The Present and Future of Insulin Therapy in the Era of Pathophysiologic

Treatment of T2DM:

Marked Reduction of Insulin Use

Outline• Value of Glycemic Control• But do without Hypo Weight Gain• Hypo topics

– In general, SU, Insulin

Duggal, Evidence-Based Medicine in Practice,, Int’l j. Clinical Practice,65:639-644,2011Allan D. Sniderman, MD; Kevin J. LaChapelle, MD; Nikodem A. Rachon, MA;and Curt D. Furberg, MD, PhDMayo Clin Proc The Necessity for Clinical Reasoning in the Era of Evidence-Based Medicine October 2013;88(10):1108-1114 Trisha Greenhalgh et al, Evidence based medicine: a movement in crisis? BMJ 2014; 348

Lecture Based on Evidence -Based PRACTICE

==EBM=Evidence Based Medicine

Has Led to Students/MDs who don’t Think-Eg: if no evidence, continue doing same old dangerous

therapy (SU); Specialists are abrogating their responsibility to evaluate and lead in use of new medications, processes of care

= Evidence Based Practice

EBM=Evidence Based Medicine

Research Evidence

Randomized, ProspectivePublication TrialsCritical Appraisal

Patient-Based Experience

Clinical expertiseExpert OpinionsGuidelines

+ +

Why Bother to Treat Agressively?

There’sYour‘Market’

Date of download: 4/17/2014

From: Trends in Prevalence and Control of Diabetes in the United States, 1988–1994 and 1999–2010Trends in Prevalence and Control of

Diabetes in the United States

Ann Intern Med. 2014;160(8):517-525. doi:10.7326/M13-2411

Prevalence of total confirmed diabetes and obesity.

Data from U.S. adults aged ≥20 y in NHANES 1988–1994, 1999–2004, and 2005–2010. Total confirmed diabetes was defined as diagnosed diabetes or undiagnosed diabetes with diagnostic levels of both hemoglobin A1c (≥6.5%) and fasting glucose (7.0 mmol/L [≥126 mg/dL]). Obesity was defined as body mass index ≥30 kg/m2; 601 persons were missing body mass index data. Prevalence estimates for total confirmed diabetes and obesity were obtained using only the subsample of participants who attended the morning fasting session (7385 participants for 1988–1994, 5680 participants for 1999–2004, and 6719 participants for 2005–2010). The midpoint for obesity prevalence between 1988–1994 and 1999–2004 was calculated as the average of the prevalence of the 2 periods. NHANES = National Health and Nutrition Examination Survey.

Figure Legend:

EPIDEMIC

One third of adults with diabetes are undiagnosed

• ~10% of US adults have diabetes/~20 million persons in 2005

• Nearly one third don’t know they have diabetes

• 26% of US adults have impaired fasting glucose (IFG)*

*100–125 mg/dLCowie CC et al. Diabetes Care. 2006;29:1263-8.

NIDDK. National Diabetes Statistics. www.diabetes.niddk.nih.gov.

Total: 35% of US adults with diabetes or IFG~73.3 million persons

Considering the Epidemic of Metabolic Syndrome, Considering the Epidemic of Metabolic Syndrome, Prediabetes, Prevention Data, Undiagnosed Diabetes-Prediabetes, Prevention Data, Undiagnosed Diabetes-

ER Office and Pre-Admission ER Office and Pre-Admission IDENTIFICATION IS CRITICAL!IDENTIFICATION IS CRITICAL!

• Family history: whether parents or siblings have had Family history: whether parents or siblings have had diabetesdiabetes

• Obesity: especially with an increase in abdominal girthObesity: especially with an increase in abdominal girth

• High-risk ethnic group: African Americans, Hispanics,High-risk ethnic group: African Americans, Hispanics,Native Americans, Asians, and Pacific IslandersNative Americans, Asians, and Pacific Islanders

• Age: Age: wewe’’re looking at all ages, if patient seems at riskre looking at all ages, if patient seems at risk

• Impaired fasting glucose or impaired glucose toleranceImpaired fasting glucose or impaired glucose tolerance

• Hypertension: blood pressure ≥ 140/90 mm Hg in adultsHypertension: blood pressure ≥ 140/90 mm Hg in adults

• High density lipoproteins < 35 mg/dL or triglyceride High density lipoproteins < 35 mg/dL or triglyceride levels ≥ 250 mg/dLlevels ≥ 250 mg/dL

• Gestational diabetes or given birth to an infant Gestational diabetes or given birth to an infant weighing > 9 poundsweighing > 9 pounds

• Pre-adm , pre-cath, pre-op , pre-CABG Pre-adm , pre-cath, pre-op , pre-CABG

FBS >100, ppg >140, POC HgA1c >6.0FBS >100, ppg >140, POC HgA1c >6.0

9

HyperglycemiaSpike

(variability) PPG

ContinuousA1C

Acute toxicityChronic toxicity

Tissue lesion

Diabetic complications

Microvascular Macrovascular

Retinopathy NephropathyNeuropathy PVD MI Stroke

American Diabetes Association. At: http://www.diabetes.org/diabetes-statistics/complications.jsp.Brownlee M. Diabetes mellitus: theory and practice. Elsevier Science Publishing Co., Inc; 1990:279-291.

Ceriello A. Diabetes. 2005;54:1-7.

Hyperglycemia Leads to Complications

BROWNLEE’s Unified Theory

Often Present at Diagnosis

Trends in Age-Standardized Rates of Diabetes-Related Complications among U.S. Adults with and without Diagnosed

Diabetes, 1990–2010.

Gregg EW et al. N Engl J Med 2014;370:1514-1523

Impact of Intensive Therapy in Type 2 Diabetes Summary of Major Clinical Trials:

BUT Subset Evaluations Show Reduced CV Outcomes if shorter duration of DM, without significant pre-existing complications

Study Microvascular Macrovascular Mortality

UGDP ↔ ↔ ↔UKPDS ↓ ↓ ↔ ↓ ↔ ↓

DCCT/EDIC* ↓ ↓ ↔ ↓ ↔ ↔ACCORD ↓ ↔ ↑(unadj.), ↔ (adj.)

ADVANCE ↓ ↔ ↔VADT ↔ ↔ ↔

Initial Trial Long Term Follow-up

↑↑- likely due to hypoglycemia and weight - likely due to hypoglycemia and weight gaingain

Hypoglycemia Outcomes VADT, ACCORD, ADVANCE

Consequences of Hypoglycemia

• Prolonged QT- intervals- Diabetologia 52:42,2009

– Can be of pronged duration IJCP Sup 129, 7/02

– Greater with higher catecholamine levels Europace 10,860

• Associated with Angina Diabetes Care 26, 1485, 2003 / Ischemic EKG changes Porcellati, ADA2010

• Associated with Arrhythmias• Associated with Sudden Death Endocrine Practice 16,¾ 2010

• Increased Variabilty- increases inflammation, ICU mortality Hirsch ADA2010

CV Risk of SU and Insulin

Pharmacoepidemiology and Drug Safety. 2008;(17):753-759.

So benefit of both SU/Insulin in research studies –UKPDS, DCCT/EDIC

But adverse risk in ‘real world’ use-

would not pass current FDAguidelines for CV risk with a new agent

Increased Mortality with SU

Acute coronary syndrome in patients with diabetes mellitus: perspectives of an interventional cardiologist.Sanon S, Patel R, Eshelbrenner C, Sanon VP, Alhaddad M, Oliveros R, Pham SV, Chilton R.Am J Cardiol. 2012 Nov 6;110(9 Suppl):13B-23B

Endo 2012, abstractFits FDA criteria for market withdrawal

DOI: 10.1177/1479164112465442Diabetes and Vascular Disease Research published online 4 January 2013Thomas Forst, Markolf Hanefeld, Stephan Jacob, Guido Moeser, Gero Schwenk, Andreas Pfutzner and Axel Hauptreview and meta-analysis of observational studies

Complications CAN Be Reduced;MUST Avoid Hypoglycemia, Weight Gain

1. DCCT/EDIC and UKPDS- decreased Micro, Macrovascular disease

2. Confusion with VADT, ADVANCE, ACCORD Trialsa. Older, longer duration DM, one third with CV diseaseb. Decreased micro, no benefit CV reduction, ACCORD increased Mortalityc. we believe because undue hypoglycemia, weight gain

3. ADA says adjust HgA1c goal Higher if Older, longer duration DM, CV disease

4. I DISAGREE

5. We have 8 classes of drugs that have no undue risk hypoglycemia, weight gaina. so I’m Older, longer duration DM, CV disease

-on 3 meds with no undue risk hypoglycemia, weight gainb. my HgA1c 5.4 !!- c. so I still aim for lowest without no undue risk hypoglycemia,

weight gain