Diabetes Update: Diabetes Management In Primary Care. Jonathon M. Firnhaber, MD, FAAFP

Transcription

1 Diabetes Update: Diabetes Management In Primary Care Jonathon M. Firnhaber, MD, FAAFP

2 Learning objectives 1. Critically evaluate the evidence emerging within diabetes research as it applies to recommendations for physician change. 2. Evaluate current standards of care (screening, prevention, diagnosis, treatment, management) for patients with diabetes, or who are at risk for developing diabetes, for opportunities to update standards in accordance to current research and evidence-based guidelines. 3. Assess new and novel treatments for diabetes in terms of efficacy, safety, contraindications and cost/benefit relative to existing treatments. 4. Apply a patient-centered approach to incorporate guideline recommendations for intensifying therapy to achieve glycemic control. 2

3 American Diabetes Association Standards of Medical Care in Diabetesd2018 Diabetes Care. January 2018, Volume 41, Supplement 1

4 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 Jun;35(6):

5 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(1):

6 ADA evidence-grading system for Standards of Medical Care in Diabetes A: Clear evidence from well-conducted, generalizable randomized controlled trials that are adequately powered B: Supportive evidence from well-conducted cohort studies C: Supportive evidence from poorly controlled or uncontrolled studies E: Expert consensus or clinical experience 6

7 Classification of diabetes Diabetes can be classified into the following general categories: 1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to absolute insulin deficiency) 2. Type 2 diabetes (due to a progressive loss of b-cell insulin secretion frequently on the background of insulin resistance) 7

8 Classification of diabetes Diabetes can be classified into the following general categories: 3. Gestational diabetes mellitus (GDM) 4. Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), and drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treatment of HIV/AIDS, or after organ transplantation) 8

9 Immune-mediated diabetes This form, previously called insulin-dependent diabetes or juvenile-onset diabetes, accounts for 5 10% of diabetes and is due to cellular-mediated autoimmune destruction of the pancreatic b-cells. Autoimmune markers include islet cell autoantibodies and autoantibodies to GAD (GAD65), insulin, the tyrosine phosphatases IA-2 and IA-2b, and ZnT8. Type 1 diabetes is defined by the presence of one or more of these autoimmune markers. 9

10 Diagnosis A1C > 6.5% (Performed in lab using NGSP certified, DCCT assay-standardized method) * OR FPG > 126 mg/dl (Fasting = no caloric intake x 8h) * OR 2h glucose > 200 mg/dl during 75g OGTT * OR Random glucose > 200 mg/dl (in a patient with classic symptoms of hyperglycemia) * In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing.

11 Prediabetes diagnosis Impaired glucose tolerance: 2 hr glucose in 75g OGTT mg/dl OR Impaired fasting glucose: FPG mg/dl OR A1C %

12 Prediabetes Each year, 5-10% of people with prediabetes become diabetic. Isolated IGT: 4-6% Isolated IFG: 6-9% Both IGT and IFG: 15-19% According to an ADA expert panel, up to 70% of individuals with prediabetes will eventually develop diabetes.

13 Associated metabolic abnormalities Hyperuricemia Dyslipidemia: low HDL / elevated triglycerides Urinary microalbuminuria Hepatic steatosis

14 Other autoimmune diseases Consider screening patients with type 1 diabetes for autoimmune thyroid disease and celiac disease soon after diagnosis. B 14

15 Testing for diabetes or prediabetes in asymptomatic adults For all patients, testing should begin at age 45 years. B If tests are normal, repeat testing carried out at a minimum of 3-year intervals is reasonable. C To test for type 2 diabetes, fasting plasma glucose, 2-h plasma glucose after 75-g oral glucose tolerance test, and A1C are equally appropriate. B 15

16 Criteria for testing for diabetes or prediabetes in asymptomatic adults Testing should be considered in all adults who are overweight (BMI >25 kg/m 2 or >23 kg/m 2 in Asian Americans) and have additional risk factors: physical inactivity first-degree relative with diabetes high-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) women who delivered a baby weighing >9 lb or were diagnosed with GDM history of CVD 16 HDL cholesterol level <35 mg/dl and/or a triglyceride level >250 mg/dl women with polycystic ovary syndrome A1C >5.7%, IGT, or IFG on previous testing other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) hypertension (>140/90 mmhg or on therapy for hypertension)

17 women who delivered a baby weighing >9 lb or were diagnosed with GDM Due to recent data, delivering a baby weighing 9 lb or more is no longer listed as an independent risk factor for the development of prediabetes and type 2 diabetes. (no reference cited) Standards of Medical Care in Diabetes 2017 : Summary of Revisions. Diabetes Care. 2016;40(Supplement 1):S4 S5. 17

18 Prevention of diabetes Metformin therapy for prevention of type 2 diabetes should be considered in those with prediabetes, especially for those with BMI >35 kg/m 2, those aged >60 years, and women with prior gestational diabetes mellitus. A 18

19 Frequency of AIC testing Perform the A1C test at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control). E Perform the A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic goals. E Point-of-care testing for A1C provides the opportunity for more timely treatment changes. E 19

20 A1C goals A reasonable A1C goal for many nonpregnant adults is <7%. A Providers might reasonably suggest more stringent A1C goals (such as <6.5%) for selected individual patients if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Appropriate patients might include those with short duration of diabetes, type 2 diabetes treated with lifestyle or metformin only, long life expectancy, or no significant cardiovascular disease. C 20

21 A1C goals Less stringent A1C goals (such as <8%) may be appropriate for patients with a history of: severe hypoglycemia limited life expectancy advanced microvascular or macrovascular complications extensive comorbid conditions or long-standing diabetes in whom the general goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucoselowering agents including insulin. B 21

22 Hemoglobin A1C targets ACCORD 10,251 patients, mean age 62.2 Mean A1C at initiation = 8.1% Intensive therapy (goal A1C < 6.0%) vs. standard therapy (goal A1C %) Median A1C achieved: 6.4% vs. 7.5% N Engl J Med 2008;358:

23 Hemoglobin A1C targets ACCORD Primary outcome (nonfatal MI, nonfatal stroke, death from cardiovascular causes): 352 (intensive) vs. 371 (standard) (HR 0.90; 95% CI 0.78 to 1.04) Death: 257 vs. 203 (HR 1.22; 95% CI 1.01 to 1.46) Intensive therapy arm discontinued at 3.5 years.

24 Factors to consider: ADA/EASD More stringent Less stringent Patient attitude / effort Motivated, adherent Less motivated Risk of hypoglycemia / other adverse events Low High Disease duration Newly diagnosed Long-standing Life expectancy Long Short Important comorbidities Absent Severe Established vascular complications Absent Severe Resources / support system Readily available Limited

25 Older adults: Factors to consider: Age Greater atherosclerotic burden Reduced renal function More comorbidities More likely to be compromised by hypoglycemia Glycemic targets for older patients, or those with longerstanding, more complicated disease should be less aggressive than for younger, healthier individuals.

26 Factors to consider: Chronic kidney disease Stage 2 CKD (egfr <60mL/min) or worse is present in 20-30% of diabetics Most insulin secretagogues are renally cleared. Exceptions include repaglinide and nateglinide Glyburide particularly should be avoided because of long duration of action and active metabolites Most DPP-4 inhibitors are renally cleared. Exception: linagliptin (enterohepatically cleared)

27 Factors to consider: Chronic kidney disease Renal impairment is associated with slower elimination of all insulins.

28 Estimated Average Glucose (eag) Hemoglobin A1C as a concept may seem arbitrary to some patients. ADA is recommending the use of eag, which is expressed in the same units patients are familiar with: mg/dl. The relationship between A1C and eag is described by the formula: 28.7 X A1C 46.7 = eag Diabetes Care 2008;31:

29 A1C and corresponding eag Hemoglobin A1C (%) eag (mg/dl)

30 Premeal glucose target: ADA The ADA now recommends a premeal blood glucose target of mg/dl, rather than mg/dl, to better reflect new data comparing actual average glucose levels with A1C targets.

31 Hypoglycemia: unawareness Hypoglycemia unawareness or one or more episodes of severe hypoglycemia should trigger reevaluation of the treatment regimen. E Insulin-treated patients with hypoglycemia unawareness or an episode of severe hypoglycemia should be advised to raise their glycemic targets to strictly avoid further hypoglycemia for at least several weeks in order to partially reverse hypoglycemia unawareness and reduce risk of future episodes. A 31

32 Hypoglycemia: numbers Based on recommendations from the International Hypoglycemia Study Group: Hypoglycemia alert value (Level 1): <70 mg/dl Clinically significant hypoglycemia (Level 2): <54 mg/dl Severe hypoglycemia (Level 3): no specific threshold Hypoglycemia associated with severe cognitive impairment requiring external assistance for recovery 32

33 Hypoglycemia: treatment Glucagon should be prescribed for all individuals at increased risk of severe hypoglycemia, defined as hypoglycemia requiring assistance, and caregivers, school personnel, or family members of these individuals should be instructed in its administration. E Glucagon administration is not limited to health care professionals. E 33

34 Initial therapy Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacological agent for type 2 diabetes. A Consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes and markedly symptomatic and/or elevated blood glucose levels or A1C. E 34

35 New consideration with metformin Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy. B 35

36 FDA loosens restrictions on metformin use Before starting a patient on metformin and at least annually thereafter, obtain the patient's estimated glomerular filtration rate (egfr). Patients with other risk factors for kidney disease, such as advanced age, should have their egfr checked more frequently. 36

37 FDA loosens restrictions on metformin use egfr below 30 ml/minute: contraindicated egfr ml/minute: do not initiate therapy If egfr declines to ml range while on treatment: assess risks and benefits of continued therapy. 37

38 Subsequent pharmacologic therapy: ADA Metformin plus: Sulfonylurea or TZD or DPP-4 inhibitor or SGLT2 inhibitor or GLP-1 receptor agonist or Basal insulin Consider starting with two drugs when A1C >9% 38

39 Subsequent pharmacologic therapy: ADA A patient-centered approach should be used to guide choice of pharmacological agents. Considerations include efficacy, cost, potential side effects, weight, comorbidities, hypoglycemia risk, and patient preferences. (E) Due to the progressive nature of type 2 diabetes, insulin therapy is eventually indicated for many patients with type 2 diabetes. (B) 39

40 Multi-drug regimens: ADA Avoid combinations of: GLP-1 receptor agonist and DPP-4 inhibitor Insulin and sulfonylurea In patients with suboptimal glucose control, especially those requiring increasing insulin doses, adjunctive use of TZD or SGLT2 inhibitors may improve control and reduce insulin need. 40

41 2018 ADA: Blood pressure goals Most patients with diabetes and hypertension should be treated to a SBP goal of <140 mmhg and a DBP goal of <90 mmhg. A Lower targets, such as < 130/80 mm Hg, may be appropriate for certain individuals at high risk of cardiovascular disease, if they can be achieved without undue treatment burden. C

42 Choice of antihypertensive To better align with existing data, the hypertension treatment recommendation for diabetes now suggests: For patients without albuminuria, any of the four classes of blood pressure medications that have shown beneficial cardiovascular outcomes may be used: ACE inhibitors Angiotensin receptor blockers Thiazide-like diuretics Dihydropyridine calcium channel blockers 42

43 Choice of antihypertensive Pharmacological therapy for patients with diabetes and hypertension should comprise a regimen that includes either an ACE inhibitor or an angiotensin receptor blocker but not both. B If one class is not tolerated, the other should be substituted. C 43

44 Hypertension in diabetes: additional points Treat at >140/90 mmhg; use two drugs if >160/100 Multiple-drug therapy is generally required ACE-I or ARB at maximally tolerated dose if albuminuria If not at goal with >3 drugs (including diuretic), consider mineralocorticoid receptor antagonist therapy 44

45 ADA: Lipid treatment For patients of all ages with diabetes and atherosclerotic cardiovascular disease, high-intensity statin therapy should be added to lifestyle therapy. A For patients with diabetes aged years [A] and >75 years [B] without ASCVD, use moderate-intensity statin in addition to lifestyle therapy. 45

46 Statin intensity High-intensity (> 50% LDL-C reduction) Moderate-intensity (30% to < 50%LDL-C reduction) Atorvastatin mg Rosuvastatin 20 mg Atorvastatin mg Rosuvastatin 5-10 mg Simvastatin mg Pravastatin mg Lovastatin 40 mg Fluvastatin 40 mg bid

47 ADA: Lipid treatment For patients with diabetes and atherosclerotic cardiovascular disease: If LDL cholesterol is >70 mg/dl on maximally tolerated statin dose, consider adding additional LDL-lowering therapy (such as ezetimibe or PCSK9 inhibitor) after evaluating the potential for further atherosclerotic cardiovascular disease risk reduction, drug-specific adverse effects, and patient preferences Ezetimibe may be preferred due to lower cost. A 47

48 Non-statin antihyperlipidemics Combination therapy (statin/fibrate and statin/niacin) has not been shown to improve ASCVD outcomes and is generally not recommended. A Statin/niacin combination may increase the risk of stroke with additional side effects. For patients with fasting triglyceride levels >500 mg/dl (5.7 mmol/l), evaluate for secondary causes of hypertriglyceridemia and consider medical therapy to reduce the risk of pancreatitis. C 48

49 Statins and diabetes risk Diabetes Prevention Program Outcomes Study Long-term follow-up to a randomized clinical trial of interventions to prevent T2DM (n=3234) Statin use was associated with greater diabetes risk irrespective of treatment group: pooled HR for incident diabetes = 1.36 (95% CI: ). Risk was not materially altered by adjustment for baseline diabetes risk factors and potential confounders related to indications for statin therapy. 49

50 Statins and diabetes risk Cardiovascular Event Reduction Versus New-Onset Diabetes During Atorvastatin Therapy Compared NOD incidence with CV event reduction among 15,056 patients with coronary disease but without diabetes at baseline in: TNT (Treating to New Targets) (n=7,595) IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering) (n=7,461) trials. CV events included coronary heart disease death, myocardial infarction, stroke, and resuscitated cardiac arrest. 50

51 Statins and diabetes risk Four factors independently predicted new onset diabetes (NOD): fasting blood glucose >100 mg/dl fasting triglycerides >150 mg/dl body mass index >30 kg/m 2 history of hypertension. 51

52 Statins and diabetes risk Among patients with 0 to 1 risk factors, NOD developed in 3.22% in the atorvastatin 80 mg group and in 3.35% in the lower dose groups (HR = 0.97; 95% CI: ). Among patients with 2 to 4 risk factors, NOD developed in 14.3% in the atorvastatin 80 mg group and in 11.9% in the lower-dose groups (HR = 1.24; 95% CI: ; p = ). CV events was significantly reduced with atorvastatin 80 mg in both NOD risk groups. 52

53 Diabetes and heart disease In patients with known ASCVD, consider ACE-I or ARB therapy to reduce the risk of cardiovascular events. B In patients with prior MI, b-blockers should be continued for at least 2 years after the event. B In patients with type 2 diabetes with stable congestive heart failure, metformin may be used if egfr remains >30 ml/min but should be avoided in unstable or hospitalized patients with congestive heart failure. B 53

54 Additional considerations in CV disease In patients with established ASCVD, therapy should: begin with lifestyle management and metformin, and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality (currently empagliflozin and liraglutide), after considering drug-specific and patient factors. A 54

55 Agents proven to reduce major adverse cardiovascular events and cardiovascular mortality Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. 1.6% ARR in primary composite outcome: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. 1.9% ARR in first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke 55

56 ADA: Aspirin therapy Aspirin therapy ( mg/day) may be considered as a primary prevention strategy in those with type 1 or type 2 diabetes who are at increased cardiovascular risk. This includes most men and women with diabetes aged >50 years who have at least one additional major risk factor (family history of premature atherosclerotic cardiovascular disease, hypertension, dyslipidemia, smoking, or albuminuria) and are not at increased risk of bleeding. C 56

57 ADA: Aspirin therapy Use aspirin therapy(75 162mg/day) as a secondary prevention strategy in those with diabetes and a history of atherosclerotic cardiovascular disease. A 57

58 Nutrition therapy: 2018 Nutrition therapy has an integral role in overall diabetes management, and each person with diabetes should be actively engaged in education, self-management, and treatment planning with his or her health care team, including the collaborative development of an individualized eating plan. There is no single ideal dietary distribution of calories among carbohydrates, fats, and proteins for people with diabetes; therefore, macronutrient distribution should be individualized while keeping total calorie and metabolic goals in mind. 58

59 Where do I find guidelines? 2018 ADA Guidelines ADA website: diabetes.org Free 2012 ADA/EASD Position Statement, 2015 Update Diabetes Care journal EASD website Free 59

60 References Standards of Medical Care in Diabetes Diabetes Care Volume 41, Supplement 1, January Inzucchi S, Bergenstal R, Buse J, 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(6): doi: /dc Zinman B, Wanner C, Lachin J, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015;373:

61 References Crandall J, Mather K, Rajpathak S, et al. Statin use and risk of developing diabetes: results from the Diabetes Prevention Program. Bmj Open Diabetes Res Care. 2017;5(1):e doi: /bmjdrc Kaul S. Mitigating Cardiovascular Risk in Type 2 Diabetes With Antidiabetes Drugs: A Review of Principal Cardiovascular Outcome Results of EMPA- REG OUTCOME, LEADER, and SUSTAIN-6 Trials. Diabetes Care. 2017;40(7): doi: /dc Mann J, Ørsted D, Brown-Frandsen K, et al. Liraglutide and Renal Outcomes in Type 2 Diabetes. New Engl J Medicine. 2017;377(9): doi: /nejmoa

62 References Marso S, Daniels G, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. New Engl J Medicine. 2016;375(4): doi: /nejmoa Liu J, Li L, Deng K, et al. Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis. BMJ. 2017;357:j2499. doi: /bmj.j2499. Nathan D, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine R. Translating the A1C Assay Into Estimated Average Glucose Values. Diabetes Care. 2008;31(8): doi: /dc

63 References Waters D, Ho J, Boekholdt M, et al. Cardiovascular Event Reduction Versus New-Onset Diabetes During Atorvastatin Therapy Effect of Baseline Risk Factors for Diabetes. J Am Coll Cardiol. 2013;61(2):

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