DA 2020

1. Presentation by
Paresh Dandona, BSc, MD, DPhil,
FRCP, FACP, FACC, FACE
SUNY Distinguished Professor of Medicine and Pharmacology
School of Medicine and Biomedical Sciences
Division Head, Endocrinology and Metabolism
State University of New York at Buffalo
Founder, Diabetes-Endocrinology Center of Western New York,
Buffalo, New York
In partnership with

2. Confidential:
Please do not share

3. • Dr. Dandona will weave these two major themes:
1. “The goals for the treatment of diabetes”
2. “The treatment plan for patients with diabetes”
into case-based learning modules based on real patients he has treated.
• The medication treatment plan will be emphasized most in the case studies.
• In the case studies, Dr. Dandona will provide background on the patient, state their
medications list, and provide specific examples of when and how he changes their
treatment regimens.
• Dr. Dandona will also provide detailed guidance on medication management strategies,
and the process by which he makes recommendations to providers via his Diabetes
Ambassadors, who are PCP-CDE-Endocrinologist liaisons.

4. GOALS FOR THE TREATMENT OF DIABETES:
To be incorporated into patient case studies
• Reduce insulin resistance-metformin and pioglitazone (TZDs), testosterone
• Increase insulin secretion-sulfonylureas, GLP-1 receptor agonists
• Reduce rate of digestion of carbohydrates-Glucosidase inhibitor-acarbose
• Suppress appetite and carbohydrate intake-GLP-1 receptor agonists
• Induce glycosuria and induce osmotic diuresis-SGLT2 inhibitors
• Replace insulin-basal and prandial
• Replace testosterone in hypogonadal males

5. MEDICATION TREATMENT PLAN FOR PATIENTS WITH DIABETES
Experience with the following medications to be incorporated into patient case studies
• Metformin-suppresses hepatic glucose production; is cardioprotective; may be anti-aging
• Pioglitazone-insulin sensitizer; anti-inflammatory and anti-atherogenic; cardioprotective
• Sulfonylurea (Glimepiride)-stimulates β-cell to secrete insulin
• Acarbose-reduces post prandial glucose peak
• GLP-1RA if atherosclerotic disease is present-stimulate β-cell to produce insulin, suppress α-cell
glucagon secretion, suppress appetite and slow gastric emptying, induce weight loss; cardioprotective
• SGLT2 inhibitors if CCF is present-induce glycosuria induce weight loss and provide cardioprotection
• Insulin-basal insulin to normalize fasting glucose levels; prandial insulin to normalize post prandial
peaks
• Testosterone replacement in hypogonadal males-reduction in adiposity and increase in muscle-
insulin sensitization

6. THERAPEUTIC PLAN SUMMARY FOR
PEOPLE WITH T2D
Start with the combination of metformin (1 g BID) and pioglitazone 15 mg daily
Add glimepiride 1 mg daily
Add acarbose 25 mg with each meal
Consider a GLP-1RA, especially if CAD, CVD or PVD is present
Consider SGLT2 inhibitor, especially if CHF present
Bed time Basal Insulin to normalize fasting glucose concentrations
Prandial insulin only if post prandial glucose levels are uncontrolled

7. Study 1:
CDE-Ambassador
A Novel Approach To Comprehensive
Diabetes Care At The Primary Care Level
Presented at American Association of Diabetes Educators
(AADE) 2015 Conference based on research led by
Paresh Dandona, BSc, MD, DPhil,
FRCP, FACP, FACC, FACE

8. Study 1:
CDE-Ambassador
A Novel Approach To Comprehensive
Diabetes Care At The Primary Care Level
Presented at American Association of Diabetes Educators
(AADE) 2015 Conference based on research led by
Paresh Dandona, BSc, MD, DPhil,
FRCP, FACP, FACC, FACE
Study Summary:
https://www.ajmc.com/journals/evidence-based-diabetes-management/2016/december-2016/utilization-of-cdes-in-primary-
care-under-the-guidance-of-an-endocrinologist-better-than-any-new-drug-researcher-says
Link to PDF of article:
https://ajmc.s3.amazonaws.com/_media/_pdf/EBDM_1216_final.pdf
ADDITIONAL REFERENCES
From 2015 AADE Conference:
https://www.aademeeting.org/news/team-approach-helps-patients-reduce-a1c-levels/
Link to full set of slides with detailed data presented at 2015 AADE Conference below:
https://www.diabeteseducator.org/docs/default-source/default-document-library/f27b.pdf?sfvrsn=0

9. “When he dispatched CDEs to work alongside a primary care physician (PCP), but under his guidance, the educators were able to gain significant improvements in
glycated hemoglobin (A1C) in patients with diabetes, which Dandona deemed “better than any new drug.”
100 patients managed by the CDEs had a mean A1C reduction of 1.6% after 6 months, while a control group of 45 patients treated only by the PCP saw a reduction
of only 0.26%. Patients treated by the CDEs lost more weight, as well, with their body mass index falling by 1.3 kg/m2 in the intervention group compared with 0.1
kg/m2 for the control group. The CDE-treated group also recorded improvements in blood pressure, low-density lipoprotein (LDL) cholesterol, and triglycerides
superior to those in the controls.
There were some differences between the 2 groups: the intervention group was slightly younger (mean age of 58 years vs 61 years in the control group), and a much
higher share of the group had been diagnosed within the past 5 years (62% vs 42%). But as Dandona explained, that may be the point. Too often, he said, PCPs fail
to make timely adjustments to treatment regimens early in the course of the disease, which is when patients are known to respond better to therapy.
Deploying trained CDEs into primary care can help tackle the “mountain of diabetes,” he said. This is a group that is highly committed, but they need guidance from
specialists. The data reveal that the CDEs were more aggressive in making medication changes: 52% of the CDE group had modifications to their regimen compared
with 37.7% of the PCP group. Of note, the A1C decline was greater among patients who had a therapy change (mean of 1.9%) compared with those whose therapy
was not changed (1.1%).
After the 6-month intervention, when patients returned to management by the PCP alone, the A1C reduction in the intervention group diminished somewhat, to 1.2%
at 12 months. This was still greater than the decline in the control group, which was 0.7% at 12 months. Notably, the average A1C for the intervention group was
below 7% at 6 months, but crept back up to 7.8% after patients stopped seeing the CDE. In the control group, the average A1C was 8% at 6 months and 7.9% at 12
months. Benefits in blood pressure, weight loss, triglycerides, and LDL cholesterol were largely maintained in the CDE group, despite the rise in A1C at 12 months.
Dandona said the results highlight the problem of clinical inertia, which affect his ability to change patient behavior when patients progress and are referred to him.
“There are a lot of patients who need attention, but we are basically sitting there doing nothing,” he said. When these patients get to the endocrinologist, “they are
already reticent in changing their habits, because for years, they’ve been told they are perfectly OK.”
The results also show how the standards of care could be revolutionized by “letting loose” CDEs to take a more active role in primary care. “CDEs working with
endocrinologists can change outcomes in a really remarkable fashion, such that the whole face of diabetes can be changed,” he said.
Study 1:
CDE-Ambassador: A Novel Approach To Comprehensive
Diabetes Care At The Primary Care Level
Summary

10. Study 2:
Certified Diabetes Educator-Ambassador (CDE-A)
Involvement Improves Diabetic Control and
Cardiovascular Risk Factors
at Primary Care Level
Presented at Endocrine Society 2016 Meeting:
Research led by
Paresh Dandona, BSc, MD, DPhil,
FRCP, FACP, FACC, FACE

11. View Full Study at: https://endo.confex.com/endo/2016endo/webprogram/Paper27541.html
Presented at Endocrine Society 2016 Meeting:
“We have previously shown that the involvement of a CDE, empowered by guidance from a diabetologist, termed CDE-Ambassador (CDE-A), in the management of
the diabetes at the primary care level, results in marked benefits. Retrospective analysis of data obtained from 100 such patients showed improvements in glycemic
control (HbA1c from 8.4% to 6.8%; p<0.0001), body weight (from 102 to 99Kg; p<0.0001), systolic blood pressure (from 134 to 128 mm; p<002), diastolic blood
pressure (from 80 to 77 mm; p<0.003) and serum triglycerides (from 189 to 162 mg/dl; p<0.003) and LDLc concentrations (from 108 to 96 mg/dl; p<0.0004) following
2 to 3 consultations over a period of 6 months. [Micro-albuminuria did not alter significantly.] There was no significant change in any of these indices in 45 control
patients who did not consult with the CDE-A. We have now investigated the durability of this effect by getting follow up data at 12 months without further intervention
after 6 months. The beneficial effect on HbA1c diminished from a reduction of 1.6% from the baseline at 6 months to 1.1% over the following 6 months without further
visits to the CDE-A. However, the benefits in BMI, blood pressure, triglycerides and LDLc were largely maintained, without significant attenuation. These indices did
not change in the control group. We conclude that the involvement of the empowered CDE-A can contribute to improvements in diabetic control and indices of
cardiovascular risk. While the maintenance of HbA1c probably requires repeated visits to CDE-A, the other indices related cardiovascular risk are effectively
controlled for at least one year. A network of CDE-As, empowered by diabetologists at the primary care level could help prevent diabetic microvascular and
macrovascular complications.”
Study 2:
Certified Diabetes Educator-Ambassador (CDE-A)
Involvement Improves Diabetic Control and
Cardiovascular Risk Factors
at Primary Care Level
Summary

12. One of the first Diabetes Ambassador/ Endocrinologist
Liaisons is Lori Crassi, RD, CDE. Lori is currently a
Diabetes Ambassador for the major health plan in Western
New York and was trained by Dr. Dandona.
Prior to that, Lori worked with the Seneca Nation of Indians
in Western NY for 16 years. A quote from Lori regarding
the excellent results of the Diabetes Ambassadors
program is below:
"During my 16 years of employment with the Seneca Nation of Indians in
Western NY, as a Registered Dietitian and Certified Diabetes Educator
(CDE), I had many opportunities to work with Native Americans and
provide health care, specializing in diabetes and nutrition. The Seneca
Nation is one of many tribes that applied for and received funding through
the Special Diabetes Project for Indians from Congress, which was
administered by Indian Health Services.
One of the most amazing programs was bringing endocrinologist, Dr.
Paresh Dandona to our clinic to assist in coordinating diabetes care for
our patients. Dr. Dandona developed an innovative and effective approach
to best utilize endocrinologists, CDEs and primary care doctors to make a
positive difference in the lives of people with diabetes. Though dedication
to each individual patient, helping them to see improvement in their
diabetes control. Always demonstrating commitment and positivity that
their blood sugars can and will improve. Watching people transform their
attitudes about diabetes and medical care and their own ability to be
successful in making a difference in their health was priceless.
The vast knowledge that was shared with me made me a better clinician
and allowed me to bring new treatment and education options to my
patients.”

13. Program Implementation at Blue Cross Blue Shield of
Western New York

14. CONFIDENTIAL: WE ASK YOU NOT TO SHARE WITH ANYONE.
PRACTICAL PLAN OF TREATMENT
Our plan for treating our diabetic patients is to start with a combination of metformin and
pioglitazone for a period of 6 weeks along with guidance linked to dietary changes: low
carbohydrate diet with a lot of greens, beans and fruit, especially berries.
Regarding meats, we encourage fish and chicken while avoiding red meats. Nuts and cheese are
encouraged for snacks. If necessary, a small dose of glimepiride, 1 mg, is then added, followed by
acarbose.
If these measures do not get us to the A1C target of <7%, we then add Novolin N as basal insulin
at night, if the patient cannot afford to be on a GLP-1RA. If financial issues are not a consideration,
a weekly GLP-1RA is started instead. This treatment has the dual advantage of improvement in
A1C and the suppression of appetite and weight loss.
If glycemia is not under control in spite of these steps, we add an SGLT2 inhibitor. Again, this gives
us the advantage of glycemic control, weight loss and a fall in systolic blood pressure.
In patients with a history of atherosclerotic complications, we start with GLP-1RA earlier while those
who have a history of cardiac failure, we start with SGLT2 inhibitors.

15. THERAPEUTIC PLAN FOR PEOPLE WITH TYPE 2 DIABETES
Less than 50% of people with diabetes have good control of their A1C—with numbers <7%. They are therefore vulnerable to the development of diabetes
complications and it is imperative that we take strong measures to improve diabetic control—since diabetes is the most common cause of adult blindness, end
stage kidney disease and peripheral neuropathy.
Diabetes also contributes to the pathogenesis of atherosclerosis. This leads to an increased risk of myocardial infarction, stroke and peripheral vascular disease
and amputations.
The innovations in the treatment of diabetes over the past 25 years have been phenomenal. However, knowledge about the appropriate use of these drugs is
lacking. We need to make primary care physicians aware of these novel innovations and their effective and appropriate use.
Another important issue is the cost of these drugs—especially those that are still under patent. The cost of insulin has escalated enormously over the past
decade.
This makes the issue of good control of diabetes doubly difficult: knowledge of appropriate use, and the excessive cost. It is, therefore, essential that we attempt
to deal with both of these issues.
While we are attempting to deal with the problems at the primary care level with our network of CDE-Diabetes Ambassadors, we should also consider the
containment of cost.
With this in mind, we have set out a simple therapeutic approach using four oral agents:
1) Pioglitazone—which also has definitive evidence of cardioprotection.
2-3) Acarbose and metformin—may also be cardioprotective.
4) Glimepiride—has recently been shown to be non-inferior to Linagliptin in terms of cardiovascular outcomes.
Because of the potency of each of these 4 oral agents, it should be possible to reduce A1C by 3-4%, from a baseline of 10%, when they are used in combination.
This would translate into adequate control of 80% of patients with type 2 diabetes. Since the cost of each of these drugs is minimal, this approach would
potentially reduce treatment costs for type 2 diabetes enormously.
The use of insulin and GLP-1RA could be reserved for those patients who are still not under control. Similarly, the use of GLP-1RA and SGLT2 inhibitors could be
reserved for those who have established atherosclerotic disease, cardiac failure or high cardiovascular risk.

16. MEDICATIONS
ORALS:
Inexpensive:
Metformin. Possibly cardioprotective, accepted globally to be the first drug in type 2 diabetes. It reduces A1C by 1-1.5%. It can be used in patients with eGFR
>30. Its major side effect is diarrhea. Extended release metformin may be tried in patients with diarrhea.
Pioglitazone-Low dose 15 mg daily-definitely cardioprotective (IRIS study) and insulin sensitizing; it does not cause weight gain or fluid accumulation at this low
dose. Higher doses of 30 and 45 mg may cause weight gain and edema. It reduces A1C by 1-1.5%.
Low dose sulfonylurea-Glimepiride 1 mg daily or less (0.5 mg). This agent’s action lasts 24 hours. It is less likely to cause hypoglycemia at these small doses. It
reduces A1C by 0.5 to 1%.
Acarbose 25 mg with each meal-possibly cardioprotective. It is an α-glucosidase inhibitor and thus slows the digestion of starchy foods and reduces the
magnitude of post prandial hyperglycemia. At larger doses, it may cause diarrhea. It reduces A1C by 0.5%.
Expensive:
DPP-IV inhibitors: Linagliptin, sitagliptin, saxagliptin, alogliptin. Very expensive, not cost effective. Confine use to the elderly or those with impaired renal function.
They do not cause hypoglycemia. No evidence of cardioprotection.
SGLT2 inhibitors: empagliflozin (Jardiance), dapagliflozin (Farxiga), canagliflozin (Invokana), ertugliflozin. This class is cardioprotective, especially in the context
of cardiac failure. They induce weight loss and a reduction in systolic blood pressure.

17. INJECTABLES:
Inexpensive:
Basal: Relion Novolin N
Prandial rapidly acting: Relion Novolin R
Expensive:
GLP-1RA: Liraglutide (Victoza), weekly exenatide (Bydureon), dulaglutide (Trulicity), semaglutide (Ozempic). This class has been shown to be cardioprotective
and nephroprotective.
Prandial Rapidly acting insulin analogs:
Humalog, Novolog, Admelog, Fiasp
Prandial fast acting insulins to be avoided altogether if possible in patients with type 2 diabetes since enough other drugs are available. Prandial
insulins lead to glycemic oscillations and hypoglycemia.
Basal insulin analogs:
Glargine (Lantus, Basaglar), Detemir (Levemir), Degludec (Tresiba)
Male Hypgonadism in Type 2 Diabetes and Obesity
Apart from the direct glycemia lowering strategies, there is very important additional issue. We have discovered that 33% of male patients with type 2 diabetes and
25% patients with obesity without diabetes have hypogonadotropic hypogonadism. These observations have now been confirmed globally. These patients have
additional insulin resistance which reverses after testosterone treatment for 6 months. Testosterone treatment has other benefits: reduction in adiposity, buildup of
muscle and an increase in energy and hematocrit. Most recently, it has been shown to reverse prediabetes in hypogonadal obese. Therefore, we strongly
recommend the measurement of testosterone in all patients with type 2 diabetes and /or obesity, a clinical assessment and testosterone replacement if indicated.

18. OTHER ACTIONS OF SGLT2I
Reduction in BP
Increase in Hematocrit
Improvement in Heart Failure Outcomes
Improvement in Renal Function

19. HYPOGONADOTROPIC
HYPOGONADISM
OCCURS IN 33% MALE PATIENTS WITH T2DM
OCCURS IN 25% PATEINTS WITH OBESITY WITHOUT
DM
HYPOGONADISM IS ASSOCIATED WITH ADDITIONAL
35% INSULIN RESISTANCE
TESTOSTERONE REPLACEMENT RESULTS IN
INSULIN SENSITIZATION
TESTOSTERONE IMPROVES INSULIN SIGNALING
TESTOSTERONE REUSLTS IN LOSS OF ADIPOSITY
AND BUILD UP OF MUSCLE

20. CASE STUDY 1
60 year old male with family history of
diabetes
BMI 34
BP 150/100
LDLc 130

21. MANAGEMENT CASE 1
• Measure HbA1c
• Treat LDLc with a statin
• Treat BP with an ACE-I or ARB
• If HbA1c is >5.7% and <6.5% (prediabetes), treat with
metformin and pioglitazone
• Review in 3-6 months

22. CASE STUDY 2
52 year old female with history of 20 years of diabetes
Smoker for 35 years
Absent foot (PT and DP) pulses
HbA1c 9.5%
BP 160/105
LDLc 135
Current treatment: metformin, glipizide, basal insulin

23. MANAGEMENT-CASE 2
• Regular measurement of glucose, possibly CGM
• Introduce pioglitazone, and a GLP-1RA
• Titrate basal insulin to achieve FBS of 90-120 mg/dl
• Treat LDLc with a potent statin (rosuvastatin) to reduce
LDLc to <70 mg/dl
• Treat BP with ACEi/ARB, β blocker, calcium channel
blocker
• STOP SMOKING

24. CASE STUDY 3
• 50 year old obese male, diabetes for 15 years, erectile
dysfunction, tingling and numbness in toes, worse at
night, absent ankle reflexes. On treatment with metformin,
glyburide, basal and prandial insulin
• BP 145/100, LDLc 125 mg/dl
• HbA1c 11%

25. MANAGEMENT CASE 3
• Measure testosterone, LH and FSH in the morning (8 to 9
am)
• Assess BP to confirm hypertension
• Reduce LDLc with a statin
• Commence treatment with pioglitazone, acarbose and a
GLP-1RA
• Replace testosterone if hypogonadal-testosterone is an
insulin sensitizer and reduces adiposity

30. UKPDS: Median HbA1c Results
UKPDS Group. Lancet 1998;352:837-853.
1% A1c reduction = 14% reduction in MI

31. Stratton IM et al. BMJ 2000;321:405-411.
UKPDS: Benefits of 1% HbA1c Reduction on Risk of Complications
<0.000114%All-Cause Mortality
<0.000114%MI
0.02116%Heart Failure
<0.000119%Cataract Extraction
<0.000121%Any Diabetes-related Endpoint
<0.000121%Diabetes-related Death
<0.000137%Microvascular Endpoints
<0.000143%
Amputation or Death From
Peripheral Vascular Disease
0.03512%Stroke
P Value
Decrease in Risk
per 1% HbA1c
Reduction

33. United Kingdom Prospective Diabetes Study (UKPDS)
*Dietary advice given at 3 month intervals. FPG was targeted at best levels feasible in clinical practice. If FPG exceeded 270 mg/dL,
then patients were re-randomized to receive non-intensive metformin, chlorpropamide, glibenclamide, or insulin. If FPG exceeded
270 mg/dL again, then those on SU would have metformin added. If FPG exceeded 270 mg/dL after this, then insulin was substituted.
UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352:854-865.
Traditional Therapies Do Not Maintain
A1c Control Over Time
Conventional*
Insulin
Glibenclamide (glyburide)
Metformin
MedianA1c(%)
0
6
7
8
10
Time From Randomization (Years)
0 3 6
9
9 12 15
ADA goal

34. *Dashed line shows extrapolation backward from year 0 and forward from year 6 from diagnosis based on Homeostasis Model
Assessment (HOMA) data from UKPDS. † IGT=impaired glucose tolerance. ‡ The data points for the time of diagnosis (0) and the
subsequent 6 years are taken from the obese subset of the UKPDS population and were determined by the HOMA model.
Adapted with permission from Lebovitz HE. Diabetes Rev. 1999;7:139-153. Copyright® 1999 American Diabetes Association.
Can The Decline Be Altered?
UKPDS: -Cell Decline Over Time
Patients Treated with
Metformin and/or
Sulfonylureas (SUs)‡
-CellFunction(%)*
Postprandial
Hyperglycemia
IGT†
Type 2 Diabetes
Years From Diagnosis
25 –
100 –
75 –
0 –
50 –
l
-12
l
-10
l
-6
l
-2
l
0
l
2
l
6
l
10
l
14

35. Stratton IM et al. BMJ. 2000;321:405–412.
Improved Glycemic Control Has Been
Shown to Help Reduce the Risk of
Complications
According to the United Kingdom Prospective Diabetes
Study (UKPDS) 35, every 1% decrease in A1C resulted in:
Decrease
in risk of any
diabetes-related
endpoint
(P<0.0001)
21%
Decrease
in risk of
microvascular
complications
(P<0.0001)
37%

36. Sustained Intensive Glycemic Control Can
Reduce Diabetes-Related Complications
• Long-term intensive glycemic control is associated with a significantly
decreased risk of MI or death from any cause, in addition to known risk
reductions in microvascular disease
Any diabetes-related
endpoint
(P = 0.04 for SU-insulin;
P = 0.01 for MET)
Microvascular
disease
(P = 0.001 for SU-insulin;
P = 0.31 for MET)
Myocardial
infarction
(P = 0.01 for SU-insulin;
P = 0.005 for MET)
Death from
any cause
(P = 0.007 for SU-insulin;
P = 0.002 for MET)
SU-
insulin
MET
SU-
insulin
MET
SU-
insulin
MET
SU-
insulin
MET
-21%
-24%
-15%
-13%
-16%
-33%
-27%
Risk Reductions for Intensive-Therapy Regimens at 10-Year Follow-up
-9%
Holman et al. N Engl J Med. 2008;359(15):1577–1589.

37. Steno-2: Effect of long-term
intensive multifactorial
treatment on mortality

38. Analysis of the data: Patients at DECWNY
Mean HbA1c at last visit : 6.8+1.17%
Mean LDL-cholesterol 76.9mg/dl
Mean systolic BP 125+14 mm
Mean diastolic BP 75.7+ mm
No Diabetic Foot Ulcer, Gangrene OR Amputation: 22
Years
No ESRD OR Dialysis: 18 Years

47. Cardiovascular Outcomes
Metformin-UKPDS-19%
Pioglitazone-IRIS, PROATCIVE-24%
Acarbose-STOP-NIDDM-49%

51. Incretin Effect*
*
*
*
*
*
*

52. Classical Actions of
GLP-1RA
Stimulation of insulin secretion
Inhibition of glucagon secretion
Suppression of appetite
Weight loss
Slowing of gastric emptying
No hypoglycemia

53. Novel Actions of GLP-
1RA
Lower systolic blood pressure
Exert anti-inflammatory and anti-oxidant
effects
Increase IL-1RA-protects β cell
Anti-ketotic and anti-lipolytic effects
Suppress ghrelin

54. Euglycemia
Euglycemia
Healthy Subjects (n = 14)
 Beta-Cell
Workload
 Beta-Cell
Response
 Beta-Cell
Workload
Hyperglycemia
Type 2 Diabetes (n = 12)
 Beta-Cell
Workload
 Beta-Cell
Response
 Beta-Cell
Workload
Mean (SE)
The Pathogenesis of Type 2 Diabetes
Beta-Cell Workload Outpaces Beta-Cell Response
Carbohydrate Meal

57. 1) DF
Pre-
Victoza
HBA1C =
7.4
On Victoza
Post
Victoza