receptor agonists may retard gastric emptying, especially with initial use

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SGLT2 inhibitors

This class of drugs have a glucosuric effect that results in decreased A1C, weight, and systolic BP. SGLT2 inhibitors are associated with increased risk of mycotic genital infections and slightly increased LDL-C levels, and because of their mechanism of action, they have limited efficacy in patients with an eGFR <45 mL/min/1.73 m².

There are ongoing investigations into SGLT2 inhibitor-associated diabetic ketoacidosis (DKA), which has been reported to occur in type 1 diabetes (T1D) and T2D patients with less than expected hyperglycemia (euglycemic DKA).

After a thorough review of the evidence during an October 2015 meeting, an AACE/ACE Scientific and Clinical Review expert consensus group recommended stopping SGLT2 inhibitors 24 to 48 hours prior to scheduled surgeries and anticipated metabolically stressful activities (e.g., extreme sports) and that patients taking SGLT2 inhibitors with insulin should avoid very-low-carbohydrate meal plans and excess alcohol intake.

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Dipeptidyl peptidase 4 (DPP4) inhibitors

These exert antihyperglycaemic effects by inhibiting DPP4 and thereby enhancing levels of GLP1 and other incretin hormones. This action stimulates glucose-dependent insulin synthesis and secretion and suppresses glucagon secretion.

DPP4 inhibitors have modest A1C-lowering properties; are weight-neutral; and are available in combination tablets with metformin, SGLT2 inhibitors, and a TZD. The risk of hypoglycaemia with DPP4 inhibitors is low.

Except linagliptin, dose adjustments have to be made for all DPP4 inhibitors advised to patients with renal dysfunction. Caution should be exercised when using these agents in patients with a history of pancreatitis.

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Thiazolidinediones (TZDs)

These are the only antihyperglycaemic agents to directly reduce insulin resistance, have relatively potent A1C-lowering properties, a low risk of hypoglycemia, and durable glycemic effects.

Side effects include weight gain, increased bone fracture risk in postmenopausal females and elderly males, and elevated risk for chronic edema or heart failure. These side effects can be reduced with a moderate dose (e.g., ≤30 mg) of pioglitazone, or in the case of fluid retention, by combining the TZD with an SGLT2 inhibitor.

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Alpha-glucosidase inhibitors (AGIs)

This class of drugs has modest A1C-lowering effects and low risk for hypoglycaemia. Clinical trials suggested ASCVD benefit in patients with impaired glucose tolerance and diabetes. They should be used with caution in CKD patients.

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Insulin-secretagogue Sus

The insulin-secretagogue SUs have relatively potent A1C-lowering effects but lack durability and are associated with weight gain and hypoglycaemia.

SUs have the highest risk of serious hypoglycaemia of any noninsulin therapy, and previous studies have raised concerns regarding the cardiovascular safety of this class when the comparator is metformin, which may itself have cardioprotective properties.

The secretagogue glinides have somewhat lower A1C-lowering effects and a shorter half-life and thus carry a lower risk of prolonged hypoglycaemia relative to Sus.

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Bile acid sequestrant (BAS)

Colesevelam lowers glucose modestly, does not cause hypoglycaemia, and decreases LDL-C. A perceived modest efficacy for both A1C and LDL-C lowering as well as gastrointestinal intolerance (constipation and dyspepsia, which occurs in 10% of users), may contribute to limited use.

In addition, colesevelam can increase triglyceride levels in individuals with pre-existing triglyceride elevations, but this is somewhat preventable by concomitant statin use.

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Bromocriptine

The quick-release sympatholytic dopamine receptor agonist bromocriptine mesylate has modest glucose lowering properties and does not cause hypoglycaemia.

It can cause nausea and orthostasis, which may be alleviated by limiting use to less than maximal recommended doses and should not be used in patients taking antipsychotic drugs.

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Clinical considerations

1. For patients with recent-onset T2D or mild hyperglycemia (A1C <7.5% [58 mmol/mol]), lifestyle therapy plus antihyperglycaemic monotherapy (preferably with metformin) is recommended.
2. GLP1 receptor agonists and SGLT2 inhibitors with proven ASCVD and/or CKD benefits may be preferred in patients with those complications. Other acceptable alternatives to metformin as initial therapy include DPP4 inhibitors and TZDs. AGIs, SUs, and glinides may also be appropriate as monotherapy for select patients.
3. In patients who do not reach their glycaemic target on metformin monotherapy, metformin should be continued in combination with other agents, including insulin.
4. Patients who present with an A1C >7.5% (whether newly diagnosed or not) and who are not already taking any antihyperglycaemic agents should be started initially on metformin plus another agent in addition to lifestyle therapy.
5. In metformin intolerant patients, two drugs with complementary mechanisms of action from other classes should be considered.
6. Patients with A1C >9.0% (75 mmol/mol) who are symptomatic (presenting with polyuria, polydipsia, or polyphagia) would likely benefit largely from the addition of insulin, but if presenting without significant symptoms these patients may initiate therapy with maximum doses of two or three other medications.
7. Although several antihyperglycaemic drug classes carry a low risk of hypoglycaemia (e.g., metformin, GLP1 receptor agonists, SGLT2 inhibitors, DPP4 inhibitors, and TZDs), significant hypoglycaemia can still occur when these agents are used in combination with an insulin secretagogue or exogenous insulin.
8. When such combinations are used, one should consider lowering the dose of the insulin secretagogue or insulin to reduce the risk of hypoglycaemia.
9. Many antihyperglycaemic agents (e.g., metformin, GLP1 receptor agonists, SGLT2 inhibitors, some DPP4 inhibitors, AGIs, and SUs) have limitations in patients with impaired renal function and may require dose adjustments or special precautions.
10. In general, diabetes therapy does not require modification for mild to moderate liver disease, but the risk of hypoglycaemia increases in severe cases.