Improving Patient Care through Evidence Treatment of Type 2 Diabetes This information is based on a comprehensive review of the evidence for best practices in the treatment of type 2 diabetes and is sponsored by the Agency for Health Care Research and Quality.
Improving Patient Care through Evidence: Treatment of Type 2 Diabetes The growing epidemic of type 2 diabetes 1 Diabetes affects over 25 million Americans. 27% of people over 65 have diabetes. Rates of stroke and death due to heart disease are 2-4 times higher in adults with diabetes. Figure 1. Rapidly increasing rate of diabetes 2 Percentage 10.0 9.0 8.0 Crude Age-Adjusted 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 80 85 90 95 00 05 10 Year Patients with diabetes are likely to have other important co-morbid conditions Nearly 60% of adults with diabetes have hypertension. People with diabetes are twice as likely to suffer from depression. Diabetes is the leading cause of kidney failure, lower limb amputations, and blindness. Achieving the best outcomes For most patients with diabetes, the target for HbA1c should be below 7%. Achieving this level of control reduces the risk of end-organ damage including renal insufficiency, visual impairment, and neuropathy. Less strict targets may be appropriate for older patients and other vulnerable populations. 2
Evidence-based treatment can improve outcomes Every 1% drop in HbA1c reduces the risk of microvascular complications by 40%, and death by 21%. 1,3 Reducing diastolic blood pressure from 90 mmhg to 80 mmhg in people with diabetes reduces the risk of major cardiovascular events by 50%. 1 Figure 2. Death related to diabetes 3 4 Hazard ratio 1 21% decrease per 1% reduction in HbA1c p < 0.0001 0.5 0 5 6 7 8 9 10 11 Mean HbA1c over time Treatment approach 4,5 Successful treatment of diabetes requires a persistent approach that begins with modification of diet and lifestyle and then, when medication is needed, adds medications in a stepwise fashion, guided by periodic assessment of HbA1c. The foundation: Lifestyle management 4,5 Any diabetes treatment plan starts with weight management, diet, and exercise. Weight loss reduces insulin resistance reduces the risk of developing diabetes in patients with pre-diabetes. Combined weight loss and exercise can result in an average HbA1c reduction of 0.3%. Adding medication Most patients with type 2 diabetes, even with diligent work on lifestyle management, will ultimately have HbA1c levels above 7%, and will require medication. Guidelines from the American Diabetes Association and other groups focus on: setting specific HbA1c targets, stepwise approach for initiation of drug therapy, and prompt intensification of treatment when goals are not met. 3
Improving Patient Care through Evidence: Treatment of Type 2 Diabetes Non-insulin agents 1 STEP Start with metformin For patients not meeting HbA1c targets with diet and exercise, metformin (Glucophage) is the recommended first choice medication in all major guidelines. Why metformin? Well documented effectiveness for controlling glucose and preventing end-organ damage Best evidence for reducing long term complications of diabetes Most beneficial effects on lipids and body weight Predictable and manageable side effect profile Affordable for patients GI side effects are common with initial use of metformin; these effects may be minimized by starting with a low dose and slowly increasing it. Metformin can increase the risk of lactic acidosis when used in patients with low creatinine clearance, but the absolute risk is very low. Because of this risk, it should not be used in patients with renal insufficiency. STEP2Add a second agent if HbA1c goal is not achieved Monotherapy with an oral agent will generally lower HbA1c by 1% in most patients. Wait no more than 3 months before stepping up the regimen if HbA1c remains above goal (7% for most patients). The natural course of diabetes is a progressive loss of insulin sensitivity and production. Half of patients initially controlled on a single agent will require an additional drug after 3 years. 4
Choosing a second line agent There are many non-insulin agents available, with differing mechanisms of action. A second non-insulin drug will generally reduce HbA1c by an additional 0.5 1%. There are no significant differences among the agents for HbA1c lowering, with the exception of DPP4 inhibitors, which appear to produce smaller reductions in HbA1c. Insulin provides significantly greater reductions in HbA1c than any other alternative. Table 1. Classes and mechanisms of action of major non-insulin agents Class Examples Mechanisms of Action biguanides metformin (Glucophage) Decreases hepatic glucose production (major); increases uptake of glucose from blood into the tissues (minor) sulfonylureas* glyburide (Diabeta, Micronase) glipizide (Glucotrol) glimepiride (Amaryl) Increases insulin secretion glitazones pioglitazone (Actos) Increases insulin-mediated glucose uptake into adipose tissues and skeletal muscles (major); decreases hepatic glucose production (minor) DDP4 inhibitors sitagliptin (Januvia) saxagliptin (Onglyza) linagliptin (Tradjenta) Increases incretin hormones, which augments glucose-dependent insulin secretion and decreases glucagon release GLP-1 receptor agonists exenatide (Byetta)** exenatide ER (Bydureon)** liraglutide (Victoza)** Mimics naturally occurring incretin hormones, which stimulates insulin production and the response to elevated blood glucose; inhibits release of glucagon after meals; slows nutrient absorption; increases satiety * sulfonylureas refers only to second generation agents and not older agents (such as chlorpropamide), which are seldom used in current practice. ** These agents are given by subcutaneous injection. 5
Improving Patient Care through Evidence: Treatment of Type 2 Diabetes Non-insulin agents have some important differences Second line agents can differ with respect to side effect profile, cost, and impact on other outcomes such as weight gain and lipids. While all are effective in reducing blood glucose levels, most newer agents do not have the same level of evidence for reduction of actual end-organ damage, compared to metformin, the sulfonylureas, or insulin. Cost: Costs for diabetes medications can vary from a few dollars to hundreds of dollars per month. Experience: After metformin, the sulfonylureas have the longest track record. Side effect profile: The glitazones substantially increase the risk of CHF and peripheral edema compared to other agents, as well as increase the risk of fracture in women. Pioglitazone may increase the risk of bladder cancer. Sulfonylureas and meglitinides increase the risk of hypoglycemia, while other classes of agents do not. Longer-acting sulfonylureas (e.g., glyburide) are more likely to cause prolonged hypoglycemia than short-acting agents (e.g., glipizide). Table 2. Summary of comparative efficacy, safety, and cost of non-insulin agents Drug metformin Risk of death, and/or major CV events Control of HbA1c Weight gain or loss Hypoglycemia Heart failure and edema LDL GI side effects Cost Overall sulfonylureas glitazones a-glucosidase inhibitors meglitinides DPP4 inhibitors GLP-1 receptor agonists Best outcome Intermediate Problem Unknown LDL = LDL cholesterol level; GI = gastrointestinal intolerance 6
STEP3Add a third-line agent If adequate control is not achieved after introducing a second line therapy, further intensification is necessary. Insulin offers the best chance to control HbA1c when added as a third agent, though non-insulin agents remain an option for patients unable or unwilling to use insulin. Why insulin? Additional non-insulin agents are unlikely to add more than a 0.5% 1% reduction in HbA1c, whereas insulin can do much more. Further delay in achieving control can allow end-organ damage to proceed unchecked. Prescribing three or more oral agents can make a patient s medication regimen more confusing and difficult to afford. Prompt initiation of insulin can improve HbA1c control 7
Improving Patient Care through Evidence: Treatment of Type 2 Diabetes Insulins Delays in insulin initiation The initiation of insulin therapy is often delayed unnecessarily. Only about 37% of patients achieve the goal of < 7% HbA1c. Insulin is the most effective glucose lowering medicine available. One study found that the average delay of initiation of insulin therapy after failure of non-insulin therapy was 4-6 years. Figure 3. Evolution of nephropathy in patients with type 2 diabetes treated with intensive vs. conventional treatment 6 Percentage of patients 50 40 Conventional treatment 30 20 10 Intensive treatment 0 0 1 2 3 4 5 6 7 8 Year Choose the right time to start Combination therapy with oral agents and insulin can produce improved glucose control and less weight gain than therapy with insulin alone. Insulin combined with metformin offers the greatest synergy for clinical effect and the lowest risk of adverse events. If a diabetic patient has an HbA1c > 8.5% on maximal dose oral diabetic monotherapy, or an HbA1c > 8% on two non-insulin agents, insulin therapy should generally be initiated. Also consider insulin if HbA1c is between 7% and 8% on two non-insulin agents. Choices for insulin treatment Several types of insulin are available, varying mainly in their dosing and cost. Rapid acting: lispro (Humalog), aspart (NovoLog), glulisine (Apidra) Intermediate acting: NPH (Humulin N / Novolin N) Long acting (basal): glargine (Lantus), detemir (Levemir) 8
Figure 4. Time-activity curves for selected insulin formulations 7 Relative glycemic effect 0 Lispro, aspart, glulisine Regular human NPH Detemir Glargine 12 24 Hours Premixed insulins combine rapid and slower acting insulins. Long-acting insulin (e.g., glargine) and intermediate-acting insulin (NPH) are similarly effective for glucose control in patients with type 2 diabetes. Longeracting insulins cause modest reductions in overnight hypoglycemic events. Biphasic and rapid-acting formulations produce more hypoglycemia and are more difficult for patients to manage. 3 3 Start with a basal insulin Most patients should begin with basal insulin at night, either intermediate or long-acting insulin. Such a regimen will be easier for patients to manage and can provide a good foundation for improving glucose control. Insulin choices should be tailored to the needs of individual patients, including considerations of convenience and cost for patients. Intensify insulin treatment as needed Many patients will not achieve glycemic control on their initial dose of basal insulin. Intensification of insulin therapy should be guided by daily glucose values and periodic checks of HbA1c levels. Treating to target A commonly used algorithm for insulin intensification comes from the Treat-to-Target study. 8 This randomized controlled trial demonstrated that most patients inadequately controlled on one or two oral agents (metformin, sulfonylurea, or glitazone) could achieve an HbA1c < 7% by following this simple algorithm. Start with 10 units per day of bedtime basal insulin. Adjust insulin every week. To adjust, calculate the mean self-monitored fasting plasma glucose (FPG) values from the previous 2 days. Mean FPG Increase insulin by 100-120 mg/dl 2 units 120-140 mg/dl 4 units 140-180 mg/dl 6 units 180 mg/dl 8 units 9
Improving Patient Care through Evidence: Treatment of Type 2 Diabetes Treatment of type 2 diabetes 4 Healthy eating, weight control, increased physical activity Initial drug monotherapy: Metformin If needed to reach individualised HbA1c target after ~3 months, proceed to two-drug combination (order not meant to denote any specific preference): Two-drug combinations: Metformin + one other drug a + Sulfonylurea b + Thiazolidine- + DPP-4 + GLP-1 receptor + Insulin dione Inhibitor agonist (usually basal) If needed to reach individualised HbA1c target after ~3 months, proceed to three-drug combination (order not meant to denote any specific preference): Three-drug combinations: Metformin + two other drugs + Sulfonylurea b + Thiazolidine- + DPP-4 + GLP-1 receptor + Insulin dione Inhibitor agonist (usually basal) + TZD + SU b + SU b + SU b + TZD or DPP-4 I or DPP-4 I or TZD or TZD or DPP-4 I or GLP-1-RA or GLP-1-RA or Insulin c or Insulin c or GLP-1-RA or Insulin c or Insulin c If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with one or two non-insulin agents: More complex insulin strategies Insulin d (multiple daily doses) 10 a. Consider beginning at this stage in patients presenting initially with very high HbA1C (e.g., 9%). b. Consider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. c. Usually a basal insulin (NPH, glargine, detemir) in combination with noninsulin agents. d. Certain noninsulin agents may be continued with insulin. Consider beginning at this stage if patient presents with severe hyperglycemia 16.7 19.4 mmol/l [ 300 350 mg/dl]; HbA1C 10.0 12.0% with or without catabolic features (weight loss, ketosis, etc.).
Careful management of lipids and blood pressure also plays a critical role in reducing the risk of cardiovascular complications of diabetes. Table 3. Treatment of related conditions Condition Identification Goal of Therapy Recommended Interventions Hypertension Check BP at all visits SBP 140 mmhg DBP 80 mmhg Begin with lifestyle modification Drug therapy should include ACEI (ARB if ACEI not tolerated) Add thiazide-type diuretic if 2 nd agent needed Hyperlipidemia Check fasting lipids LDL < 100 mg/dl (LDL < 70 mg/dl if CAD) Treat with statin if elevated LDL Smoking Assess for tobacco use Smoking cessation Nicotine replacement Bupropion/varenicline Counseling programs References: 1. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services. 2. Centers for Disease Control and Prevention. Crude and Age-Adjusted Percentage of Civilian, Noninstitutionalized Adults with Diagnosed Diabetes, United States, 1980 2010. Accessed August 30, 2012 from http://www.cdc.gov/diabetes/statistics/ prev/national/figageadult.htm 3. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. Aug 12 2000; 321:405-12. 4. Inzucchi SE, Bergenstal RM, Buse JB et al, Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach. Diabetes Care. Apr 19 2012;35(6):1264-1379. 5. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. Jan 2009;32(1):193-203. 6. American Diabetes Association, From Diabetes Care, Vol. 23, Suppl. 1, 2000; B21-B29. 7. McMahon GT, Dluhy RG. Intention to treat initiating insulin and the 4-T study. The New England Journal of Medicine. Oct 25 2007;357(17):1759-1761. 8. Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. Nov 2003;26(11):3080-3086. 11
Key components of the treatment of type 2 diabetes Aggressive treatment reduces risk of short-term and long-term health problems. Target HbA1c < 7% for most patients, with less strict targets for elderly and other vulnerable patients. Lifestyle management should include: weight management, diet, and exercise. Most patients will need drug therapy in addition to lifestyle management. Follow a stepwise approach for drug therapy, with prompt intensification of treatment when HbA1c goals are not met. Begin drug treatment with metformin, adding a second non-insulin agent if HbA1c remains above goal for 3 months. Insulin should be initiated if HbA1c is > 8.5% on the maximum dose of metformin or > 8% on two non-insulin agents. Using insulin as the third agent if HbA1c is between 7 and 8% on two non-insulin agents is the most effective way to lower HbA1c further. Adding a third non-insulin agent is an option for patients unable or unwilling to add insulin. Careful management of lipids and blood pressure, as well as smoking cessation, improve outcomes for patients with type 2 diabetes. This brochure was developed by NaRCAD (the National Resource Center for Academic Detailing) with support from a grant from the Agency for Healthcare Research and Quality to the Division of Pharmacoepidemiology and Pharmacoeconomics of the Brigham and Women s Hospital Department of Medicine. It was adapted from materials originally developed by the non-profit Alosa Foundation. Complete references and a longer discussion of the evidence underlying these recommendations is provided at www.rxfacts.org. Neither NaRCAD nor Alosa has any affiliations with any pharmaceutical company, and none of the physicians who prepared this material accepts any personal compensation from any drug manufacturer. These are general recommendations only; specific clinical decisions should be made by the treating physician based on an individual patient s clinical condition. DoPE 2013 Alosa Foundation, Inc.