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Diabetes Update Exploring lifestyle and risk in preventing type 2 diabetes
Mellitus NICOLE TEMOFONTE D.O. MARCH 2017
Objectives 1. Identify the prevalence of diabetes and obesity in the United States over time. 2. Review the classification and diagnosis of diabetes. 3. List recent diabetes and obesity guidelines. 4. List the pharmacologic agents used for treatment of diabetes. 5. Explain the recent changes to metformin labeling. 6. Describe adverse events
associated with some oral antihyperglycemic agents. 7. Review the different types of insulin and describe new insulin therapies. 8. Identify the risk factors
for DM Type 2. 9. Review the categories of increased risk for DM Type 2. 10. Discuss how to prevent/delay Type 2 DM. *Focus is Type 2 DM-adult nonpregnant patient
Percentage with Diabetes Number with Diabetes (Millions)
Number and Percentage of U.S. Population with Diagnosed Diabetes, 1958-2014
Percentage with Diabetes
Number with Diabetes
2 5 1
1958 61 64 67 70 73 76 79 82 85 88 91 94 97 00 03 06 09 11 14
CDC's Division of Diabetes Translation. United States Diabetes Surveillance System available at http://www.cdc.gov/diabetes/data
Age-adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults
Obesity (BMI 30 kg/m2)
No Data <14.0% 14.0%17.9% 18.0%21.9% 22.0%25.9% > 26.0%
No Data <4.5% 4.5%5.9%
NOTE: Survey method changes in 2011 may impact trends http://www.cdc.gov/surveillancepractice/reports/brfss/brfss.html. CDC's Division of Diabetes Translation. United States Diabetes Surveillance System available at http://www.cdc.gov/diabetes/data
Types of Diabetes Appropriate nomenclature DM Type 1 Type 1 Diabetes DM Type 2 Type 2 Diabetes Old nomenclature; no longer used IDDM NIDDM Insulin dependent Non-insulin dependent Diabetic in reference to a person Will no longer be used to refer to patients with diabetes ADA position that diabetes does not define people
Classification of Diabetes 1. Type 1 Diabetes 2. Type 2 Diabetes 3. Gestational diabetes mellitus 4. Specific types of diabetes due to other causes
Classification of Diabetes Type 1 Diabetes Previously referred to as juvenile onset or insulin dependent diabetes mellitus (IDDM) Most commonly due to cellular mediated autoimmune pancreatic islet cell destruction Autoimmune markers: Glutamic acid decarboxylase (GAD 65) antibodies Islet cell antibodies (ICA) Insulin autoantibodies (IAA) Tyrosine phosphatases IA-2, and Ia-2 ZnT8 Ultimately leads to absolute insulin deficiency Rate is variable HLA associations Linkage to DQA and DQB genes American Diabetes Association. diabetes care
. 2017;40(suppl 1):S1-S35.
Classification of Diabetes Type 2 diabetes Previously referred to as adult onset or noninsulin dependent diabetes mellitus (NIDDM) Results from relative insulin deficiency Insulin secretion is defective or insufficient to compensate for insulin resistance 90-95% (ADA guidelines) Do not initially or may not ever require insulin therapy Greenspan, Francis S. and Gardner, David G. (2011) Greenspans' Basic and Clinical Endocrinology (9th ed.). Lange/McGraw Hill.
Classification of Diabetes Gestational Diabetes Mellitus (GDM) Diabetes diagnosed in the second or third trimester of pregnancy that is not clearly preexisting diabetes American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S35.
Classification of Diabetes
Other specific types of diabetes:
Autosomal dominant genetic defects of pancreatic cells
Maturity onset diabetes of the young (MODY)
Onset of hyperglycemia in late childhood or <25 years of age
Characterized by impaired insulin secretion with minimal or no defects in insulin action (in nonobese patients
Autosomal dominant inheritance
3 most common forms:
· GCK-MODY (MODY 2)
Mild stable fasting hyperglycemia
Often do not require therapy except during pregnancy
· HNF1A-MODY (MODY 3) · HNF4A-MODY (MODY 1)
Usually respond well to low dose sulfonlyureas
Diseases of the exocrine pancreas
Drug or chemical induced diabetes
After organ transplantation
American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S35.
How is diabetes diagnosed? Fasting blood sugar
126 mg/dl How is fasting defined? Fasting is defined as no caloric intake for 8 hours. OR 2 hour plasma glucose 200 mg/dl during an oral glucose tolerance test How is the test performed? How much glucose is ingested? OR HbA1C 6.5% OR Random plasma glucose greater than or equal to 200 AND symptoms of hyperglycemia or hyperglycemic crisis What are symptoms of hyperglycemia? *In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing. American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S35.
Guidelines Some recent guidelines Diabetes 2017 American College of Physicians- Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practical Guideline Update from the American College of Physicians. American Diabetes Association-Standards of Medical Care in Diabetes 2015 American Association
of Clinical Endocrinologists and American College of Endocrinologyclinical practice
Guidelines for Developing A Diabetes Mellitus Comprehensive Care Plan Obesity 2016 American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for Comprehensive Medical Care of Patients with ObesityExecutive Summary
2015 The Endocrine Society-Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guideline 2013 American Heart Association/American College of Cardiology/The Obesity Society-Guideline for the Management of Overweight and Obesity
Pharmacologic Therapy For DM Type 2 Oral agents Biguanides Metformin Sulfonylureas Glyburide Glipizide Glimepiride Meglitinides Repaglinide Nateglinide Thiazolidinediones Pioglitazone Rosiglitazone American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S35.
Pharmacologic Therapy for DM Type 2 Oral agents DPP-4 inhibitors Sitagliptin Saxagliptin Linagliptin Alogliptin Alpha-glucosidase inhibitors Acarbose Miglitol Bile acid sequestrant Colesevelam Sodium glucose co-transporter 2 (SGLT2) inhibitors Canagliflozin Dapagliflozin Empagliflozin Dopamine-2 agonist Bromocriptine American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S35.
Pharmacologic Therapy for DM Type 2 Injectable agents GLP-1 Agonists Exenatide Exenatide extended release Liraglutide Abliglutide Dulaglutide Lixisenatide Amylin analog Pramlintide Insulin (see next slide) American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S35.
Pharmacologic Therapy for DM Type 2 Insulin Rapid acting analogs Lispro Aspart Glulisine Inhaled Short acting Human Regular Intermediate acting Human NPH Concentrated Human Regular Insulin U-500Human Regular insulin Basal analogs Glargine Detemir Degludec Mix insulin 70% NPH and 30% regular 50% insulin lispro protamine and 50% insulin lispro 75% insulin lispro protamine and 25% insulin lispro 70% insulin aspart protamine and 30% insulin aspart
Oral Agents In the news: Metformin Changes to labeling Periodic measurement of B12 levels (and supplementation as needed) with prolonged use Adverse events DPP-4 inhibitors SGLT-2 inhibitors
FDA LABEL CHANGES FOR METFORMIN Before starting metformin, obtain the patient's eGFR. Metformin is contraindicated in patients with an eGFR <30mL/min/1.73m2. Starting metformin in patients with an eGFR between 30 45mL/min/1.73m2 is not recommended. Obtain an eGFR at least annually in all patients taking metformin. In patients at increased risk for the development of renal impairment such as the elderly, renal function should be assessed more frequently. In patients taking metformin whose eGFR later falls <45mL/min/1.73m2, assess the benefits and risks of continuing treatment. Discontinue metformin if the patient's eGFR later falls <30mL/min/1.73m2. Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30 60mL/min/1.73m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin if renal function is stable. Metformin-containing Drugs: Drug Safety Communication-Revised Warnings for Certain Patients with Reduced Kidney Function Posted online 4/8/2016 www.fda.gov
DPP-4 Inhibitors Joint pain 2015- FDA warning that DPP-4 Inhibitors may cause joint pain that can be severe and disabling. Pancreas Post marketing reports of acute pancreatitis in association with DPP4 inhibitors. Currently insufficient data to know if there is a causal relationship Insufficient evidence to confirm an increased risk of pancreatic cancer. Monitoring and reporting continues. Heart failure FDA warning Saxagliptan and Alogliptan No causal relationship established. Further studies... www.fda.gov
SGLT-2 Inhibitors Reports of: "Euglycemic" DKA More frequent bone fractures-Canagliflozin Increase in leg and foot amputations-Canagliflozin
Types of Insulin
Rapid acting (analogs) Lispro Aspart Glulisine Short acting (human) Regular Intermediate acting (human) NPH Long acting (analogs) Glargine Detemir
Prandial Bolus Basal
Types of Insulin
Rapid acting (analogs) Human insulin inhalation powder
Ultra-long acting (analogs) Degludec
Insulin Ultralong acting insulin Concentrated insulin
Degludec Ultralong acting basal insulin Ѕ life ~25 hours Duration of action >42 hours Glucose lowering effect is evenly distributed over 24 hour dosing interval Vora, Jiten et al. (2015) Clinical use of insulin degludec. Diabetes Research and Clinical Practice. 109(1)19-31.
New Agents Combination insulin and GLP-1 agonist
New Technology FreeStyle Libre Pro System FDA approved for use by physicians for monitoring glucose in patient with diabetes Tucker, M.E. (2016) FDA Approves Abbott's FreeStyle Libre Pro System for Diabetes. Accessed from www.medscape.com February 2017
What is your approach? Motivational Interviewing
Anticipatory guidance Patient centered care
Risk factors for DM Physical inactivity First degree relative with diabetes High risk race/ethnicity African American
, Latino, Native American
, Pacific Islander, Asian American Women who were diagnosed with GDM History of CVD Hypertension (BP 140/90 or on treatment for HTN) HDL <35 and/or Triglycerides >250 A1C 5.7%, IFG, or IGT on prior testing Women with polycystic ovarian syndrome Other clinical conditions associated with insulin resistance Severe obesity, acanthosis nigricans American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S35.
What are the categories of increased risk for diabetes (prediabetes)? Impaired fasting glucose (IFG) 100-125 mg/dl OR Impaired glucose tolerance (IGT) 2 hour plasma glucose in 75 g OGTT 140-199 mg/dl OR HbA1C 5.7-6.4% American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S35.
Diabetes Prevention Program (DPP) Participants-overweight with prediabetes Randomly assigned: Placebo Metformin 850 mg twice daily Lifestyle modification program At least 7 percent weight loss At lease 150 minutes of physical activity
per week Results: Compared with placebo Lifestyle intervention reduced incidence of diabetes by 58% Metformin reduced incidence of diabetes by 31% Conclusions: Lifestyle changes and metformin both reduced incidence of diabetes in persons at high risk. Lifestyle interventions were more effective than metformin. Knowler WC1, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England
Journal of Medicine. 2002 Feb 7;346(6):393-403.
Is it sustainable? DPP reduced incidence over three years Other studies of lifestyle intervention for diabetes prevention have shown sustained reduction in the rate of conversion to type 2 diabetes DaQing study 43% reduction at 20 years Finnish Diabetes Prevention Study (DPS) 43% reduction at 7 years U.S. Diabetes Prevention Program Outcomes Study (DPPOS) 34% reduction at 10 years American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S35. Khavandi, K., Amer, H., Ibrahim, B., Brownrigg, J. (2013) Strategies for preventing type 2 diabetes: an update for clinicians. Therapeutic Advances in chronic disease
Management of Prediabetes Preferred treatment approach is intensive lifestyle management Medical nutrition therapy Appropriately prescribed physical activity Avoidance of tobacco products Adequate quantity and quality of sleep Limited alcohol consumption
Stress reduction American Association of Clinical Endocrinologists AACE Diabetes Resource Center. Management of Prediabetes. Accessed online ouptpatient.aace.com/prediabetes/management-of-prediabetes February 2017.
How to prevent/delay DM Type 2? Patients with IGT, IFG or HgbA1C 5.7-6.4% Refer to effective ongoing support
program targeting weight loss of 7% of Body Weight
and increasing physical activity to at least 150 min/week moderate activity Metformin may be considered in those at highest risk for developing DM Type 2 Off label use-not FDA approved for Type 2 DM prevention Follow-up counseling should be provided and monitoring of labwork Screening for and treatment of modifiable CVD risk factors Diabetes self management and support programs Use of technology American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S35.
Weight Loss Modest persistent weight loss Can delay progression from prediabetes to Type 2 diabetes American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S35.
Weight Loss Modest weight loss (defined as sustained reduction of 5% of initial body weight) in overweight and obese patients with DM Type 2 Improves glycemic control Reduces need for glucose lowering medications American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S35.
What is the role of pharmacology in preventing DM Type 2? What have the studies shown? Antidiabetic medications Antihypertensive medications Weight loss medications
Metabolic Surgery Bariatric surgery Data supporting treatment of DM Type 2 No randomized studies of prevention of Type 2 DM in obese patients without Type 2 DM Swedish Obese Subjects Trial Nonrandomized study-surgically treated patients have reduced risk of progression to DM Type 2 for up to 15 years Sjostrom, L. (2013) Review of the key results from the Swedish Obese Subjects (SOS) trial-a prospective controlled intervention study of bariatric surgery. Journal of internal medicine
"The diabetic who know the most lives the longest." Elliot P. Joslin, M.D.
References American Association of Clinical Endocrinologists AACE Diabetes Resource Center. Management of Prediabetes. Accessed online ouptpatient.aace.com/prediabetes/managementof-prediabetes February 2017. American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S35. Aroda VR, Rosenstock J, Wysham C, et al; LixiLan-L Trial Investigators. Efficacy and safety of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide in type 2 diabetes inadequately controlled on basal insulin and metformin: The LixiLan-L Randomized Trial. Diabetes Care. 2016;39:1972-1980. Diabetes Data and Statistics accessed from www.cdc.gov/diabetes/data/ January 2017. Garber, A., Handelsman, Y., Einhorn, D., Bergman, D., Bloomgarden, Z., Fonseca, V., Garvey, W.T., Gavin III, J., Grunberger, G., Horton, E., Jellinger, P, Jones, K., Lebovitz, H., Levy, P., McGuire, D., Moghissi, E., Nesto, R. (2008) Diagnosis and Management of Prediabetes in the Continuum of Hyperglycemia--When do the Risks of Diabetes Begin? A Consensus Statement from the American College of Endocrinology and the American Association of Clinical Endocrinologists. Endocrine Practice. 14(7):933-946. Glauber, H., Karnieli, E. (2013) Preventing Type 2 Diabetes Mellitus: A Call for Personalized Intervention. The Permante Journal. 17(3):74-79. Greenspan, Francis S. and Gardner, David G. (2011) Greenspans' Basic and Clinical Endocrinology (9th ed.). Lange/McGraw Hill.
References Jensen MD, et al. 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults. A Report of the American College of Cardiology/American Heart Association Task Force
on Practice Guidelines and The Obesity Society. Downloaded from http://circ.ahajournals.org Khavandi, K., Amer, H., Ibrahim, B., Brownrigg, J. (2013) Strategies for preventing type 2 diabetes: an update for clinicians. Therapeutic Advances in Chronic Disease. 4(5):242-261. Knowler WC1, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine. 2002 Feb 7;346(6):393-403. Lamos, E. M., Younk, L. M., & Davis, S. N. (2016). Concentrated insulins: the new basal insulins. Therapeutics and Clinical risk management
References Li, Guangwei et al. (2008) The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. The Lancet. 371(9626):1783-1789. Linjawi S, Bode BW, Chaykin LB, et al. The efficacy of IDegLira (insulin degludec/liraglutide combination) in adults with type 2 diabetes inadequately controlled with a GLP-1 receptor agonist and oral therapy: DUAL III Randomized clinical trial
. Diabetes Ther. 2016 Dec 10. Mainous, A.G., Tanner, R.J., Baker, R. (2016) Prediabetes Diagnosis and Treatment in Primary Care. Journal American Board of Family Medicine; 29:283-285 Mechanick JI, Garber AJ, Handelsman Y, Garvey WT. American Association of Clinical Endocrinologists' Position Statement on Obesity and Obesity Medicine. Endocrine Practice. 2012; 18(5):642-648. Metformin-containing Drugs: Drug Safety Communication-Revised Warnings for Certain Patients with Reduced Kidney Function Posted online 4/8/2016 www.fda.gov Qaseem, A., Barry, M.J., Humphrey, L.J., Forciae, M.A. (2017) Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practical Guideline Update from the American College of Physicians. Annals of Internal Medicine. 166:279-290.
References Rosenstock J, Aronson R, Grunberger G, et al; LixiLan-O Trial Investigators. Benefits of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide, versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled on oral agents: the LixiLan-O Randomized Trial. Diabetes Care. 2016;39:2026-2035. Rosenstock J, Diamant M, Aroda VR, et al; LixiLan PoC study group
. Efficacy and safety of LixiLan, a titratable fixed-ratio combination of lixisenatide and insulin glargine, versus insulin glargine in type 2 diabetes inadequately controlled on metformin monotherapy: The LixiLan Proof-of-Concept Randomized Trial. Diabetes Care. 2016;39:1579-1586 Sjostrom, L. (2013) Review of the key results from the Swedish Obese Subjects (SOS) trial-a prospective controlled intervention study of bariatric surgery. Journal of Internal Medicine. 273(3):219-234. Tucker, M.E. (2016) FDA Approves Abbott's FreeStyle Libre Pro System for Diabetes. Accessed from www.medscape.com February 2017 Vora, Jiten et al. (2015) Clinical use of insulin degludec. Diabetes Research and Clinical Practice. 109(1)19-31. Vilsboll T, Vora J, Jarlov H, Kvist K, Blonde L. Type 2 diabetes patients reach target glycemic control faster using IDegLira than either insulin degludec or liraglutide given alone. Clin Drug Investig. 2016;36:293-303.