III. Therapeutics of Type 2 Diabetes Mellitus Flashcards
The risk of heart disease and stroke is commonly stated to be ___ times higher for people with diabetes than for those without diabetes.
2-4 times
Lower-extremity amputation is approximately ___ times higher for people with diabetes than for those without diabetes.
20 times
Life expectancy is reduced by approximately ___ years in people with diabetes.
10 years
The hazard ratio for death is most pronounced in those having diabetes under ___ years.
55 years
Convert mmol/L to mg/dL by ___
Multiply by 18
Fasting plasma glucose in mg/L that is diagnostic for prediabetes and diabetes (no calorie intake at least 8 hours)
100-125
>=126
2-hour plasma glucose in mg/L that is diagnostic for prediabetes and diabetes (after 75g oral glucose)
140-199
>=200
Random plasma glucose in mg/L that is diagnostic for diabetes (with classic symptoms)
> =200
(not applicable for prediabetes)
HbA1c that is diagnostic for prediabetes and diabetes
5.7-6.4%
>=6.5%
TRUE or FALSE: Diagnosis of diabetes should be confirmed by repeat testing.
TRUE, in the absence of unequivocal hyperglycemia
A confirmatory test by the same or a different method is usually required to confirm the diagnosis.
The primary endpoint used to evaluate the relationship between glucose levels and complications
Retinopathy
Not recommended for routine use in diagnosing diabetes
a. Fasting plasma glucose
b. 2-hour plasma glucose (OGTT)
c. Random plasma glucose
d. HbA1c
B
People with undiagnosed T2DM have approximately ___fold greater risk for coronary heart disease, stroke, and peripheral vascular disease.
Twofold
Who among the following should be tested for diabetes (ADA 2018)? (all that applies)
a. 44/M, Asian, BMI 22, with active lifestyle
b. 32/F, Asian, BMI 24, active lifestyle
c. 24/F, Asian, BMI 22, with PCOS
d. 50/M, Caucasian, BMI 19, with no comorbidity
e. 28/F, Asian, BMI 18, with history of GDM lost to follow-up
A, B, D, and E
4 Populations that should be tested for prediabetes
- Overweight or obese (BMI >=25 or >=23 in Asians) + 1 or more risk factor
- Patients with prediabetes (yearly)
- Patients with prior GDM (at least every 3 years)
- All others - begin at age 45 (begin at age 35 based on ADA 2022)
Risk factors that, if present in an overweight/obese person, should prompt testing for prediabetes
General profile:
1. High-risk ethnicity (e.g., African, Latino, Native American, Asian, Pacific Islander)
Past Medical History:
1. History of cardiovascular disease
2. Hypertension (BP >=140/90 or using BP-lowering therapy)
3. PCOS
Personal/Social History:
1. Physical inactivity
Family History:
1. First-degree relatives with diabetes
Objective:
1. Severe obesity
2. Acanthosis nigricans
3. HDL <35 mg/dL and/or triglycerides >250 mg/dL
*Other conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans)
Level of HDL and triglycerides considered a risk factor for prediabetes in asymptomatic adults
HDL <35 mg/dL and/or triglycerides >250 mg/dL
Frequency of testing for asymptomatic adults with prediabetes
Yearly
Frequency of testing for asymptomatic adults with history of gestational diabetes
At least every 3 years
Age at which to start testing for prediabetes in asymptomatic adults (if without other risk factor)
45 years old (35 based on ADA)
If initial results for testing for prediabetes are normal, when to repeat?
At least every 3 years
What is the United Kingdom Prospective Diabetes Study (UKPDS)?
Prospective, randomized trial that documented reduced rates of microvascular complications in T2DM patients treated to lower glycemic targets and with pharmacotherapy compared to lifestyle alone
Treatment effect of sulfonylurea or insulin in the UKPDS (% relative risk reduction and if significant) at end of randomized treatment
a. Any diabetes-related endpoint
b. Microvascular disease
c. Myocardial infarction
d. All-cause mortality
a. Any diabetes-related endpoint - 12% (significant)
b. Microvascular disease - 25% (significant)
c. Myocardial infarction - 16% (NS)
d. All-cause mortality - 6% (NS)
Treatment effect of sulfonylurea or insulin in the UKPDS (% relative risk reduction and if significant) after 10 years of further observation
a. Any diabetes-related endpoint
b. Microvascular disease
c. Myocardial infarction
d. All-cause mortality
a. Any diabetes-related endpoint - 9% (significant)
b. Microvascular disease - 24% (significant)
c. Myocardial infarction - 15% (significant)
d. All-cause mortality - 13% (significant)
Treatment effect of metformin in the UKPDS (% relative risk reduction and if significant) at end of randomized treatment
a. Any diabetes-related endpoint
b. Microvascular disease
c. Myocardial infarction
d. All-cause mortality
a. Any diabetes-related endpoint - 32% (significant)
b. Microvascular disease - 29% (NS)
c. Myocardial infarction - 39% (significant)
d. All-cause mortality - 36% (significant)
Treatment effect of metformin the UKPDS (% relative risk reduction and if significant) after 10 years of further observation
a. Any diabetes-related endpoint
b. Microvascular disease
c. Myocardial infarction
d. All-cause mortality
a. Any diabetes-related endpoint - 21% (significant)
b. Microvascular disease - 16% (NS)
c. Myocardial infarction - 33% (significant)
d. All-cause mortality - 27% (significant)
This “effect” is believed to be responsible for the persistence of the relative benefits of more intensive management of glucose after 10 more years of observation in the UKPDS (even though the difference in glycemic control was not maintained)
“Legacy effect” of initially good glycemic control, likely based on persisting changes of tissue structure in blood vessels and elsewhere
Kumamoto study results
Japanese patients with T2DM with normal weight randomized into standard or intensive treatment with insulin –> Lower HbA1c with modestly increased risk of hypoglycemia and weight gain, reduction in microvascular complications, and a (not statistically significant) trend toward reduced rates of cardiovascular events
TRUE or FALSE: The Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease - Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and the Veterans Affairs Diabetes Trial (VADT) - which randomized middle-aged and older individuals into standard and intensive treatment - all demonstrated significant benefit in combined cardiovascular endpoints.
FALSE
None of the trials demonstrated significant benefit in combined cardiovascular endpoints.
The ACCORD study showed that a __% increase in total mortality accompanied intensive therapy.
22%
ADA target preprandial plasma glucose
80-130 mg/dL
ADA target peak postprandial plasma glucose
<180 mg/dL (1 to 2 hours after any meal)
ADA target mean plasma glucose
<154 mg/dL
ADA target HbA1c
<7%
ADA - may pursue lower target HbA1c in ___
Those with recent-onset disease, long life expectancy, and no significant cardiovascular disease, if they can be achieved without significant hypoglycemia or other adverse effects of treatment
ADA - may pursue less stringent HbA1c at 7-8% in ___
Those at high risk, including a history of severe hypoglycemia, limited life expectancy, advanced complications, or extensive comorbid conditions, as well as inability to achieve HbA1c less than 7% despite the usual initial therapeutic efforts
ACE target fasting glucose
<110 mg/dL
ACE target 2-hour postprandial glucose
<140 mg/dL
ACE target HbA1c
<6.5%
Frequency of HbA1c monitoring
When treatment is started or intensified, measurement at approximately 3-month intervals will reveal the success of the intervention.
When treatment is established and glycemic control appears stable, testing one or two times a year is usually sufficient.
Term used to refer to the mismatch between glucose and HbA1c levels
Glycation cap
Increased red cell turnover such as in occult blood loss or iron treatment of iron deficiency anemia could lead to a ___ HbA1c
Lower
Low red cell turnover such as in untreated iron deficiency anemia could lead to a ___ HbA1c
Higher
Use of self-monitoring of blood glucose is particularly recommended for patients with T2DM who are taking ___
Insulin or sulfonylureas
TRUE or FALSE: One basic principle is that patients should test blood glucose at the same time each day.
FALSE
One basic principle is that patients should periodically vary the time of day at which glucose is tested.
Finding of the Structured Testing Program (STeP) trial
Use of 7-point daily glucose testing for 3 days each quarter increased the frequency of treatment adjustments and improved HbA1c levels
Criteria for ADA Level 1 Hypoglycemia (Alert value)
Blood glucose <70 mg/dL and >=54 mg/dL
Triggers physiologic responses of the so-called counterregulatory hormones
Criteria for ADA Level 2 Hypoglycemia (Clinically significant)
Blood glucose <=54 mg/dL
Can cause blunting of compensatory hormone responses and loss of warning symptoms (“hypoglycemia unawareness”)
Criteria for ADA Level 3 Hypoglycemia (Severe)
Altered mental and/or physical status requiring assistance
Strongly associated with risk of physical injury, cardiovascular events, and death
Diabetes self-management education and support (DSMES) is recommended to be emphasized at these 4 critical settings in the evolution of T2DM
- At diagnosis
- Annual assessment
- When complicating factors arise
- When critical transitions in medical care occur or life circumstances
Recent guidelines recommend ___ MNT sessions in the first 6 months after diagnosis
3-6
Medical nutrition therapy has been shown to decrease HbA1c by __ to __%.
0.3% to 2%
Achieving a __% weight loss more consistently yields significant metabolic benefits than lower levels of weight loss, and benefits obese and overweight prediabetic and diabetic patients.
5%
In general, the critical nutrient for glycemic consistency
Carbohydrate
TRUE or FALSE: Whereas the beta cell in T2DM has usually lost its immediate response to glucose, the second phase of insulin secretion is largely spared in T2DM and is in part driven by amino acids and fatty acids.
TRUE
TRUE or FALSE: There is no single ideal dietary distribution of calories among macronutrients.
TRUE
What is the glycemic index?
The glycemic index refers to the glucose response to equal amounts of carbohydrates in various foods.
Nutrient that is most closely associated in epidemiologic studies with the risk of developing T2DM
Fat (but has little effect on glycemia)
Critical nutrient for cardiovascular risk management
Fat
TRUE or FALSE: Dietary protein has little impact on glucose levels.
TRUE
TRUE or FALSE: Metabolism of protein results in the formation of acids and nitrogenous waste, which can lead to bone demineralization and glomerular hyperfiltration.
TRUE
At least ___g of high-quality dietary protein per kilogram of body weight is generally recommended.
0.8g
Recent guidelines do not support the notion that dietary protein need to be reduced in those with CKD.
No evidence for a distinction between the effects of vegetable-based versus animal-based protein sources in kidney function.
Restriction of protein intake to __ to __% of total calories minimizes potential adverse long-term effects of high protein intake.
10 to 20%
Carbohydrate sources high in ___ should be avoided when trying to treat or prevent hypoglycemia.
Proteins
Ingested protein appears to increase insulin response without increasing plasma glucose concentrations.
Eating foods rich in ___, such as fatty fish (EPA and DHA) and nuts and seeds (ALA), is recommended to prevent or treat CVD.
Long-chain n-3 fatty acids
(However, evidence does not support a beneficial role for routine use of n-3 dietary supplements.)
Eating foods rich in long-chain n-3 fatty acids, such as fatty fish (EPA and DHA) and nuts and seeds (ALA), is recommended to prevent or treat ___.
CVD
TRUE or FALSE: Micronutrients and herbal supplements have proven benefit and are generally recommended in T2DM patients.
FALSE
There may be some benefit on HbA1c and lipid profiles for those ingesting at least __g of fiber per 1000kcal compared to lower fiber diets.
15g
TRUE or FALSE: Alcohol in moderation (up to 1 drink per day for adult women or 2 drinks per day in adult men) is not specifically recommended.
TRUE
..but is considered acceptable.
Risk of excessive intake of alcohol by people with T2DM, especially those who use sulfonylureas or insulin
Delayed hypoglycemia, which typically occurs at night when ability to recognize hypoglycemia is impaired
TRUE or FALSE: Moderate red wine intake may result in mild improvement in some lipid parameters but seems to have little effect on glucose control.
TRUE
TRUE or FALSE: Nonnutritive sweeteners do not appear to impact lipid parameters, insulin secretion, or blood pressure independent of weight loss, and are deemed safe in any amount.
FALSE
Deemed safe for use in T2DM if consumed within the FDA recommended daily intake amounts
Recommended sodium restriction in patients with diabetes
Less than 2300 mg per day (as with the general population, but those with hypertension may have additional benefit from lower sodium diets)
TRUE or FALSE: Ketogenic diets or low carbohydrate diets have evidence of long-term benefit in patients with diabetes.
FALSE
Limited long-term evidence of benefit or risk at the present time.
3 most validated meal plans in T2DM
- Mediterranean diet
- Dietary Approaches to Stop Hypertension (DASH)
- Plant-based diets
Meal plan that has the best experiment support for glycemic control, cardiovascular protection, and perhaps other outcomes
Mediterranean diet (emphasizing the use of monounsaturated and polyunsaturated fats)
Self-directed structured exercise programs have been associated with mean HbA1c reductions of __ to __%.
0.4 to 0.9%
After exercise, improvements in glycemic control are usually apparent immediately, but the improvement in insulin resistance may not last more than __ to __ hours.
48 to 72 hours
Recommended duration of physical activity
150 minutes of moderate-intensity physical activity (50-70% of maximum heart rate) or 75 minutes of vigorous exercise (>70% of maximum heart rate) on at least 3 days per week, with no more than 2 consecutive days without exercise
*Max heart rate = 220 - age
Recommended type of physical activity
Both aerobic and resistance exercise are effective and recommended.
Major role for the physician in terms of physical activity of patients with T2DM
The major role for the physician is to screen for complications (neuropathy, nephropathy, retinopathy, vascular disease) and discover ways for patients to be able to exercise safely.
For the average patients with T2DM starting an exercise program it is best to start with ___-level activity such as ___ at a pace of ___.
Low-level
Walking
2 miles per hour
TRUE or FALSE: Exercise can increase albuminuria acutely.
TRUE
Exercise does not appear to accelerate kidney disease but will increase albuminuria acutely and could cause false-positive albumin:creatinine ratios temporarily.
Recommended frequency of activity break in all individuals
At least every 30 minutes, to include brief walks, resistance exercise, or at least standing
Recommended frequency for screening for diabetes distress
At least once yearly, as depression is present in about 25% of screened patients
Mechanism of effect on glucose of biguanide
Decrease hepatic glucose production
Mechanism of effect on glucose of secretagogue
Increase insulin secretion
Mechanism of effect on glucose of thiazolidinedione
Decrease insulin resistance
Mechanism of effect on glucose of DPP4 inhibitor
Increase insulin, decrease glucagon
Mechanism of effect on glucose of alpha-glucosidase inhibitor
Delay carbohydrate absorption
Mechanism of effect on glucose of SGLT inhibitor
Increase renal clearance of glucose, sodium
Mechanism of effect on glucose of bile acid sequestrant
Delay carbohydrate absorption?
Mechanism of effect on glucose of dopamine agonist
Decrease insulin resistance
Mechanism of effect on glucose of insulin
Increase insulin availability
Mechanism of effect on glucose of GLP1 receptor agonist
Increase insulin, decrease glucagon, slow gastric emptying
Mechanism of effect on glucose of amylin receptor agonist
Decrease glucagon, slow gastric emptying
Which classes of agents have +++ basal glucose control?
Insulin
Secretagogue
Biguanide
Thiazolidinedione
GLP1 receptor agonist
Which classes of agents have +++ prandial glucose control?
Insulin
GLP1 receptor agonist
Alpha-glucosidase inhibitor
Amylin receptor agonist
Which classes of agents have +++ weight control?
SGLT inhibitor
GLP1 receptor agonist
Amylin receptor agonist
Which classes of agents cause weight increase?
Insulin
Secretagogue
Thiazolidinedione
Which classes of agents have no effect on weight?
DPP4 inhibitor
Bile-acid sequestrant
Which classes of agents have ++ BP control?
SGLT inhibitor
GLP1 receptor agonist
Which classes of agents have +++ short-term CV reduction?
SGLT inhibitor
*Table 35.10 Classes of antihyperglycemic agents for type 2 diabetes. Page 1385
*
Most common adverse events of biguanides
Gastrointestinal: nausea, abdominal pain or bloating, and diarrhea
Advantage of using sustained-release metformin
Less frequent and less severe upper GI symptoms, but can increase the frequency of diarrhea, which is overall less common
TRUE or FALSE: Lactic acidosis from metformin is common.
FALSE
Metformin has been said to cause lactic acidosis, which is quite rate and occurs almost exclusively in patients who are at high risk for development of the condition independent of metformin therapy.
Route of metabolism and clearance of metformin
Metformin is not metabolized and is cleared only through the kidney.
Recommended eGFR monitoring if metformin is to be given
Obtain an eGFR before starting metformin and at least annually thereafter
Treatment decisions regarding metformin if eGFR is below 45 mL/min/1.73m2
Initiation is not recommended;
If treatment is established, consider dose reduction
Treatment decisions regarding metformin if eGFR is below 30 mL/min/1.73m2
Initiation is contraindicated;
If treatment is established, metformin should be stopped
Contraindications for metformin use
Hepatic insufficiency
Alcohol abuse
eGFR <30 mL/min/1.73m2
Vitamin supplementation for patients using metformin
Supplementation with vitamin B 12(e.g., 1000 mcg daily) or intermittent monitoring may sometimes be prudent.
Maximal daily dose of metformin
2550 mg
But does not generally provide additional benefit beyond that seen at 2000 mg daily
Drug class that arguably has the best record among oral antihyperglycemic agents in medical outcome studies
Metformin
Drug that is generally recommended to be started in all patients with T2DM at or near the time of diagnosis of diabetes, provided no contraindications are present
Metformin
Currently available secretagogues all bind to the ___ receptor
SUR1, subunit of K ATP potassium channel on the plasma membrane of pancreatic beta cells
TRUE or FALSE: The effect of secretagogues on insulin secretion wane on subsequent doses.
TRUE
A direct effect on insulin secretion, independent of ambient glucose levels, is seen with the first dose of any secretagogue. However, this direct effect wanes during continued occupancy of SUR1, while potentiation of the effect of current glucose levels continues.
Classes of secretagogues
Sulfonylureas
Non-sulfonylureas: Meglitinides, Nateglinides
Differentiate the secretagogues in terms of risk of hypoglycemia, effect on postprandial glucose, and effect on fasting glucose
Long-acting Sulfonylureas (glipizide-ER, glimepiride, gliclazide-MR) - Lower fasting glucose levels with little effect on postprandial glucose levels, and relatively low risk of hypoglycemia compared with other secretagogues
Shorter-acting Sulfonylureas (glipizide, glyburide, gliclazide) - As effective as longer-acting agents in overall glucose control, but have greater effect on postprandial hyperglycemia and can cause daytime hypoglycemia when food intake is reduced
Meglitinides (repaglinide) - Have faster and briefer stimulus to insulin secretion than short-acting sulfonylureas, hence better postprandial control and generally less hypoglycemia, but has long residence time on SUR1 and therefore some effect on fasting glucose
Nateglinide - Quicker onset and shorter duration of action than repaglinide, hence, its effect in lowering postprandial glucose is quite specific, and has little effect on fasting glucose, and less overnight hypoglycemia. Disadvantage is less overall glucose-lowering effectiveness
Long-acting sulfonylurea that is cleared only by the kidney and thus can cause severe hypoglycemia when renal function becomes impaired
Chlorpropamide
None of the other agents is strongly dependent on renal excretion
Short-acting sulfonylurea that has an active metabolite that can be cleared only by the kidney
Glyburide (hence associated with greater risk of hypoglycemia than other currently used sulfonylureas)
Reason for the concern that sulfonylureas might cause increased arrhythmic cardiovascular events in patients with diabetes
They have an effect on SUR2 subunits of the K ATP complex in vascular and cardiac cells. Binding to SUR2 can blunt ischemic preconditioning, a normal cardioprotective mechanism.
TRUE or FALSE: The ADVANCE trial did not show any evidence of cardiovascular toxicity with sulfonylureas.
What drug was used as its dominant glucose-lowering strategy?
TRUE
Extended-release gliclazide (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation)
TRUE or FALSE: The UKPDS demonstrated long-term safety relative to lifestyle intervention for glyburide, glipizide, and chlorpropamide. (with emphasis on cardiovascular toxicity)
TRUE
The adverse effect of increased arrhythmic cardiovascular events has been confirmed with these sulfonylureas
Tolbutamide and glyburide (especially relevant to glyburide)
The maximum approved dose for the sulfonylureas is __ to __ times higher than the maximum effective dose.
Two to four times
Initiating treatment with no more than a ____ of the maximal approved dose provides significant glucose lowering while limiting costs and adverse events.
Quarter
Small doses of the longer-acting modern sulfonylureas (e.g., 0.5-1 mg of glimepiride or 2.5 mg of extended-release glipizide) are often effective, particularly in patients receiving metformin concomitantly, and are almost always well tolerated.
Leading disadvantages of sulfonylureas
Tendency to cause hypoglycemia and usually modest weight gain
Maximum dose of repaglinide
4 mg with each meal
Rationale of using non-sulfonylureas, and probable reason why they are still only modestly used
They stimulate insulin secretion at mealtime to improve postprandial control without increasing the risk of overnight hypoglycemia. They also demonstrate little binding to the vascular smooth muscle and cardiac SUR2 receptors.
However, there is need for multiple daily doses, higher cost than sulfonylureas, and lack of head-to-head comparative studies that demonstrate superiority over the newer sulfonylureas.
Mechanism of thiazolidinediones (pioglitazone and rosiglitazone)
Bind to and modulate the activity of a family of nuclear transcription factors termed peroxisome proliferator-activated receptors (PPARs). They are associated with slow improvement in glycemic control over weeks to months in parallel with an improvement in insulin sensitivity and a reduction in free fatty acid levels.
Recommended tests prior to beginning TZD therapy
Liver function tests
Consider assessment of risk factors and measurement of bone density before prescribing a TZD, especially for women
Contraindications for TZDs
Active hepatocellular disease
Unexplained serum ALT levels greater than 2.5 times the upper limit of normal
TRUE or FALSE: No substantial evidence has linked the newer TZDs to hepatotoxicity.
TRUE
(Nonetheless, recent studies show a favorable effect of pioglitazone on nonalcoholic steatohepatitis, a common an otherwise difficult to treat condition.)
Compare the effects of the TZDs to triglyceride, HDL, and LDL levels
Pioglitazone
- Reduced triglycerides by approx 20%
- Modestly greater improvement in HDL particle number and size
- Improvement in LDL particle size and number
Rosiglitazone
- Increased triglycerides on average by 5%
- Increase in LDL particle number and improved LDL particle size
What is the PROactive Study
PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) Study
Randomized, double-blind, placebo-controlled trial comparing placebo vs 45 mg pioglitazone
Primary endpoint: Time from randomization to macrovascular outcomes –> No significant improvement with pioglitazone
Secondary endpoint: Cardiovascular composite endpoint –> Marginally significant 16% reduction
What is the RECORD Trial
Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) Trial
Compared effect of adding rosiglitazone vs either metformin or SU to patients who had T2DM inadequately controlled with SU or metformin –> No difference in cardiovascular hospitalizations or death
What is ADOPT
A Diabetes Outcome Progression Trial
Found that patients with early diabetes had a slower rate of secondary glycemic failure when they were treated with rosiglitazone compared with metformin and glyburide
Adverse effects and concerns with use of TZDs (5)
Weight gain
Fluid retention
Increased risk of bone fractures
Anemia
Bladder cancer
Cause of weight gain during use of TZDs
The weight gain has been shown to result both from extracellular fluid accumulation and an increase in subcutaneous but not visceral fat.
Patients most likely to experience edema while using TZDs
Those using insulin and those with preexisting edema
Recommendation to patients using TZDs who develop 1) Weight accompanied by increasing edema, 2) Clinically apparent heart failure
1) Restrict sodium intake, start a diuretic, or to increase their diuretic dosage as needed
Many patients with mild edema respond to a thiazide diuretic or spironolactone, and combination therapy with a moderate-dose loop diuretic may be considered.
2) Discontinue TZD
Initial and highest approved dose of pioglitazone
Usually prudent to begin therapy with lowest available dose of 15mg daily. May increase to 30mg after 3 months if inadequate glycemic response and no significant edema. Highest approved dose of 45mg is less well tolerated.
Regarding bone fractures with TZD use - gender and age mainly affected, and sites primarily affected
Older women
Distal sites
Mechanism of increased bone fractures in TZDs
Preclinical studies suggest that activation of PPAR gamma inhibits bone formation by diverting stem cells from the osteogenic to the adipocytic lineage.
TRUE or FALSE: Pioglitazone has a confirmed association with bladder cancer.
FALSE
Large, long-term studies have not confirmed this association. However, current recommendations to avoid its use in patients with a history of bladder cancer seem prudent (due to inconsistent preclinical and clinical observations).
TRUE or FALSE: Oral glucose has a greater stimulatory effect on insulin secretion than does intravenous glucose at the same circulating glucose concentration.
TRUE
Cells that secrete GLP1
Intestinal L cells
Duration before secreted GLP is inactivated in plasma by enzyme dipeptidyl peptidase-4
Very rapidly (1-2 minutes)
DPP4 inhibitors increase fasting and postprandial levels of GLP1 about __fold.
Twofold
TRUE or FALSE: DPP4 inhibitors elevate GLP1 and potentiate glucose-dependent insulin secretion, suppresses basal and postprandial glucagon, improves satiety, and slows gastric emptying.
Elevation of GLP1 potentiates glucose-dependent insulin secretion and suppresses basal and postprandial glucagon. However, NEITHER satiety NOR the rate of gastric emptying is affected.
Main clinical effect of DPP4 inhibitors
Lower fasting glucose levels
Reduction of HbA1c with use of DPP4i
0.5 to 1%
Relatively weak glucose-lowering power that is partly dependent on retained beta-cell function
TRUE or FALSE: DPP4i have no consistent effect on weight and no tendency to cause hypoglycemia when used alone or with metformin.
TRUE
Contraindication for DPP4i use
Prior history of pancreatitis
DPP4i that has shown increased risk for heart failure hospitalizations in cardiovascular outcome trials.
Saxagliptin
DPP4i in current use are partially cleared by the kidney, the usual dose is the maximum marketed dose, and smaller doses are recommended in the setting of stage 3 or greater CKD, except ___.
Linagliptin
Mechanism of action of alpha-glucosidase inhibitors (acarbose, miglitol, voglibose)
Slow the terminal step of carbohydrate digestion at the brush border of the intestinal epithelium, hence carbohydrate absorption is shifted more distally in the intestine and is delayed, allowing the sluggish insulin secretory dynamics characteristic of T2DM to catch up with carbohydrate absorption
Regarding alpha-glucosidase inhibitors (acarbose, miglitol, voglibose) - timing of administration, common side effect, and intensity of blood glucose reduction
At beginning of each meal
Flatulence (also diarrhea, abdominal discomfort)
Modest reduction in blood glucose level
TRUE or FALSE: Some evidence suggest that acarbose improves cardiovascular outcomes better than most antihyperglycemic agents.
TRUE
Under normal conditions about ___g of glucose is filtered from plasma at the glomerulus and reabsorbed in the ___ tubule
180g
Proximal tubule
Differentiate SGLT2 and SGLT1 with regards to capacity, affinity, and percentage of renal tubular glucose reabsorbed
SGLT2 - high-capacity, low-affinity, responsible for 90%
SGLT1 - low-capacity, high-affinity, responsible for 10% (but critically important for glucose absorption from the gut)
TRUE or FALSE: SGLT2 inhibitors reduce both fasting and postprandial glucose levels and promote modest weight loss through loss of calories as glucosuria.
TRUE
TRUE or FALSE: SGLT2 inhibitors have no effect on blood pressure.
FALSE
They also reduce blood pressure, at least in part by increasing sodium clearance and reducing extracellular gluid volume.
TRUE or FALSE: All SGLT2i are relatively specific for inhibiting SGLT2.
TRUE
But others in development also have some effect on SGLT1
In 26-week studies, SGLT2i lead to approximately __ to __kg more weight loss than placebo.
2 to 3 kg
What is the EMPA-REG OUTCOME trial?
Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients - Removing Excess Glucose trial
Empagliflozin - 32% relative risk reduction of all-cause mortality, 38% reduction of CV mortality, and 35% reduction of hospitalization for heart failure
What is the CANVAS program?
CANagliflozin cardioVascular Assessment Study
Canagliflozin - generally similar effects as EMPA-REG, although quantitatively less prominent, cardiovascular and renal results
Most common side effects of SGLT2i
Urinary frequency, genital infections, and relatively rare episodes of lower UTIs as well as dehydration and its consequences
Regarding genital infections in SGLT2i use - gender more commonly affected, and type of microbe commonly related
10-15% of women (about a fivefold increase of risk)
Yeast
May recur
In males - genital mycotic infections are much less common and predominantly found in those who have not been circumcised
SGLT2i associated with increased lower extremity amputations in a cardiovascular outcome trial
Canagliflozin (CANVAS?)
TRUE or FALSE: Good renal function is not essential for full efficacy of SGLT2 inhibitors.
FALSE
Good renal function IS essential for full efficacy of SGLT2 inhibitors.
Initiation of SGLT2 is not recommended, or if already in use, should be discontinued when eGFR is below ___.
45 ml/min/1.73m2
The only SGLT2 with a warning against use in patients with bladder cancer.
Dapagliflozin
Possible mechanisms of euglycemic DKA in T2DM patients on SGLT2i
Tendency toward dehydration, elevation of circulating glucagon levels, and accelerated gluconeogenesis due to glucosuria during fasting
Second-generation bile acid sequestrant that has been observed to mediate modest reductions in glucose during the clinical development program
Colesevelam
HbA1c reduction with use of colesevelam
0.5% (on table: 0.5 to 1%)
Effects of colesevelam on lipid parameters
Approximately 15% improvement in LDL. HDL changes tent to be trivial. Triglycerides can increase by 5-20%. (Correlate with rosiglitazone)
Basis for use of bromocriptine in T2DM
It is suggested that creating a circadian peak in central dopaminergic tone improves insulin sensitivity
Timing of administration of quick-release formulation of bromocriptine for T2DM
Within 2 hours of rising in the morning
HbA1c reduction with use of bromocriptine
As high as 1.2% (on table - 0.5 to 1%)
TRUE or FALSE: In a 1-year safety study, bromocriptine has shown that broad cardiovascular outcomes were improved 40% compared with placebo.
TRUE
TRUE or FALSE: Based on Table 35.11, T1D and DKA are contraindications to all commonly used OHAs
TRUE
HbA1c reduction with use of metformin
1 to 2%
HbA1c reduction with use of secretagogues
1 to 2%
HbA1c reduction with use of TZDs
0.75 to 1.5%
Side effect of DPP4i
Hypersensitivity
Side effects of SGLT2i aside from urinary frequency and urogenital infections
Nausea, diarrhea, hypotension
HbA1c reduction with use of alpha-glucosidase inhibitors
0.5 to 1%
HbA1c reduction with use of SGLT2i
0.5 to 1%
OHAs with 1 to 2% HbA1c reduction as first or second therapy (2)
Metformin
Secretagogues
OHAs with 0.75 to 1.5% HbA1c reduction as first or second therapy (1)
Thiazolidinediones
OHAs with 0.5 to 1% HbA1c reduction as first or second therapy (5)
DPP4i
AGI
SGLT2i
Colesevelam
Bromocriptine
Side effects of bromocriptine
Somnolence, dizziness, hypotension
Most common adverse effect of bromocriptine, occurring in about 30% of patients and leading to discontinuation in about 10% at highest doses.
Nausea
Side effect of colesevelam
Constipation
Table 35.13 Clinical Features of Commonly Used Insulins, page 1392
*
Molecular basis of longer action of insulin detemir
Fatty acid side chain is covalently bound to the insulin molecule, resulting in slowing of both absorption from subcutaneous tissue and clearance from circulation
TRUE or FALSE: Detemir’s time of onset and duration of action are longer than that of NPH.
FALSE
Detemir’s time of onset and duration of action are quite similar to those of NPH, but more consistent from injection to injection.
Molecular basis of longer action of insulin glargine
Soluble at acid pH but precipitates when neutralized in tissues after injection
Cause for longer action of insulin degludec and insulin glargine 300
Insulin degludec - due both to slower absorption after injection and to delayed clearance
Insulin glargine 300 units/mL - results entirely from an effect on absorption
TRUE or FALSE: Regular human insulin administered intravenously is immediately effective, with a half-life on the order of 30 minutes.
FALSE
Regular human insulin administered intravenously is immediately effective, with a half-life on the order of 10 minutes.
Lispro, aspart, and glulisine are approved in the US for intravenous use but offer no advantage over regular insulin for this purpose and cost much more.
Peak activity of inhaled human insulin (Afrezza)
In 30 minutes (the tmax is about 10 minutes), much earlier than lispro
Required testing prior and during use of inhaled insulin
The current formulation requires spirometry before initiation, at 6 months, and annually thereafter.
Side effects of use of inhaled insulin aside from usual hypoglycemic risk
Cough or throat irritation
TRUE or FALSE: Allergies to currently available insulins are common, as are chronic skin reactions, which include lipoatrophy and lipohypertrophy.
FALSE
Allergies to currently available insulins are rare, as are chronic skin reactions, which include lipoatrophy and lipohypertrophy.
TRUE or FALSE: The onset and time to peak of insulins are similar regardless of dose.
FALSE
Both short-acting and long-acting insulins have profiles of action that vary by the size of the dose injected. With higher doses the onset and time to peak effect become more delayed and the total duration longer.
First GLP1-based therapeutic agent to be approved for human use
Exenatide (synthetic exendin-4)
Exendin-4 is a naturally occurring component of the saliva of the ___
Gila monster (Heloderma suspectum)
TRUE or FALSE: Exendin-4 shares 53% sequences identity with GLP1 but is relatively resistant to degradation by DPP4.
TRUE
Exenatide peak of action and total duration of action
Peak of action at about 2 hours
Total duration of action no more than 6 hours
Twice-daily injection before breakfast and dinner
HbA1c reduction with use of exenatide
1%
Weight loss with use of exenatide
Modest (2-4 kg)
Most common adverse effect of exenatide
Nausea (50% of patients)
GLP1 agonist that has properties similar to exenatide except for a slightly longer duration of action
Lixisenatide (once daily before breakfast; reduces postprandial increments of glucose during the daytime but has much less effect overnight)
Long-acting GLP1 agonist that is administered once daily without any restriction as to timing or relation to meals
Liraglutide (the other long-acting agents are to be given once weekly)
TRUE or FALSE: Long-acting GLP1 agonists are associated with greater HbA1c-lowering efficacy than short-acting agonists.
TRUE
Owing to their greater effects on overnight fasting glucose levels. Much less effect on postprandial increments of glucose than short-acting agents.
What is the LEADER study?
Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results
Randomized to treatment with liraglutide or placebo for a median of more than 3 years –> Significant reductions of risk for primary composite cardiovascular endpoint (CV death, nonfatal MI, or nonfatal stroke) (13%), CV death (22%), all-cause mortality (15%), and progression of albuminuria (26%). No significant effect on hospitalization for heart failure.
What is SUSTAIN-6?
Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 DIabetes
Randomized to semaglutide vs placebo for about 2 years –> Somewhat greater reduction of risk for its primary cardiovascular composite endpoint (26%) compared with LEADER and showed a reduction in renal endpoints. Nonsignificant effect on CV death, all cause death, hospitalization for heart failure, and progression of albuminuria.
Endpoint that didn’t show any improvement in both LEADER and SUSTAIN-6
Hospitalizations for heart failure (Up to now, these favorable outcomes have not been found with short-acting GLP1 agonists.)
TRUE or FALSE: Hypoglycemia is a direct effect of GLP1 receptor agonists.
FALSE
Hypoglycemia is not a direct effect of GLP1 receptor agonists but can occur when they are added to other agents.
Hence, reduce to minimum dose of secretagogue, and 20% reduction of insulin dosage is advised unless HbA1c is >8%.
The only GLP1 agonist that is renally cleared and is contraindicated in the setting of advanced kidney disease (eGFR <30)
Exenatide
Contraindications for GLP1 agonists (4)
Type 1 diabetes
Diabetic ketoacidosis
History of pancreatitis
Personal or family history of medullary thyroid cancer (clear increase in preclinical testing with rodents)
Side effects of GLP1 agonists
Nausea, diarrhea, abdominal pain
Pancreatitis?
TRUE or FALSE: Most of the effect of pramlintide on glycemic pattern is a reduction of basal glucose levels.
FALSE
Most of the effect of pramlintide on glycemic pattern is a reduction of postprandial increments, with little effect on overnight control.
HbA1c reduction with use of pramlintide
0.5 to 0.7%
Most common adverse effect of pramlintide
Mild or moderate nausea, which wanes with continued therapy
Timing of administration of oral medications that require rapid absorption for effectiveness if pramlintide is also being given
Either 1 hour before or 2 hours after injection of pramlintide
Contraindication for pramlintide
Confirmed gastroparesis
TRUE or FALSE: A deficiency of amylin is evident in patients with T1DM or T2DM.
TRUE
In parallel with insulin deficiency
Mechanisms of pramlintide
Amylin and insulin have complementary actions in regulating plasma glucose. Amylin binds to brain nuclei and promotes satiety and reduces appetite. Through efferent neural pathways it mediates a decrease in the rate of gastric emptying and limits inappropriate glucagon secretion in a glucose-dependent fashion. By these means it regulates the rate of plasma glucose appearance from the GI tract and the liver.
Largest pathophysiologic subgroup of diabetes
Latent autoimmune diabetes of adulthood
Another term for Latent autoimmune diabetes of adulthood
Adult-onset type 1 diabetes
Diabetes pathophysiologic subgroup that comprises up to 12% of patients with diabetes after age 20
Latent autoimmune diabetes of adulthood or Adult-onset type 1 diabetes
TRUE or FALSE: Regarding Latent autoimmune diabetes of adulthood / Adult-onset type 1 diabetes:
a. Frequently are obese
b. May have other autoimmune disorders or a family history of these
c. Diagnosis requires detection of anti-glutamic acid decarboxylase antibodies or anti-islet cell antibodies
d. Can only be treated with insulin
a. FALSE. Frequently are not obese
b. TRUE
c. FALSE. Lack of antibodies does not exclude an autoimmune process
d. FALSE. Insulin has been considered the main therapy from the outset, but other therapies may be possible in those with slow progression.
Leading causes of pancreatic diabetes (Type 3c diabetes)
Acute or chronic pancreatitis, pancreatectomy for cancer or pancreatitis, hemochromatosis, and cystic fibrosis
TRUE or FALSE: Patients with pancreatic diabetes share a tendency to have significant deficiency of insulin secretion and prominent fasting hyperglycemia.
FALSE
Patients with pancreatic diabetes share a tendency to have significant deficiency of insulin secretion and prominent postprandial hyperglycemia.
Commonly need insulin at or relatively soon after diagnosis and quite frequently require both basal and prandial
TRUE or FALSE: Patients with pancreatic diabetes have significant decreases in glucagon secretion and in the effects of incretin hormones.
TRUE
TRUE or FALSE: Regarding maturity-onset diabetes of the young (MODY):
a. Proportion of newly diagnosed adults with one of these conditions is estimated to be between 1 and 2%
b. All have a strong family history consistent with autosomal dominant inheritance with high penetrance
a. TRUE
b. FALSE. A strong family history consistent with autosomal dominant inheritance with high penetrance is typical but not always present.
Presentation of GCK-MODY
Presents typically in youth as mild fasting hyperglycemia that is not progressive and causes little or no tissue damage over time (deficiency of glucokinase –> altered glucose sensing in the beta cell)
Importance of diagnosis of GCK-MODY
To avoid unnecessary treatment of the patient and other identified members of the family. Current evidence indicates that those with a GCK mutation will not develop chronic complications of diabetes, and treatment is not likely to render significant changes in glucose control.
Most common form of monogenic diabetes
Hepatic nucleocyte factor-1A (HNF1A)
Presentation of Hepatic nucleocyte factor-1A (HNF1A)
In adulthood with progressive hyperglycemia, more postprandial than fasting, that responds very well to sulfonylureas
Can be suspected when there is a prominent history of adult-onset but quite stable and slowly progressive diabetes on one side of the patient’s family, often in the absence of obesity
Default choice for initial drug therapy in type 2 diabetes
Metformin
Used in combination with diet, exercise, and a DSMES program, can usually provide impressive lowering of glucose with essentially no risk of hypoglycemia. Initial use also has evidence for reducing CV risk
What is the ORIGIN trial?
Outcome Reduction with an Initial Glargine Intervention trial
Showed effectiveness of combination therapy. Randomized into glargine as basal insulin with continuation of prior oral therapy, and use of oral therapies with insulin added only if necessary. Both regimens maintained HbA1c levels close to 6.5%. No differences in medical outcomes were observed other than more hypoglycemia and less progression from dysglycemia to overt diabetes in the group assigned to initial glargine therapy.
Usual initial dose of basal insulin
Treatment can be started either with a fixed daily dose of 10 units or with a dose calculated as 0.1 to 0.2 units per kilogram body weight.
Failure to maintain HbA1c close to __% despite use of a regimen that includes properly titrated basal insulin calls for attention to postprandial hyperglycemia.
7%
After therapy of basal glucose has been optimized, the postprandial glucose excursion is highest after ___, and the highest postprandial glucose is after ___.
Breakfast
Dinner
Recent studies suggest that adding a single injection of short-acting insulin (at the morning meal or at the largest meal) is just as effective as basal-bolus therapy and is less likely to cause weight gain or hypoglycemia. Aim for glucose prior to next meal (or at bedtime if the dose is prior to dinner) approaching __ mg/dL.
120 mg/dL
When prandial insulin is added to basal insulin with continuation of one or more oral agents, optimal control often requires total daily insulin doses greater than __ unit per kilogram of body weight daily
1
Fig. 35.6. Glucose-lowering medication in type 2 diabetes. Page 1400
*
First-line therapy in type 2 diabetes
Metformin and comprehensive lifestyle (including weight management and physical activity)
*To avoid clinical inertia, reassess and modify treatment regularly (3-6 months)
Additional treatment if patient has established ASCVD or CKD - ASCVD predominates
EITHER GLP-1 RA with proven CVD benefit OR SGLT2i with proven CVD benefit
liraglutide > semaglutide > exenatide ER
empagliflozin > canagliflozin
Additional treatment if patient has established ASCVD or CKD - HF or CKD predominates
PREFERABLY SGLT2i OR GLP-1 RA
Medications to avoid if patient has HF
TZD
Saxagliptin
Additional treatment if patient has compelling need to minimize hypoglycemia
DPP-4i
GLP-1 RA
SGLT2i
TZD
Additional treatment if patient has compelling need to minimize weight gain or promote weight loss
EITHER GLP-1 RA OR SGLT2i
(ADA 2022: PREFERABLY GLP-1 RA OR SGLT2i)
Later on.. preferably DPP4-i if not on GLP-1 RA
Additional treatment if cost is a major issue
SU or TZD
(ADA 2022: Certain insulins, SU, TZD)
As a general rule, patients diagnosed with HbA1c above 9% should seek a gradual improvement of control with HbA1c below 7% within 6 months, with continuation of at least metformin after that. – What is the rationale for this?
Aside from the risk of hypoglycemia from use of insulin by relatively inexperienced patients, there is potential for worsening of retinopathy or neuropathy accompanying overly rapid reduction of glucose.
Risk of reapperance of hyperglycemia consistent with the diagnosis of T2DM in women with history of GDM
50-70% after 15 to 25 years, a risk that is increased 10 to 18-fold
Risks of GDM
Complicated delivery
Neonatal complications
Children exposed to hyperglycemia in utero have increased risk of later obesity and/or T2DM
Glucose targets during gestation
Fasting <95 mg/dL
1-hr postprandial <140 mg/dL
2-hr postprandial <120 mg/dL
OHAs that are sometimes used in GDM instead of insulin, but there are concerns about their safety
Metformin
Glyburide
Lifestyle interventions can provide a reduction of ___ to ___ % in progression to diabetes over a period of 3 to 5 years
30 to 60%
Intervention with metformin in patients at high risk for T2DM was associated with a somewhat smaller reduction in progression to diabetes. It had LESS effect in the following patients:
Older than 60 years of age
BMI of <30 kg/m2
Fasting plasma glucose <100 mg/dL
Metformin therapy brings little risk and offers SUBSTANTIAL benefit for some individuals, notably those:
Under age 60 years
BMI >35 kg/m2
Women with previous gestational diabetes
*Therefore on balance, consideration of metformin in patients who are at particularly high risk is recommended.
Best candidates for preventive strategies (preventing type 2 diabetes)
Patients with prediabetes:
- HbA1c >5.7% and particularly >=6%
- FPG >=100 mg/dL and particularly >=110 mg/dL
- Impaired glucose tolerance
