1. John Hopkins Modules - Diabetes
N. Regmi

2. Diagnosis of Diabetes Options for evaluation a) Fasting glucose
no calorie for > 8 hrs
Ease of use, Low cost, Acceptable to patients
b) Random plasma glucose
Useful when symptoms suggestive of hyperglycemia (polyuria, polydipsia)
c) Glycosylated Hb
represents the pathologic process of persistent hyperglycemia that is associated with the microvascular complications of diabetes (i.e., protein glycosylation). 
Levels correlate more with retinopathy than FPG

3. Diagnostic criteria for Diabetes

4. Prediabetes – Individual at increased risk
Note that patients with normal glucose (or even normal A1C) are not free from risk of developing diabetes. A cohortof young men followed for an average of almost 6 years showed that those with the risk of developing diabetes increased with increasing glucose, even for those with a normal glucose.

5. Diabetes Variants
Most common – 90% - Type II diabetes – insulin resistance with hyperinsulinemia.
Even though, insulin are elevated – inadequate relative to hyperglycemia --- relative insulin deficiency
Type I diabetes – 5-7% with diabetes
characterized by islet cell failure, insulinopenia, and ketosis, and is due to autoimmune destruction of beta cells.
The peak age of incidence - is the early-teens but can occur at older ages
Require Insulin to remain healthy
Secondary Diabetes –
corticosteroids, Cushing syndrome, hemochromatosis, acromegaly, pheochromocytoma, glucagonoma, Chronic pancreatitis
(about 33% of Americans with type 2 diabetes are currently taking insulin to control hyperglycemia).  

6. MODY Mature Onset Diabetes of Young
 syndrome in which a relatively young individual presents with hyperglycemia, but is relatively unlikely to develop ketosis
individual is young, presenting at an age in which type 1 diabetes is predominant, but with clinical characteristics of type 2 diabetes
autosomal dominant disorder --- the most common monogenic syndrome associated with diabetes (defect is on the short arm of chromosome 7 in the glucokinase gene).

7. LADA Latent Autoimmune Diabetes of Adults
autoimmune destruction of beta cells (as seen in type 1 diabetes), but presenting at a later age (i.e., age > 25)
anti-islet antibodies (anti-GAD 65 antibodies) will be present, C-peptide levels will be low, and insulin resistance is not seen

8. Screening for Diabetes
Screening asymtomatic – no decrease in mortality,
Since there is no evidence of the impact of screening for diabetes, there is no evidence as to which test is best to use for screening. According to the ADA, the fasting plasma glucose, hemoglobin A1C or oral glucose tolerance test are acceptable to use for screening. 

9. Screening for DM associated Morbidity

10. Screening for DM associated Morbidity
The ADA recommends low-dose aspirin for the primary prevention of coronary artery disease in patients with type 2 diabetes who have increased cardiovascular risk (i.e., 10-year risk of MI of >10%, which includes most  patients with diabetes 50 or older who have at least one additional major cardiovascular risk). 

11. Prevention of Diabetes – Risk Factors
Most imp risk factor- Obesity
Increased risk with increasing BMI even in the normal range
Other RF - lack of exercise, regardless of BMI, and cigarette smoking.
A diet rich in fiber and polyunsaturated fat that is low in saturated fats and concentrated sweets is associated with a reduced risk of developing diabetes, as is moderate alcohol intake.

12. Lifestyle modification
losing an average of 4.2kg and exercising reduced the risk of developing diabetes by 58%.
Those that lost weight but did not exercise, and those that exercised but did not lose weight, also had significant reductions in the development of diabetes.

13. Pharmacotherapy for prevention
Metformin decreases the incidence of diabetes by 31%.
Lifestyle intervention is nearly twice as effective, reducing the incidence of diabetes by 58%. 

14. ADA recommendations for Prevention
Patients at increased risk of developing diabetes should have goal weight loss of 5-10% and increase physical activity to 150 minutes a week
Metformin may be considered in those under age 60 with an increased risk of diabetes who are obese and have at least one other risk factor for developing diabetes (e.g., family history, low HDL-C, others).
The ADA does not recommend use of drugs other than metformin to prevent diabetes, due to expense, risk of side effects, and lack of long term efficacy

15. Dietary recommendations for Diabetics
Individuals with diabetes should limit alcohol intake to 2 drinks/day (men) or 1 drink/day (women). Alcohol does increase the risk of delayed hypoglycemia, especially in those taking insulin or insulin secretagogues. 
The ADA recommends at least 150 minutes of moderate-intensity cardiovascular exercise weekly, spread over 3 days/week, with no more than 2 consecutive days without exercise. Resistance training twice weekly should also be encouraged. 
Unfortunately, there is some evidence that lifestyle changes (i.e., weight loss and exercise) do not reduce cardiovascular outcomes in patients with diabetes. 

16. Non Insulin pharmacotherapy
Metformin
Cornerstone of therapy
Less wt gain, low risk of hypoglycemia
Demonstrated efficacy in reducing complications
Adr- lactic acidosis esp in renal failure, hepatic failure and CHF
Contraindicated if GFR < 30ml/min
decreases hepatic glucose output by reducing hepatic gluconeogenesis and glycogenolysis, as well as enhancing peripheral glucose uptake and enhancing insulin sensitivity
Metformin also has a modest effect on decreasing glucose absorption in the GI tract (hence the common GI side effects), and reduces hemoglobin A1C levels by 1.5%. 

17. Insulin secretagogues: Sulfonylureas and glitinides
Stimulate beta cells to produce insulins
Sulfonylureas
Reduce HbA1c by 1.5%, decrease microvascular complications
Glinitides
Less potent than sulfonylureas
shorter half-life -- dosed with meals and serve a role in those with irregular eating patterns
Repaglinide + Gemfibrozil = hypoglycemia - contraindicated

18. GLP-1 agonist
Injectibles - Decrease glucose with low risk of hypoglycemia
Evidence that  liraglutide reduces cardiovascular mortality when added to standard of care
Adr
Nausea and Vomiting, avoid in gastroparesis,
increased risk of pancreatitis
theoretical risk of Medullary carcinoma of thyroid, avoid in MEN 2

19. DPP-4 Inhibitos
Dipeptidyl peptidase 4 (DPP-4) -enzyme that degrades incretin
Should not be used in combination with GLP-1 agonist
No weight gain
Few side effects - pancreatitis

20. Thiazolidinediones and alpha-glucosidase inhiitos
sensitize muscle, fat and liver cells to the effects of insulin
 reductions in fasting plasma glucose levels and hemoglobin A1C, and have a low risk of hypoglycemia
ADR- CHF and fluid retention esp when used with insulin
Acarbose
intra-intestinal polysaccharidase activity, preventing breakdown of carbohydrates 
Limited role in management of DM
Adr – GI effects

21. SGLT inhibitos
locking glucose reabsorption in the kidney, essentially causing glycosuria
genital fungal infections and dehydration are possible side effects
should not be used in chronic kidney disease (i.e., GFR < 60ml/min/m2

22. Insulins Insulin Very effective to reduce microvascular complications
no scientific evidence that newer formulations improve outcomes relative to older, less-expensive insulins (e.g., NPH insulin)
treatment of choice for women who are, or who may become pregnant
monotherapy with insulin --becomes less effective over time, but there is no ceiling in insulin use

24. Does "tight" glycemic control reduce microvascular or macrovascular complications?

25. 50% reduction of new-onset retinopathy (primary prevention)
DCCT trial
compared those treated with usual care (usually with one or two insulin injections daily) to those treated with intensive therapy (frequent monitoring and adjustment of insulin dosing, which was administered three to four times daily)
 Compared to the usual care group, those getting intensive control experienced the following:
50% reduction of new-onset retinopathy (primary prevention)
54% reduction in progression of established retinopathy (secondary prevention)
34% reduction of new-onset microalbuminuria (primary prevention)
43% reduction of progression of established microalbuminuria (secondary prevention)
69% reduction of new-onset neuropathy (primary prevention)
57% reduction of progression of established neuropathy (secondary prevention)
- Impact on macrovascular unknown

26. What level of tight glycemic control is best – ADA guidelines
A reasonable A1C goal for many non-pregnant adults is <7%.
Providers might reasonably suggest more stringent A1C goals (such as <6.5%) for selected individual patients if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Appropriate patients might include those with short duration of diabetes, type 2 diabetes treated with lifestyle of metformin only, long life expectancy, or no significant cardiovascular disease.
Less stringent A1C goals (such as <8%) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, or long-standing diabetes in whom the general goal is difficult to maintain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin.

28. Management of Diabetes
Metformin based approach vs Insulin based approach
Choosing based on the clinical presentation (i.e., the severity of hyperglycemia), patient preferences, resources, and goals of therapy
In all patients, the first step in glycemic control is to control the morning fasting glucose.
Both approaches include continued improvement of lifestyle (i.e., diet and exercise)

29. Hyperglycemia and initial pharmacotherapy

30. Monotherapy Metformin – should be the 1st choice Dosing
Start with metformin 500mg once or twice) daily, or 850mg once daily
After 5-7 days, if GI side effects absent, double dose
Maximal dose is either 850mg twice daily or 1000mg twice daily for most individuals
If GI side effects occur, lower dose to previous tolerated dose 
Once metformin dose is at the maximally-tolerated dose, check the A1C every three months, and continue without change if the A1C is at goal.

31. Dual therapy Metformin plus oral agent or metformin plus basal insulin
Metformin- not tolerated/contraindicated, then dual therapy will be with two oral agents from different classes, or an oral agent plus basal insulin
Avoid GLP-1 agonist and DPP-4 inhibitor

33. When choosing the 2nd or 3rd drug for dual therapy and triple therapy

35. Insulin based therapy

37. Thank You