What’s new in type 2 diabetes?

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Applied Evidence

What’s new in type 2 diabetes?

J Fam Pract. 2012 November;61(11):646-651

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References

1. Ogawa H, Nakayama M, Morimoto T, et al. Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2008;300:2134-2141.

2. Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ. 2008;337:a1840.-

3. Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Diabetes Care. 2010;33:1395-1402.

4. American Diabetes Association. Standards of medical care in diabetes–2012. Diabetes Care. 2012;35(suppl 1):S11-S63.

5. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.

6. Turner R, Holman R, Stratton I, et al. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703-713.

7. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351:1755-1762.

8. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412-419.

9. Cushman WC, Evans GW, Byington RP, et al. ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575-1585.

10. Bangalore S, Kumar S, Lobach I, et al. Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and Bayesian random-effects meta-analyses of randomized trials. Circulation. 2011;123:2799-2810.

11. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417-2428.

12. Hermida R, Ayala D, Mojon A, et al. Influence of time of day of blood-pressure lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes. Diabetes Care. 2001;34:1270-1276.

13. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.

14. Cushman W, Evans G, Byington R, et al. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563-1574.

15. Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255-2267.

16. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379.

17. Qaseem A, Humphrey L, Sweet D, et al. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2012;156:218-231.

18. Varanasi A, Chaudhuri A, Dhindsa S, et al. Durability of effects of exenatide treatment on glycemic control, body weight, systolic blood pressure, C-reactive protein, and triglyceride concentrations. Endocr Pract. 2011;17:192-200.

19. Vilsboll T, Christensen M, Junker A, et al. Effects of glucagon-like peptide-1 receptor agonist on weight loss: systemic review and meta-analyses of randomized controlled trials. BMJ. 2012;344:d7771.-

20. Diamant M, Van Gaal L, Stranks S, et al. Safety and efficacy of once-weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes over 84 weeks. Diabetes Care. 2012;35:683-689.

21. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374:39-47.

22. Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized controlled trial. Ann Intern Med. 2011;154:103-112.

23. Drucker DJ, Sherman SI, Bergenstal RM, et al. The safety of incretin-based therapies—review of the scientific evidence. J Clin Endocrinol Metab. 2011;96:2027-2031.

24. Elashoff M, Matveyenko A, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141:150-156.

25. Piccinni C, Motola D, Marchesini G, et al. Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care. 2011;34:1369-1371.

26. Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. 2011;34:916-922.

27. European Medicines Agency. European Medicines Agency recommends new contra-indications and warnings for pioglitazone to reduce small increased risk of bladder cancer, updated July 7, 2011. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/07. Accessed March 22, 2012.

28. Sawyer M, Hoerger T. Use of hepatitis B vaccination for adults with diabetes mellitus: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2011;60:1709-1711.

29. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126:460-468.

DPP-4 inhibitors promote the effects of endogenous GLP-1 by inhibiting its breakdown by the enzyme DPP-4. By increasing GLP-1, these agents achieve mild glucose lowering while remaining weight neutral.¹⁶ DPP-4 inhibitors can be combined with metformin and other oral agents and are not associated with hypoglycemia.¹⁶

Injectable GLP-1 receptor agonists provide supraphysiologic levels of GLP-1, resulting in increased insulin secretion, reduced glucagon secretion, delayed gastric emptying, increased satiety, and weight loss.¹⁶ Research has shown that exenatide can decrease mean weight by 7 kg over 2.4 years.^18,19 Exenatide is dosed subcutaneously twice daily, while liraglutide is administered once daily. Once-weekly exenatide was approved by the US Food and Drug Administration (FDA) in February 2012. A recent study showed once-weekly exenatide lowered A1C levels, reduced weight, and caused fewer episodes of hypoglycemia compared with adding insulin glargine to the regimen when diabetes was uncontrolled on metformin (with or without a sulfonylurea).²⁰ Patients may experience nausea, vomiting, and diarrhea at the onset of use of GLP-1 agonists.²¹ Slow titration and forewarning the patient of these adverse effects will help with compliance.

In October 2011, the FDA approved the use of exenatide with basal insulin. For patients already taking basal insulin with or without metformin or pioglitazone, adding exenatide resulted in improved A1C values and weight loss over a 30-week period.²² Reducing the dose of basal insulin at the initiation of exenatide helps decrease the incidence of hypoglycemia when considering this combination.²² Basal insulin lowers fasting glucose levels, while exenatide reduces postprandial glucose.

Although gaining in popularity, incretin therapy is being monitored for long-term safety. Cases of pancreatitis have been reported in both classes of medicines.⁴ Liraglutide has been associated with medullary thyroid cancer (MTC) in rodents.^23,24 The FDA has recommended against using liraglutide and extended-release exenatide in patients with a personal or family history of MTC.¹⁶ Although the long-term safety of GLP-1 agonists and DPP-4 inhibitors is unknown, their novel mechanisms of action can prove useful for the right patient.

Concerns over TZDs. In addition to the FDA recommendation to avoid TZDs in patients with symptomatic heart failure, 2 studies have recently found that pioglitazone may be associated with an increased risk of bladder cancer.^25,26 The FDA recommends avoiding use of pioglitazone in patients with active bladder cancer, and that it should be used with caution in patients with a history of cured bladder cancer. The European Medicines Agency also recommends against pioglitazone use in patients with uninvestigated macroscopic hematuria.²⁷ The potential association between pioglitazone and bladder cancer requires further study. At this point, TZDs remain a valid second- or third-line treatment option in patients only after they are made aware of the potential risks and benefits.

CASE JR’s A1C of 7.6% is above his individualized goal of 7%. He feels he has maximized his efforts in the realm of lifestyle changes and is interested in another medication. Using the recommended patient-centered approach, we discuss with him the risks and benefits of each medication in the TABLE and we select the medication best suited to him based on adverse-effect profile.

TABLE
Matching diabetic medication attributes to patient needs

Class	Medications	Actions	Benefits	Possible adverse effects and disadvantages	A1C-lowering (%)	Cost*
Biguanides	Metformin	↓ Hepatic glucose production	Weight neutral or loss No hypoglycemia ↓ CV mortality	GI side effects Lactic acidosis Impaired B₁₂ absorption Use caution or avoid in renal dysfunction	1-2	$
Sulfonylureas	Gliclazide Glimepiride Glipizide Glyburide	↑ Insulin secretion	Fast-onset glucose lowering	Hypoglycemia Lack of durable glycemic control Weight gain	1-2	$
Meglitinides	Repaglinide Nateglinide	↑ Insulin secretion	Improve meal-related insulin release and postprandial glucose	Hypoglycemia Weight gain	0.1-2.1	$$-$$$
Thiazolidinediones	Pioglitazone	↑ Insulin sensitivity	No hypoglycemia ↑ HDL ↓ Triglycerides	Bladder cancer concerns Edema Fracture risk Heart failure Weight gain	0.5-1.4	$$$
GLP-1 receptor agonists	Exenatide Liraglutide	↑ Insulin secretion ↓ Glucagon secretion Delayed gastric emptying Early satiety	Possible beta-cell preservation Weight loss	GI (nausea, vomiting, diarrhea) Injectable Medullary thyroid tumors in rodents Pancreatitis	0.5-1.5	$$$
DPP-4 inhibitors	Linagliptin Saxagliptin Sitagliptin Vildagliptin	↓ Glucagon secretion ↑ Insulin secretion	No hypoglycemia Weight neutral	Angioedema Pancreatitis	0.5-0.8	$$$
Alpha-glucosidase inhibitors	Acarbose Miglitol	Delays carbohydrate absorption	Nonsystemic medication Reduces postprandial glucose	Frequent dosing GI side effects (abdominal cramping, flatulence)	0.5-0.8	$$
Insulin	Aspart Detemir Glargine Lispro NPH Regular	Replaces endogenous insulin	Mimics physiology Rapidly effective	Hypoglycemia Weight gain	1.5-3.5	$-$$$
CV, cardiovascular; DPP, dipeptidyl peptidase; GI, gastrointestinal; GLP, glucagon-like peptide, HDL, high-density lipoprotein. Monthly cost of an average daily maintenance dose of available products: $, <$50; $$, $50.01-$100; $$$, >$100. Source:* www.drugstore.com; accessed October 10, 2012. Adapted from: Reid TS. Options for intensifying diabetes treatment. J Fam Pract. 2011;9(suppl 1):S7-S10; American Diabetes Association Position Statement. Standards of Medical Care in Type 2 Diabetes-2012. Diabetes Care. 2012;35(suppl 1):S11-S63.

Immunizations

An often overlooked but important part of the diabetes visit is reviewing the patient’s immunization history. Unless there are contraindications, all individuals with diabetes should receive the pneumococcal and annual influenza vaccines.⁴ In addition, the Advisory Committee on Immunization Practices now recommends hepatitis B virus (HBV) vaccine for unvaccinated adults with diabetes from ages 19 to 59.²⁸ Unvaccinated adults with diabetes over age 60 should be vaccinated at the discretion of the provider after risk assessment.²⁸ Patients may be at risk of contracting HBV in long-term care facilities where assisted blood sugar monitoring commonly occurs.²⁸ Studies have shown that patients with diabetes may progress to chronic hepatitis B infection more often than patients without diabetes, and are at higher risk for nonalcoholic liver disease and hepatocellular carcinoma.²⁹