What Diabetes Medicine Do I Use When? Elizabeth J. Murphy, MD, DPhil - PowerPoint PPT Presentation

What Diabetes Medicine Do I Use When? Elizabeth J. Murphy, MD, DPhil June 15, 2020

I have no financial interests or relationships to disclose.

Today • Overview of the advantages and disadvantages of the different classes of drugs (thinking like an internist) • Review the data (as of now) for cardiovascular and renal outcomes • Practice critical review of diabetes drug comparator studies • Put some of it together? • Won’t cover: – Insulins – Role of CGM and insulin pumps

2008 ADA Type 2 Consensus Statement Diabetes Treatment Algorithm An American Diabetes Association consensus statement represents the authors’ collective analysis, evaluation, and opinion at the time of publication and does not represent official association opinion. Diabetes Care. Published online Oct 22, 2008

Revised Consensus Algorithm - ADA and EASD Diabetes Care 31:173, 2008.

Diabetes Care, Diabetologia. 19 April 2012

Less Well ‐ Validated Buffet for DM2 ADA Standards of Medical Care in Diabetes 2017

Glucose-lowering medication in type 2 diabetes: overall approach. Diabetes Care 2020;43:S98-S110

Decision cycle for patient ‐ centered glycemic management in type 2 diabetes. Davies MJ, D’Alessio DA, Fradkin J, et al. Diabetes Care 2018;41:2669–2701.

Diabetes Complications in the US Microvascular Macrovascular • CAD, stroke, PVD • Retinopathy, nephropathy, neuropathy • 2 x increase risk for CVD death • Leading cause of – end stage renal disease • 2 ‐ 4 x increased risk of stroke – blindness • Prevalence of DM in patients – non ‐ traumatic amputations hospitalized for HF > 40% • DM is strongest risk factor for PVD (OR 2.72)

Managing Complications • Tight glucose control reduces microvascular complications – The lower you go the better – The earlier in the disease the better – Effects last long after tight control is over • Tight glucose control early in the disease reduces macrovascular complications many years later • BP control reduces micro and macrovascular complications • Lipid management reduces macrovascular complications

Tight Control Trials 1970s ‐ 1990s • United Kingdom Prospective Diabetes Study ( UKPDS ) ‐ Type 2 DM • Diabetes Control and Complications Trial ( DCCT ) and follow on Epidemiology of Diabetes Interventions and Complications ( EDIC ) ‐ Type 1 DM 12

Tight Glucose vs Tight Blood Pressure Control in the UKPDS 7% v. 7.9% A1C DM Microvascular Any Diabetic Deaths Complications Stroke Endpoint 0 % Reduction I n Relative Risk 5 % 1 0 % -1 0 1 2 % + -2 0 2 4 % + * -3 0 3 2 % 3 2 % + * 3 7 % + -4 0 + * 4 4 % Tight Glucose Control Tight BP Control + * -5 0 + P < 0 .0 5 com pared to conventional rx * P < 0 .0 5 com pared to glucose control 13 Turner RC, et al. BMJ. 1998;317:703-713.

Nathan D for the DCCT/EDIC Research Group Diabetes Care 2014;37:9 ‐ 1614

DCCT/EDIC –T1DM Tight Control A1C 7.2 v Usual Care 9.1% Prevalence and Incidence of Albuminuria EDIC Both Groups A1C 8% 15 JAMA 2003;290:2159 ‐ 2167.

DCCT/EDIC ‐ Cumulative Incidence CVD Outcomes 42% reduction in CVD risk 57% reduction in risk of nonfatal MI, stroke or CVD death 8.0 v 8.1 % A1C [----------------------------------------------] At 30 y Follow up 30% reduction in CVD risk 32% reduction in risk of nonfatal MI, stroke or CVD death A1C 7.2 v 9.1% N Engl J Med 2005;353:2643-2653

Glycemic Targets Over the Years 9% 8% Before DCCT, 7% UKPDS After DCCT After DCCT, UKPDS Sulfonylurea + Metformin + TZD Insulin 1980s 1990s 1997

Crude and Age-Adjusted Incidence of End-Stage Renal Disease Related to Diabetes Mellitus (ESRD-DM) per 100,000 Diabetic Population, United States, 1980–2008 http://www.cdc.gov/diabetes/statistics/esrd/fig7.htm

Glycemic Targets Over the Years 9% 8% Before DCCT, 7% UKPDS After DCCT ? 6% After And focus on CVD DCCT, prevention UKPDS Sulfonylurea + Metformin + TZD Insulin + Incretin 1980s 1990s 1997 2006

Glycemic Targets Over the Years 9% 8% Before DCCT, 7% UKPDS After DCCT ? 6% After DCCT, UKPDS Sulfonylurea + Metformin + TZD Insulin + Incretin 1980s 1990s 1997 2006

Follow on Effects • FDA mandated CV outcome trials for safety • Recognition that tight control in established CVD is likely not beneficial

Glycemic Targets Over the Years 9% 8% Before DCCT, 7% 7% UKPDS After DCCT ? 6% After After DCCT, ACCORD UKPDS Sulfonylurea + Metformin + TZD + Incretin + Mortality Insulin 2008 1980s 1990s 1997 2006

A1C Goal Cardiovascular Efficacy Benefit/Harm Comorbidities Complications Cost (CKD, obesity, HF , CAD) Adverse Effects Patient Risks/Hypoglycemia Acceptance

A1C Targets • < 7% ‐ is appropriate for many nonpregnant adults. A • < 6.5% ‐ might be reasonable for select patients C • < 8% (“less stringent A1C goals”) may be appropriate if: ( B ) – h/o severe hypoglycemia – limited life expectancy – advanced micro or macrovascular complications – extensive comorbid conditions – longstanding DM and can’t get to goal despite trying really hard ADA Diabetes Standards of Care 2020

A1C COST Good Rx.com 10/2019 10/2014 6/2020 Metformin 1-2% $4 $4 Sulfonylurea 1-2% $5 $4 Pioglitazone 0.5-1.5% $20 $11 Exenatide 0.5-1.5% $450 $731 $728 Canagliflozin 0.5-1.0% $330 $520 $498 Sitagliptin 0.5-0.8% $320 $475 $455 Acarbose 0.5-0.8% $30 $19 25

Metformin Advantages Disadvantages • Lowers A1C 1.5 ‐ 2% • Majority of patients with GI SE • Weight loss (0 ‐ 2 kg) • Minimal risk of lactic acidosis • Lowers TG, LDLc; Increases HDLc • Impairs B12 absorption • Data supports decrease in CVD • Need to stop when GFR < 30 mortality and perhaps all cause mortality • No hypoglycemia when used alone • Inexpensive 26

Sulfonylureas Advantages Disadvantages • Lowers A1C 1.5 ‐ 2% • Weight gain • Inexpensive • Hypoglycemia CVD??? 27

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Forest plot summarising the primary analysis and all sensitivity analyses Antonios Douros et al. BMJ 2018;362:bmj.k2693

77,138 Metformin Monotherapy Users 25,699 Adding or switching to SU 9,800 13,217 Switching to SU Adding SU

Adjusted HR Myocardial Infarction (95% CI) Adding SU Switching to SU Ischemic Stroke Adding SU Switching to SU CV Death Adding SU Switching to SU All Cause Mortality Adding SU Switching to SU 0.5 2.5 4.5 6.5 8.5

Adding a sulfonylurea to metformin does not increase the risk of cardiovascular disease but replacing metformin with a sulfonylurea does

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Sulfonylureas Advantages Disadvantages • Lowers A1C 1.5 ‐ 2% • Weight gain • Inexpensive • Hypoglycemia CVD: The Jury’s Still Out 35

Thiazolidinediones (rosiglitazone, pioglitazone) (PPAR ‐γ Agonists) Advantages Disadvantages • Lowers A1C 0.5 ‐ 1.5% • Weight gain (2 ‐ 5 kg) • No hypoglycemia when used alone • Increased fracture (osteoporosis) and bladder cancer • Inexpensive • Edema (up to 30% of patients) • Likely benefit in fatty liver and NASH • Contraindicated in HF • Benefit shown in diabetes prevention Notes: ‐ Stop TZDs when insulin is started ‐ Effectiveness is very patient dependent, stop if it’s not doing anything 36

Thiazolidinediones – CVD Good Not So Good • Benefit post stent/revascularization • Increases rates of serious HF • Benefit after stroke/TIA in insulin • Some studies with increased mortality resistant patients without diabetes 1 • Some studies with decreased death, MI, Stroke 2 Preference for pioglitazone 1 N Engl J Med 2016; 374:1321 ‐ 1331. 2 JAMA 2007; 298: 1180 ‐ 1188 37

The Incretins

Insulin Response to Oral vs Intravenous Glucose Normal Control Subject Oral 90 Intravenous Insulin (  U/mL)  GIP, GLP-1, CCK 60  Reduced in DM2  T 1/2 2-5 minutes 30  Breakdown by DPPIV 0 0 30 60 90 120 150 180 Minutes J Clin Invest 1967; 46:1954-1962

DPPIV Inhibitors (gliptins) Advantages Disadvantages • No hypoglycemia when used alone • Poor A1C lowering (0.5 ‐ 0.8%) • ? • Expensive • Possibly higher rates of admission for Notes: HF (worse with sitagliptin?), otherwise ‐ Weight neutral CV neutral ‐ Stop when insulin is started • Pancreatitis? ‐ Don’t start if you are more than • Joint pain? 0.8% from your A1C goal 40

CD26 /DPPIV • Expressed on the surface of most cell types • T ‐ cell activation marker • 62 known substrates • Tumor suppressor role • Inhibitors inhibit T ‐ cell proliferation • Good or evil: CD26 and HIV infection. J Derm Sci. 2000; 22:152 ‐ 60. • Role of CD26/dipeptidyl peptidase IV in human T cell activation and function. Front Biosci. 2008;13:2299 ‐ 310. • Dipeptidyl peptidase IV (DPPIV), a candidate tumor suppressor gene in melanomas is silenced by promoter methylation. Front Biosci. 2008 13:2435 ‐ 43. 41