Initiating the conversation

Transcription

1 Patient Case Study: Janice Janice - Medical History 6-year-old Hispanic woman comes to see you. She has not been to the doctor in almost 2 years. She reports feeling tired and has clearly gained weight since her last visit. Height: 5 2 ; Weight: 176 lb; BMI: 32.2 kg/m 2 (Class 1 Obesity) Works at an insurance agency, is married with one adult child (daughter in high school). Family history Hypertension mother and three siblings Diabetes both parents and two siblings. Father recently had toe amputated due to severe infection. Hypertension X 2 years Dyslipidemia X 12 years At her last visit: Prediabetes was diagnosed: HbA1c was 6.3%; FBG 19 mg/dl; BMI 31.2 kg/m 2 At that time she was advised to lose weight, improve her diet and add an exercise routine. She was referred to a dietitian; no other intervention was provided. BMI = body mass index Janice 1 year later At this visit: Random glucose: 158 mg/dl HbA1c: 7.5% LDL-C: 128 mg/dl; HDL-C: 4 mg/dl Triglycerides: 215 mg/dl BP: 128/8 mmhg Current medications Irbesartan 3 mg daily Atorvastatin 4 mg every evening ASA 81 mg daily Initiating the conversation Evidence for Benefit of Glycemic Control in Type 2 Diabetes According to the United Kingdom Prospective Diabetes Study (UKPDS) 35,* Every 1% Decrease in HbA1c Resulted in: 21% 14% 12% 37% Decrease in risk of any diabetes-related endpoint (P <.1) Decrease in risk of myocardial infarction (P <.1) Decrease in risk of stroke (P =.4) Decrease in risk of microvascular complications (P <.1) UKPDS 1-Year Follow-Up of Intensive Glucose Control in T2DM: Legacy Effect Intensive control in the sulfonylurea insulin group, relative reductions in risk persisted at 1 years for: Any diabetes-related endpoint (9%, P =.4) Microvascular disease (24%, P =.1) Risk reductions for myocardial infarction (15%, P =.1) and death from any cause (13%, P =.7) increased over time, as more events occurred In the metformin group, significant risk reductions persisted for any diabetes-related endpoint (21%, P =.1), myocardial infarction (33%, P =.5), and death from any cause (27%, P=.2) *The study population was 82% White, 1% Asian Indian, and 8% Afro-Caribbean. Stratton IM, et al. BMJ. 2;321: Holman RR, et al. N Engl J Med. 28;359(15):

2 A Broad View of CVD and Diabetes: Implications of ACCORD, ADVANCE and VADT Study Microvascular CVD Mortality UKPDS DCCT/EDIC* ACCORD ADVANCE VADT Initial Trial Adapted from Bergenstal RM, Bailey C, Kendall DM. Am J Med. 21;123:374e9-e18. Long-term Follow-up UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352: Holman RR. N Engl J Med. 28;359(15): DCCT Research Group. N Engl J Med. 1993;329; Nathan DM, et al. N Engl J Med. 25;353: Gerstein HC, et al. N Engl J Med. 28;358: Patel A, et al. N Engl J Med. 28;358: Duckworth W, et al. N Engl J Med. 29;36: Hayward RA, et al. N Engl J Med. 215;372: HbA1c Goal is not One-size-fits-all More Stringent (as close to 6% as possible) Short diabetes duration Long life expectancy No cardiovascular disease Garber MJ. Endocr Pract. 216 Jan;22(1): ADA < 7% AACE 6.5% Less Stringent (< 8%) Long diabetes duration Short life expectancy Complications, comorbidities History of severe hypoglycemia ADA = American Diabetes Association AACE = American Association of Clinical Endocrinologists Challenges in Achieving Target HbA1c Levels Late diagnosis and initiation of therapy Hesitancy to intensify therapy in patients who are not at or below target (clinical inertia) Adverse events associated with anti-hyperglycemic therapies Secondary drug failure due to continued programmed beta-cell death Complexity of care from both patient and physician perspectives Modifiable Variables Impact Treatment and Glycemic Control of T2DM Three Modifiable Variables Accounted for 48% Variance in Diabetes Control Initial HbA1c Therapeutic inertia Visit frequency and patient participation Greater attention to: early diagnosis and treatment ensuring regular healthcare visits overcoming therapeutic inertia Could improve diabetes control and health equity Adapted from Unger J. Diabetes Management in Primary Care. Philadelphia, PA; LWW; 27: Egan B, et al. Ethnicity & Disease 212 Winter:22(1): Adults Who Should Be Screened for Diabetes and Prediabetes Symptoms consistent with diabetes Anyone over age 45 Overweight (BMI 25) and at least one additional risk factor Physical inactivity First degree relative with diabetes Member of high-risk ethnic population Known previous prediabetes If results are normal, testing should be repeated every 3 years, with consideration of more frequent testing depending on initial results and risk status ADA. Diabetes Care. 214;37(1):S14-S8. Diagnostic Measures of Hyperglycemia Tests Prediabetes Diabetes Fasting plasma glucose (mg/dl)* Impaired fasting glucose Two-hr glucose during OGTT (mg/dl)* *Should be confirmed by repeat testing on a separate day OGTT = oral glucose tolerance test ADA. Diabetes Care. 214;37(1):S14-S Impaired glucose tolerance HbA1c (%) * High risk Random plasma glucose (mg/dl) in patient with classic symptoms of hyperglycemia NA 2 2

3 Janice Next Steps Old vs New Metformin Safety USE You refer her to a diabetes educator and a dietician. Your office provides literature on physical activity options and community resources. Metformin therapy 5 mg BID is started and up-titrated to 1 mg BID. OLD: Creat.<1.5 mg./dl Men, 1.4 mg./dl Women NEW: Before starting metformin, obtain the patient s egfr. Metformin is contraindicated in patients with an egfr below 3 ml/minute/1.73 m2 Starting metformin in patients with an egfr between 3-45 ml/minute/1.73 m2 is not recommended BID = twice daily FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function 4/8/216 Old vs New Metformin Safety USE Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an egfr between 3 and 6 ml/minute/1.73 m2; 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 FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function 4/8/216 Metformin Titration 5 mg QD 5 mg BID 85 mg BID Further modest decreases (HbA1c) by increasing to 25 mg/day Nathan DM, et al. Diabetes Care. 29;32(1): Start w/ OR Start w/ 5-7 days 5-7 days 5 mg TID 5-7 days 1 mg BID All doses should be taken before breakfast and/or dinner 85 mg QD 5-7 days QD = once daily BID = twice daily TID = three times daily If GI side effects appear as doses advance decrease to previous dose or consider extended release Metformin: First-Line Therapy in T2DM Metformin: GI Intolerance Reasonable HbA1c reductions, especially at high baseline HbA1c CV benefits in obese patients Low risk of hypoglycemia Modest weight loss or weight neutral Extensively researched Inexpensive Limitations Contraindicated in patients with significant renal impairment GI effects common diarrhea, cramping Risk of lactic acidosis Risk of developing vitamin B-12 deficiency (6% prevalence) According to the package insert for one brand of metformin commonly available in the US, one study showed that more than 25% of patients experienced nausea and vomiting, and more than 5% of patients experienced diarrhea. Other less common GI side effects include flatulence, indigestion, and abdominal discomfort. XR use may benefit with GI tolerance Glucophage, Glucophage XR. [package insert]. Accessed 14 November 214 Reinstatler L, et al. Diabetes Care. 212 Feb;35(2):

4 Janice - 6 Months Later ADA and AACE Recommendations She has lost 1 lbs BMI now 3.4 (compared with 32.2 at first visit) She walks the dog daily for 15 minutes and tries to stick to a ~16 cal/day diet BID = twice daily BP = blood pressure ASA = aspirin Labs Random glucose = 142 mg/dl HbA1c = 7.3% Lipids/BP at goal Meds Metformin 1 mg BID Irbesartan 3 mg daily Atorvastatin 4 mg every evening ASA 81 mg daily Intensify therapy after 3 months if treatment goals are not being met ADA = American Diabetes Association AACE = American Association of Clinical Endocrinologists Garber MJ. Endocr Pract. 216 Jan;22(1): Advancing Therapies With Stages of T2DM Beta-Cell Function (%, HOMA) Metformin and Lifestyle Janice Combination Therapy (orals and injectables) Insulin Intensive or in Combination 2 Type 2 Type 2 Diabetes Diabetes Phase I Phase II Phase III Years From Diagnosis Criteria for Advancing to the Next Stage? HbA1c Level Not at Target HOMA = homeostasis model assessment. Based on data from UKPDS 16. Diabetes. 1995;4(11): UK Clinical Practice Research Datalink: HbA1c >8% in 24 6 Followed to 211, Adding Another Oral Agent or Insulin On 1 oral agent, n = 25,96 67% given 2 nd oral, median 1.6 years 9% given insulin, median >6 years Probability OAD or insulin OAD Insulin Probability Time From HbA1c Above 7.% (years) OAD = oral antidiabetic drug. Khunti K et al. Diabetes Care. 213 July 22. [Epub ahead of print] On 2 oral agents, n = 16,991 3% given 3 rd oral, median >7 years 2% given insulin, median >7 years Time From HbA1c Above 7.% (years) Multiple Metabolic Defects of T2DM Decreased Insulin Secretion Islet cell Increased Glucagon Secretion Increased Hepatic Glucose Production DeFronzo R, et al. Diabetes. 29;58: HYPERGLYCEMIA Neurotransmitter Dysfunction Decreased Incretin Effect Increased Lipolysis Decreased Glucose Uptake Increased Glucose Reabsorption Pharmacological Actions of Diabetes Drugs* Glucagon Suppression GLP-1 agonists DPP-4 inhibitors Amylin Liver Hepatic Glucose Production Metformin GLP-1 agonists DPP-4 inhibitors *Other than insulin Pancreas Insulin Secretion Sulfonylureas Glinides GLP-1 agonists DPP-4 inhibitors HYPERGLYCEMIA Intestine Absorption AGIs Colesevelam GI Motility/Satiety GLP-1 agonists Amylin Brain Sympatholytic, Circadian Rhythm Bromocriptine QR Skeletal Muscle Insulin Sensitivity TZDs Kidney Glucosuria SGLT2 inhibitors 4

5 216 ADA/EASD Consensus Statement Recommendations AACE/ACE Glycemic Control Algorithm Diagnosis of Type 2 Diabetes Lifestyle Intervention + Metformin Continue Current Management Yes HbA1c at Goal? No Add Sulfonylurea (SU) TZD* DPP-4 Inhibitor GLP-1 Receptor Agonist SGLT2 Inhibitor Insulin (basal) *pioglitazone Garber MJ. Endocr Pract. 216 Jan;22(1): Sulfonylureas: Glyburide, Glipizide, Glimepiride (2 nd gen) Meglitinides (Glinides): Repaglinide, Nateglinide Insulin secretagogues Stimulate insulin release Inexpensive Extensive experience Decreased microvascular risk (UKPDS) Side Effects Weight gain Risk of hypoglycemia Precautions and Contraindications Associated with risk of both severe and non-severe hypoglycemia (elderly, renal disease) Avoid glyburide in elderly Reduces postprandial glucose excursions Flexibility in patients who eat irregularly Mechanism of action (MOA) Close K ATP channels on -cell plasma membranes, which increases insulin secretion Risks Risk of hypoglycemia, especially when combined with other drugs that associated with hypoglycemia Can cause weight gain Can interact with inducers/inhibitors of drug metabolizing enzymes and highly protein bound drugs Inzucchi SE, et al. Diabetes Care. 212;35: Inzucchi SE, et al. Diabetes Care. 212;35: Alpha-Glucosidase Inhibitors: Acarbose, Miglitol Bile Acid Sequestrant: Colesevelam Modest HbA1c reduction Reduction in CV events? MOA Slows the digestion of carbohydrates, such as starch and table sugar. Inzucchi SE, et al. Diabetes Care. 212;35: Adverse Reactions MOA is non-systemic, but frequent flatulence and diarrhea limits use in United States Cirrhosis contraindication with acarbose Not recommended if serum Cr >2. mg/dl Hypoglycemia: Use glucose instead of sucrose Elevated serum transaminase (acarbose) HbA1c reductions of.5% to.8% as add-on to metformin, sulfonylurea, or insulin therapy Limited data combined with TZD, none with incretins Significant LDL-C reductions of 12.3% to 16.1% vs. placebo MOA for glycemic control: Unknown Bays HE, et al. Arch Intern Med. In press. Fonseca VA, et al. Diabetes Care. 28;31: Goldberg RB, et al. Arch Intern Med. 28;168: Indications T2DM: Adjunct to diet and exercise to improve glycemic control in adults Primary hyperlipidemia: Adjunct to diet and exercise to reduce elevated LDL-C as monotherapy or in combination with a statin LDL = low-density lipoprotein 5

6 Colesevelam: Precautions Can increase triglycerides, particularly when used with insulin or sulfonylureas Most commonly reported side effects: constipation (9-11%) and dyspepsia (4-8%) Contraindications History of bowel obstruction Serum triglycerides > 5 mg/dl History of hypertriglyceridemiainduced pancreatitis Drug Interactions Many drugs can bind to colesevelam so Take them 4 hours prior to colesevelam Monitor levels/activity of drugs with narrow therapeutic indices Metformin ER exposure increases with colesevelam Thiazolidinediones (TZDs): Pioglitazone Reduces insulin resistance Durable antihyperglycemic effects Minimal hypoglycemia when used as monotherapy Favorable impact on lipid profile ( TG s and HDL) and may have possible positive CVD effects although not certain Handelsman Y, et al. Endocr Pract. 211;17(Suppl 2):1-53. Risks Black box warning for CHF Dose-related edema Weight gain, especially with sulfonylureas and insulin Macular edema reported Increased distal fracture risk Data suggests possible increased bladder cancer risk TG = triglycerides; HDL = high density lipoprotein; CHF = congestive heart failure Amylin Mimetic: Pramlintide Modest HbA1c reduction Reduces postprandial glucose excursions Weight loss No hypoglycemia MOA Suppresses appetite, slows gastric emptying and digestive secretion, suppresses glucagon. Inzucchi SE, et al. Diabetes Care. 212;35: Adverse Reactions Dizziness/syncope Nausea Fatigue Rhinitis Dopamine-D2 Agonists: Bromocriptine Quick-Release Potential MOA to improve glucose tolerance Dopaminergic activity in morning Sympathetic activity Serotonergic activity Bromocriptine QR Dopaminergic activity in morning Sympathetic activity Serotonergic activity Hepatic glucose output Insulin resistance Free fatty acids Triglycerides Improved glucose tolerance Hepatic glucose output Insulin resistance Free fatty acids Triglycerides MOA = mechanism of action Inzucchi SE, et al. Diabetes Care. 212;35: Bromocriptine Quick-Release The Incretin Effect Adverse Reactions Controls (n = 8) Type 2 Diabetes (n = 14) HbA1c reductions: ~.5-1.% Composite CV endpoint occurred in 1.5% bromocriptine vs. 3.% placebo RR =.58 ( ) Nausea Fatigue Dizziness Vomiting Headache In phase 3 trials of 3564 patients, 24% bromocriptine vs 9% placebo discontinued, mainly due to nausea IR Insulin (mu/l) Incretin Effect 6 12 Time (minutes) Oral glucose load nmol/l IR Insulin (mu/l) The incretin effect is diminished in T2DM 6 12 Time (minutes) Intravenous (IV) glucose infusion nmol/l Inzucchi SE, et al. Diabetes Care. 212;35: Scranton RE, et al. BMC Endocr Disord. 27;7:3. Adapted from Nauck M, et al. Diabetologia. 1986;29:

7 Leveraging the Incretin Effect GLP-1 and GIP Excess glucose production Liver: glucagon reduces hepatic glucose output Glucagon excess Alpha cell: glucagon secretion postmeal Excess food intake Central nervous system: promotes satiety and reduction of appetite Impaired beta-cell function Beta cell: enhances glucosedependent insulin secretion and beta-cell functional mass Stomach: regulates gastric emptying Rapid gastric emptying Flint A, et al. J Clin Invest. 1998;11(3): Larsson H, et al. Acta Physiol Scand. 1997;16(4): Nauck MA, et al. Diabetologia. 1996;39(12): Drucker DJ. Diabetes. 1998;47(2): GLP-1 and GIP Are Degraded by the DPP-4 Enzyme * Half-lives: GLP-1 ~2 minutes GIP ~5 minutes Meal Intestinal GLP-1 and GIP release Active GLP-1 and GIP * DPP-4 enzyme Rapid inactivation Deacon CF, et al. Diabetes. 1995;44: Meier JJ, et al. Diabetes. 24;53: Inactive metabolites GLP-1= glucagon-like peptide-1 GIP = glucose-dependent insulinotropic polypeptide Strategies for Enhancing GLP-1 Action: DPP-4 inhibitor versus GLP-1RA DPP-4 Inhibitors: Sitagliptin, Saxagliptin, Linagliptin, Alogliptin DPP-4 inhibitors (DPP-4i) Sitagliptin, saxagliptin, linagliptin, alogliptin Prevents the degradation of active GLP-1 by inhibiting the actions of DPP-4 * NO indication to use both Meier JJ. Nat Rev Endocrinol. 212;8(12): Pratley RE, et al. The Lancet. Diabetes and Endoc. 214;2(4): GLP-1 receptor agonists (GLP-1 RA) Greater HbA1c reduction than DPP-4 inhibitors (Pharmacological levels) Short-acting: Exenatide BID Long-acting: Exenatide ER (once weekly), liraglutide (once daily), lixisenatide (once daily), albiglutide (once weekly), dulaglutide (once weekly) Advantages Increases insulin secretion (glucosedependent) Suppresses inappropriate glucagon secretion (glucose-dependent) Low risk of hypoglycemia Weight neutral Once-daily oral agents Can use in renal dysfunction with dose adjustment; linagliptin requires no dose adjustment Generally well tolerated Low risk of drug interactions Deacon CF and Holst JJ. Expert Opin Pharmacother. 213;14: Limitations Modest HbA1c lowering Acute pancreatitis reports (some fatal) for incretin-related agents, but causation not established GLP-1 Receptor Agonists (Exenatide, Liraglutide, Albiglutide, Dulaglutide, Lixisenatide) Advantages Limitations Increases insulin secretion (glucose-dependent) Suppresses inappropriate glucagon secretion (glucose-dependent) Delays gastric emptying and enhance satiety Weight reduction GI side effects Post-marketing reports of acute pancreatitis (some fatal) with some agents, but causation not established C-cell tumors including medullary thyroid carcinoma (MTC) with longer-acting agents in animal studies. Contraindicated with personal or family history of MTC or MEN-2 Use with caution when initiating or escalating doses in patients with renal impairment Inzucchi SE, et al. Diabetes Care. 212;35: Handelsman Y, et al. Endocrine Practice. 211;17: Albiglutide REMS. ww.fda.gov. GLP-1 Receptor Agonists Gastrointestinal Side Effects Mild to moderate nausea Dose dependent Decreases over time Discuss with patient If troublesome: Leave at lower dose until GI side effects resolve on initial dose Administer closer to the meal (exenatide BID) Longer-acting agents have fewer GI side effects 7

8 SGLT-2 Inhibitor (SGLT-2i) Glucose SGLT-2 Inhibitors SGLT2 = 9% glucose reabsorption SGLT1 = 1% glucose reabsorption Proximal tubule S1 segment S3 segment Collecting ducts Glucosuria Loss of Calories SGLT2 Inhibitors: dapagliflozin, canagliflozin, empagliflozin Efficacy Adverse Effects Modest HbA1c reduction (average.6-.9%) Weight loss (2-4 kg) Reduces blood pressure Long term CVD risk reduction promising Drug Not indicated for egfr Dapagliflozin <6 ml/min/1.73m 2 Canagliflozin <45 ml/min/1.73m 2 Empagliflozin <45 ml/min/173 m 2 Hypotension Genitourinary mycotic infections Initial small decreases in egfr more pronounced in those with renal insufficiency Increased fracture risk; bone loss? Increases in LDL-C May cause hypoglycemia with concomitant use of insulin or insulin secretagogues Euglycemic DKA Hasan et al. Diabetes Res Clin Prac. 214;14: Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 213;6: CVD = cardiovascular disease Profiles of Antidiabetic Medications Janice Next Steps You encourage her to make more time for herself and join an exercise class You also talk about considering drug therapy for weight management Glimepiride is tapered off Options Discontinue sulfonylurea and add GLP-1 RA Add SGLT-2 inhibitor to metformin plus SU Garber MJ. Endocr Pract. 216 Jan;22(1): Rates of Glycemic Control Vary by Race, Ethnicity, and Education Level Goal: HbA1c <7% GARNERING PATIENT PARTICIPATION Observational and quasi-experimental analyses of repeated crosssectional data. NHANES, McWilliams JM, et al. Ann Intern Med. 29;15(8):

9 Gaps Between Good Processes of Diabetes Care and Poor Intermediate Outcomes: TRIAD Study Patients with poor control of vascular disease risk factors (HbA1c 8%; SBP 14 mm Hg; LDL-cholesterol 13 mg/dl): Younger, female, African American, lower education, lower income (P <.1 each) Conclusion Lower general health Clinical, Higher BMI socioeconomic, On insulin psychosocial and Smokers behavioral factors Physically inactive independently Depressed and hopeless associated with poor Concerned about costs of medications/care control Less trust in physician LDL = low density lipoprotein; SBP = systolic blood pressure Factors Affecting Patient Adherence to Glucose-Lowering Medications Hypoglycemia Weight gain GI adverse effects Inconvenience Aversion to injections Costs Stigma Selby JV, et al. Med Care. 27 Dec;45(12): Insulin Use Barriers from 216 EASD Barriers ID ed by Pt s Fear of Wt. Gain (52%) Frustration over time to reach goal (43%) Perception that dosing indicates worsening disease (38%) Fear of Hypo s (37%) From HCP s Perspective Fear of Hypo s (74%) Low Patient involvement/motivation(63%) DAWN: Diabetes Attitudes, Wishes and Needs What proportion of your patients do you think would agree with the following statements? I am very worried about risk of hypoglycemic events I am constantly afraid of my disease getting worse I feel that my diabetes is preventing me from doing what I want Hypo worry Afraid of diabetes worsening Diabetes limiting factor % patients who agree Peyrot M et al. Diabetes Care. 25 Nov;28(11): Sex/ethnic/racial/genetic differences Little is known MODY & other monogenic forms of diabetes Latinos: more insulin resistance East Asians: more beta cell dysfunction Gender may drive concerns about adverse effects (e.g., bone loss from TZDs) MODY = maturity onset diabetes of youth (monogenic diabetes) Inzucchi SE, et al. Diabetes Care. 212;35: Co-morbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Inzucchi SE, et al. Diabetes Care. 212;35: Metformin: CVD benefit (UKPDS) Empa, Lira: CVD benefit Data for DPP4 inhibitors and GLP-1 RAs indicate CV safety? Pioglitazone & CVD events Avoid hypoglycemia 9

10 Co-morbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Metformin: May use unless condition is unstable or severe Avoid TZDs? Increased risk of heart failure hospitalization with saxagliptin Co-morbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia egfr = glomerular filtration rate SU = sulfonylurea Increased risk of hypoglycemia Metformin current serum creatinine cut-off points being reconsidered; calls for use with mild-moderate but stable CKD Caution with SUs (esp. glyburide) DPP-4i: dose adjust for most GLP-1 RAs: use with caution when initiating or escalating doses; exenatide not indicated for egfr <3 SGLT2i: not indicated for egfr <6 (dapa); <45 (cana, empa) Inzucchi SE, et al. Diabetes Care. 212;35: Inzucchi SE, et al. Diabetes Care. 212;35: Co-morbidities Co-morbidities Coronary Disease Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Most drugs not tested in advanced liver disease Pioglitazone and incretin agents may help steatosis Insulin best option if disease severe Heart Failure Renal disease Liver dysfunction Hypoglycemia Emerging concerns regarding association with increased morbidity / mortality Proper drug selection is key in the hypoglycemia prone Inzucchi SE, et al. Diabetes Care. 212;35: Inzucchi SE, et al. Diabetes Care. 212;35: Key Considerations in Selecting T2DM Combination Pharmacotherapy SUMMARY How long has the patient had diabetes? Duration of disease relative to timeframe for interventions What is HbA1c target? e.g., < 6.5%, < 7.%, < 8.% Patient preference for route of administration e.g., oral, injectable, no preference Degree of HbA1c-lowering effect required to achieve goal Side-effect profile and the patient s tolerability Co-morbidities and co-existing conditions e.g., cardiovascular disease, chronic kidney disease, osteoporosis Burke S, et al. Clinician Reviews. 28;18: