# Presentation: 905153

## Achieving Diabetes TargetsWhere are we, and how can we do better?

- Robert E. Ratner, MD
- MedStar Research Institute
- Georgetown University Medical School
- Washington, DC

## EVERY 24 HOURS

-   New Cases – 4,100
-   Amputations – 230 (60% of non-traumatic 	amputations annually)
-   Blindness – 55 (#1 cause)
-   Kidney Failure – 120 (#1 cause)
-   Deaths – 810 - >60% due to CVD

*Derived from* NIDDK, National Diabetes Statistics fact sheet. HHS, NIH, 2005.

**Notes:**
The following are rough approximations to help emphasize what diabetes prevalence numbers mean to people with diabetes each and every day.

Approximately,

4,100 new cases of diabetes diagnosed; 

810 people die from the complications of diabetes;

230 people with diabetes will have an amputation; 

120 people with diabetes will suffer from kidney failure; and 

55 people with diabetes will go blind. 

Reference
National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics fact sheet: general information and national estimates on diabetes in the United States, 2005.Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, 2005.

## $132 Billion for Total Excess U.S. Cost Attributable to Diabetes in 2002

- American Diabetes Association. *Diabetes Care *2003;26:917-932.

**Medication **
**and Supplies**

**Outpatient**
**Care**

**Institutional**
**Care**

**Indirect **
**Costs**

**Costs in Millions of Dollars**

## Projected impact of changing demographic characteristics on the national cost of diabetes: 2002–2020 (in 2002 billions of dollars)

- Source:  *Economic Costs of Diabetes in the U.S. in 2002*, Lewin Group, Inc., for the American Diabetes Association, 2002. (http://care.diabetesjournals.org/cgi/content/full/26/3/9617)

## Preventing Diabetes Complications 

- Glucose control
- Blood pressure control
- Blood lipid control
- Preventive care practices for eyes, kidneys, feet, teeth and gums
- Aspirin as directed by physician

- NIDDK, National Diabetes Statistics fact sheet. HHS, NIH, 2005.

**Notes:**
People with diabetes and their health care providers can reduce the occurrence of diabetes complications by controlling the levels of blood glucose, blood pressure, and blood lipids, and by receiving other preventive care practices in a timely manner. 

Studies have found that improved glycemic control benefits people with either type 1 or type 2 diabetes. In general, every percentage point drop in A1C blood test results (i.e., from 8.0% to 7.0%) reduces the risk of microvascular complications—like eye, kidney, and nerve diseases—by 40%. 

Blood pressure control reduces the risk of heart disease or stroke among persons with diabetes by 33% to 50%, and the risk of microvascular complications by about 33%. 

Improved cholesterol or blood lipids control (for example, HDL, LDL, and triglycerides) can reduce cardiovascular complications by 20% to 50%.

Detecting and treating diabetic eye disease with laser therapy can reduce the development of severe vision loss by an estimated 50% to 60%. 

Comprehensive foot care programs can reduce amputation rates by 45% to 85%. 

Treating early diabetic kidney disease by lowering blood pressure can reduce the decline in kidney function by 30% to 70%. 

Studies have shown that an aspirin a day can help prevent diabetes complications. 

Reference
National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics fact sheet: general information and national estimates on diabetes in the United States, 2005. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, 2005.

## Number of Persons Initiating Treatment for End-Stage Renal Disease Related to Diabetes, United States, 1984–2002

**Source: National Diabetes Surveillance System – CDC website (http://www.cdc.gov/diabetes/statistics/index.htm****)**

## Adjusted ESRD incident rates, by primary diagnosis, & diabetes in the general population

**Incident ESRD patients; rates adjusted for age, gender, & race.**

**Adjusted ESRD incident rates, ****by primary diagnosis, & diabetes ****in the general population**

**USRDS, accessed July 13, 2007**

## Adjusted ESRD incident rates of ESRD due to diabetes

- lla

- illi

- lla

- illi

**Incident ESRD patients; adjusted for age, gender, & race. **

**USRDS, accessed July 13, 2007**

## Prevalence of Visual Impairment per 100 Adults with Diabetes, by Age, United States, 1997–2003

**Source: National Diabetes Surveillance System – CDC website (http://www.cdc.gov/diabetes/statistics/index.htm)**

## Hospital Discharge Rates for Nontraumatic Lower Extremity Amputation per 1,000 Diabetic Population, by Age, United States, 1980–2003

**Source: National Diabetes Surveillance System – CDC website (http://www.cdc.gov/diabetes/statistics/index.htm)**

## Microvascular Endpoints

## Fatal and Non-Fatal Myocardial Infarction

## Fatal and Non-Fatal Stroke

## Myocardial Infarction and Microvascular Disease

## A1c is a good biologic correlate to microvascular disease complications

- A1c is a less powerful correlate to macrovascular disease due to the multi-factorial nature of the CVD

## Aggressive Control of Type 2 Diabetes is a Challenge

- 76% of patients surveyed had an A1C level recorded in the chart in the previous 12 months
- Distribution of A1C (%) Among Patients with Recorded Test Results (n=270,758) in Community Practice

- Graham, et al. Diabetes 2002;51(Suppl 2):A274.

## Lessons from the DCCT and UKPDS:Sustained Intensification of Therapy is Difficult

**9.0**

**8.1**

**7.3**

**7.9**

**4**

**6**

**8**

**10**

**HbA****1c**** (%)**

**0**

**6.5**

**+ 4**

**+ 6   yrs**

**DCCT**

**EDIC**

**DCCT        EDIC**
**(Type 1)**

**Lessons from the DCCT and UKPDS:****Sustained Intensification of Therapy is Difficult**

**DCCT/EDIC Research Group.  *****New Engl J Med*****. 2000; 342: 381-389.**
**Steffes et al. *****Diabetes.***** 2001 (suppl. 2) 50: A63.**

**0**

**6**

**7**

**8**

**0**

**2**

**4**

**6**

**8**

**10   yrs**

**HbA****1c**** (%)**

**UKPDS (Type 2),****Insulin Group**

***Normal***

***Baseline***

**UK Prospective Diabetes Study Group (UKPDS) 33:*****Lancet*****.***** *****1998;352:837–853.**

**Notes:**
Slide Index 00030

TALKING POINTS:
Click 1:  DCCT and EDIC data in left panel:
Left panel shows data from a sub-group of patients who had been in the intensive group during the DCCT and continued in EDIC, a long-term follow-up of the DCCT
This sub-group began the DCCT with an average HbA1c of 9.0% [first bar], and ended the study with a mean of 7.3% [second bar].  
After the DCCT ended, patients returned to community-based diabetes management and were followed for an additional 4 [third bar, lighter blue] and 6 [last bar, lighter blue] years.  As can be seen by the increasing HbA1c in the last 2 lighter blue bars, these patients had difficulty sustaining HbA1c improvements achieved during the DCCT.
Click 2:  UKPDS data appears in right panel
The right panel shows data from the insulin-treated group of the UKPDS.  Initial decreases in HbA1c were not sustained during the 10-year study period.

SLIDE BACKGROUND:
EDIC:  Epidemiology of Diabetes Interventions and Complications
1375 of the 1441 DCCT participants (95%) volunteered to participate in EDIC.  1208 patients were evaluated after 4 years of follow-up in EDIC (605 of these were previously in the DCCT intensive group; N for Year 6 not yet available).
Data for DCCT/EDIC on slide are for previous participants in DCCT intensive group.  The gap between this group and their counterparts in the conventional group has diminished over time.  Data for previous participants in DCCT conventional group are:
DCCT time 0 = 9.0%
DCCT time 6.5 yrs = 9.0%
EDIC + 4 years = 8.2%
EDIC + 6 years = 8.1%
Data for DCCT/EDIC are means.

PRESENTER NOTES:

## Progress in Achieving A1C Goal

**    **
**    ****% of adult patients with**

- Diabetes Physician Recognition Program, average performance of applicants, 1997-2003 data.
- * Lower is better for this measure.

- www.ncqa.org

## Secondary Failure of MonotherapyOverweight Patients in the UKPDS

**Turner RC et al. UKPDS 49. *****JAMA.***** 1999;281:2005-2012**

**Percent with A1C <7% on monotherapy**

**Diet****	****23****	****12****	****11**
**Sulfonylureas****	****45****	****28****	****21****	**
**Metformin****	****44****	****34****	****13**

## Secondary endpoint : HbA1c

*****Significant difference rosiglitazone vs other treatment groups with Hochberg adjustment.
- Kahn SE, et al. *N Engl J Med* 2006;355:2427–2443.

**Years**

**6.0**

**7.6**

**8.0**

**6.8**

**0**

**1**

**2**

**3**

**4**

**5**

**Glycated Hemoglobin (%)**

**7.2**

**0**

**Rosiglitazone, 0.07 (0.06 to 0.09)**
**Metformin, 0.14 (0.13 to 0.16)***
**Glyburide, 0.24 (0.23 to 0.26)***

**6.4**

**No. of Patients****	****4012****	****3308****	****2991****	****2583****	****2197****	****822**

**Treatment difference (95% CI)**
**Rosiglitazone vs metformin, -0.13 (-0.22 to -0.05); *****P*****=0.002**
**Rosiglitazone vs glyburide, -0.42 (-0.50 to -0.33); *****P*****<0.001**

**Annualized slope (95% CI)**

## Clinical Inertia: Failure to Advance Therapy When Required

**0**

**20**

**40**

**60**

**80**

**100**

**Diet**

**Sulfonylurea**

**Metformin**

**Percentage of Subjects advancing when HbA****1C**** >8%**

**% Age of Subjects**

**Combination**

**66.6%**

**35.3%**

**44.6%**

**18.6%**

- 1Brown et al.  The Burden of Treatment Failure in Type 2 Diabetes.  Diabetes Care 27.  1535-1540, 2004

**At Insulin Initiation, the average patient had:**
**  ****5 years with HbA****1C**** >8%**
**  ****10 years with HbA1C >7%**

## Severe Adverse EffectsSubstantiated in Published Clinical Trials

**Hypoglycemia**

**CV**

**Insulin****	****Yes****             ****No****	****            No**
**Sulfonylureas****	****Yes****             ****Yes?****	****             No**
**Metformin****	****No****               ****No****	****             ****Yes**

**Lactic **
**acidosis**

******-Glucosidase inhibitors****	****No               No                 No**
**Glitazones (TZDs)****	****No               ****Yes(CHF)****      No**
**Repaglinide, nateglinide*****	****Yes****              No  ****	****              No**
**Incretin Mimetics/Enhancers   No              No                 No**

*** Recently available agents with few trials documenting long-term outcomes**
**  ****CV=cardiovascular; CHF=congestive heart failure**

## Weight Gain is a Common Side Effect of Most Oral Agents for Type 2 Diabetes 

**2. Bristol-Myers Squibb. Glucovance****®**** Full prescribing Information. 2004.**
**3. Bristol-Myers Squibb. Metaglip****®**** Full Prescribing Information. 2002. **
**4. Malone M. *****Ann Pharmacother. *****2005;39:2046-2055. **
**5. Eli Lilly. Actos****®**** Full Prescribing Information. 2004. **
**6. GlaxoSmithKline. Avandia****®**** Full Prescribing Information. 2005. **
**7. Novartis. Starlix****®**** Full Prescribing Information. 2004. **
**8. Novo Nordisk. Prandin****®**** Full Prescribing Information. 2004. **
**9. GlaxoSmithKline. Avandamet****®**** Full Prescribing Information. 2005. **

**Weight Gain is a Common Side Effect of Most Oral Agents for Type 2 Diabetes**** **

**TZDs****4-6**

**Metformin + TZD****5,6,9**

**Metformin + SU****1-3**

**Meglitinides****4,7,8**

**SUs****1-4**

**Metformin****1-3**

**Weight change (kg)**

**Oral antidiabetic agent***

**-5****	****-4****	****-3****	****-2****	****-1****	****0****	****1****	****2****	****3****	****4****	****5**

**-3.8-0.5**

**-0.2-4.3**

**0.9-4.6**

**0.3-3.0**

**-0.3-1.9**

**0.8-2.1**

- *Data are not from head-to-head studies

**Notes:**
Weight gain is a common side effect of most oral treatments for type 2 diabetes. The slide illustrates relative weight change observed in clinical trials of metformin,1-3 SUs,1-4 TZDs,4-6 meglitinides,4,7,8 metformin plus an SU,1-3 and metformin plus a TZD.5,6,9

A number of mechanisms may account for weight gain in patients treated with antidiabetic medication, including10,11:
Improved glycemic control, which is associated with decreased protein breakdown and synthesis
Decreased energy expenditure and metabolic rate
Decreased glycosuria, resulting in fewer calories being lost in the urine
Increased caloric intake to prevent hypoglycemia
Anabolic effects on adipose tissue

1Bristol-Myers Squibb. Glucophage® Full prescribing Information. 2004.
2Bristol-Myers Squibb. Glucovance® Full prescribing Information. 2004.
3Bristol-Myers Squibb. Metaglip® Full Prescribing Information. 2002. 
4Malone M. Ann Pharmacother. 2005;39:2046-2055. 
5Eli Lilly. Actos® Full Prescribing Information. 2004. 
6GlaxoSmithKline. Avandia® Full Prescribing Information. 2005. 
7Novartis. Starlix® Full Prescribing Information. 2004. 
8Novo Nordisk. Prandin® Full Prescribing Information. 2004. 
9GlaxoSmithKline. Avandamet® Full Prescribing Information. 2005.
10Krentz AJ and Bailey CJ. Drugs. 2005;65:385-411.
11Purnell JQ and Weyer C. Treat Endocrinol. 2003;2:33-47.

## Adherence to Prescribed Drugs in Patients with Type 2 Diabetes

| Drug class | n | % Adherent | 95% CI |
| --- | --- | --- | --- |
| Oral antidiabetic drugs | 66 | 50.0 | 37.9-62.1 |
| Antihypertensive drugs | 62 | 50.0 | 37.6-62.4 |
| Lipid-lowering drugs | 33 | 69.7 | 54.0-85.4 |
| Antiplatelet drugs | 40 | 77.5 | 64.6-90.4 |
| All drugs | 82 | 35.4 | 25.0-45.7 |

**Mateo JF et al. *****Int J Clin Pract.***** 2006;60:422-428.**

**Notes:**
A recent population-based, cross-sectional study was performed to determine adherence rates to prescribed drugs among patients with type 2 diabetes1: [1/424/2/3 + 1/425/Table 3]
Ninety patients in a primary care setting were enrolled.
Pill counts and self-report methods were used to measure adherence. Logistic regression models were used to predict factors related to nonadherence.
Of the 90 patients who enrolled in the study, 82 completed. Mean age of enrollees was 68.5 years; 41 (50%) were women; and mean duration of type 2 diabetes was 10.5 years.
As shown in the slide, adherence rates to all classes of prescribed drugs were suboptimal, ranging from 50.0% for oral hypoglycemic drugs and antihypertensive drugs to 77.5% for antiplatelet drugs. Adequate adherence to all drugs was noted only in 35.4% of patients.

1Mateo JF, et al. Int J Clin Pract. 2006;60:422-428.

**Diabetes Care. 2004 May 1; 27(5):1218-1224 **

**Insulin adherence among patients **
**with type 2 diabetes was 62-64%**

**Notes:**
Insulin adherence among patients with type 2 diabetes was 62-64%

## Medical BenefitsSubstantiated in Published Clinical Trials

**Microvascular**

**Cardiovascular**

**Insulin****	****Yes****	****Yes?**
**Sulfonylureas****	****Yes****	****No**
**Metformin****	****Yes****	****Yes?**

******-Glucosidase inhibitors****	****No****	****Yes?**
**Glitazones (TZDs)****	****No****	****No**
**Repaglinide, nateglinide*****	****No****	****No****Incretin Mimetics/Enhancers*       No                            No**

**  ***** Recently available agents with few trials documenting long-term outcomes**

## Does Treatment of Diabetes impact Mortality?

**Kahler KH, et al.  Diabetes Care 30:1689, 2007**

## Why do we need new therapies for Type 2 Diabetes?

- The epidemic of diabetes and its complications will soon swamp our medical delivery system
- A1c is a well validated short term target
- We are not currently achieving our glycemic targets
- Current therapies have either limited efficacy, marked complexity, or unacceptable side effects
- Therapies must be acceptable to patients and health care providers – They must be utilized!

## What should drive diabetes drug development and approval?

- Safety (Hepatic, CVD, Hypoglycemia – While realizing that diabetes is a serious disease!)
- Efficacy (glycemic control, risk factor reduction)
- Side Effects (weight gain)
- Patient acceptability

## The Business Case for a Comprehensive Approach

**3-YEAR MEDICAL CHARGES FOR DIABETES PATIENTS ****BY CO-MORBIDITIES AND GLYCEMIC CONTROL**

- HbA1c 6%

- HbA1c 7%

- HbA1c 8%

- HbA1c 9%

- HbA1c 10%

- $

**DM = Diabetes; HTN = Hypertension; HD = Heart Disease**

- Gilmer, et al. Diab. Care, 1997; 20:1847-1853

**The Business Case for a Comprehensive Approach**

## Cost/ QALY lifetime follow-upUS cohort >=25 years

-    Glycemia         Hypertension          Lipid
-                   Intervention  type

- CDC JAMA 2002