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STANFORD TYPE 2 DIABETES ALGORITHM

This algorithm was designed by Stanford’s Eduation Technology team in your practice for professinal and patient reference. These materials
at the School of medicine and is based off of the American Diabetes are a part of the Stanford Center for Continuing Medical Education’s
Assoiation Algorithm for 2018. Click on each therapy to jump to a online course Type 2 Diabetes Management. Visit cme.stanford.edu
detailed overview of each. Please feel free to print this out and use it for course details.

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< 9%
MONOTHERAPY
MONOTHERAPY
Metformin* + Lifestyle Management

Metformin


High
+ Lifestyle Management
EFFICACY

HYPO RISK Low risk

WEIGHT Neutral/loss
SIDE EFFECTS GI/lactic acidosis
COSTS Low


MONOTHERAPY
In patients with diabetes and HbA1C of less than 9% begin with
monotherapy. Combine lifestyle management strategies with
Metformin to lower glucose levels. At diagnosis initiate lifestyle
management and decide on an HbA1c target and then which
medications will help to get the patient to goal.
Metformin activates AMP kinase and decreases hepatic glucose
production. There is no adjustment if the patient’s GFR is > 45,
however if the GFR is 30-45 then the prescribing provider needs to
not start Metformin. If the patient is already on Metformin then the
provider needs to assess if the medication is still a good fit for the
patient and reduce the dose if medication is continued. If the GFR is
less than 30 then it is not recommended to start or take Metformin.
The medication has some benefit for ASCVD patients. ASCVD stands
for atherosclerotic cardiovascular disease. The medication is low cost
and there may be some potential for weight loss.

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DUAL THERAPY
One of the non-insulin novel therapeutic agents is the GLP-1 agonists
class. They play an important role in diabetes therapy. Beta cells make
up 70% of the overall mass of the islets within the pancreas. Insulin,
amylin and GABA, a neurotransmitter, are all secreted from the beta
cells. Alpha cells make up 20% of the total islet mass. Alpha cells
secrete glucagon which signals hepatic release of glucose. When
people are living with diabetes their glucagon is being secreted
while the patient is in a fasting state, which increases hepatic glucose
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production and elevates blood glucose. Another issue is that glucagon
can be secreted post meal despite blood glucose rise due to food
consumption. In someone who does not have diabetes, they would
not be secreting glucagon post meal. In diabetes, Alpha cells fail to
suppress their glucagon secretion post meal when the body does not
need to be increasing blood glucose, which leads to higher blood
glucose.
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GLP 1 is an incretin hormone. GLP 1 receptors are found in
the brain, duodenum, kidneys, liver, lungs, pancreas and the
stomach. As you can see from the picture, the GLP 1 level rises
when people consume food and increases glucose-dependent
insulin secretion from pancreatic beta cells. It accounts for
higher insulin levels when oral glucose is given compared to
intravenous glucose administration (see graph on the slide).
GLP-1 is produced by L-cells located in the distal ileum and
colon in response to food.
GLP-1 class effects:
• Enhances glucose-dependent insulin secretion
• Decreases postprandial glucagon secretion, thus
decreasing hepatic glucose output
• Regulates gastric emptying, decreasing the rate of peak
nutrient absorption from meals
• Decreases food intake
• There are Warnings regarding questionable acute
pancreatitis risk. There is an FDA black box for risk of
thyroid c-cell tumors.
Some clinical pearls for available medications from this
class include:
• Liraglutide – CVD benefit (LEADER trial 13% relative
reduction in major CV events, 22% reduction in CV deaths)
• Semaglutide – CVD benefit (SUSTAIN-6 trial) 26%RR
reduction in CVD (mostly nonfatal stroke)
• Exenatide – not indicated with eGFR <30
• Dulaglutide – check and add CVD if available
• There have been some new trials that have come out
that show cardiovascular benefit for some of the GLP 1
agonists. The LEADER trial showed a 13% relative risk
reduction in major cardiovascular events and a 22%
reduction in cardiovascular deaths. In the LEADER trial
liraglutide was the GLP 1 that was studied. Semaglutide
has the Sustain6 trial which showed 26% risk reduction
in cardiovascular disease. Exenetide has a cardiovascular
study that is ongoing.
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SGLT-2, or sodium glucose transporter -2 inhibitor, is another class of the
the diabetes medications. Its mechanism of action is to facilitate glucose
reabsorption in the kidney. It is responsible for 90% of glucose reabsorption.
SGLT-2 inhibitors block the reabsorption of glucose in the kidney, increase
glucose excretion, and lower blood glucose levels
Here are the highlights of SGLT-2 class agents.
• All agents increase the risk of genitourinary infections, volume
depletion, hypotension, and increase in LDL cholesterol. There is no
hypoglycemia risk and it can be weight losing or weight neutral. The
three SGLT-2’s are canglifozin, dapagliflozin and empagliflozin. Each SGLT-
2 has a different GFR criteria. For canagliflozin it is not recommended
with eGFR <45, eGFR 45-59 – 100 mg dose can be used. FDA black box
warning of amputation, risk of bone fractures
• Dapagliflozin is not recommended if eGFR <60.
• Empagliflozin is contraindicated if eGFR <30.
• DPP-IVs work by inhibiting DPP-IV enzyme (dipeptidyl peptidase 4)
activity. This enzyme is responsible for degradation of endogenous GLP-
1. By decreasing clearance of GLP-1, there is an increase in fasting and
post-prandial incretin concentrations, an increase in Insulin secretion
(glucose dependent) as well as a decrease in Glucagon secretion resulting
in decreases in fasting and post-prandial glucose levels.
• Cardiovascular outcome studies have shown an increase in
hospitalizations for heart failure (SAVORI-TIMI 53 trial) for Saxagliptin
• for Alogliptin, a higher incidence of heart failure was found in the
EXAMINE trial
• For Sitagliptin - cardiovascular safety was addressed in the TECOS trial,
where no difference in the rate of hospitalizations was found in patients
treated with Sitagliptin
• No cardiovascular data is available for Linagliptin
• Here are some important clinical highlights for the agents from this
class:
• Sitagliptin – can be used in renal insufficiency, eGFR 30-50 – 50 mg per
day, eGFR <30 – 25 mg per day
• Saxagliptin – can be used in renal insufficiency, 2.5 mg if eGFR <50
• Linagliptin – no dose adjustment needed in renal insufficiency
• Alogliptin – can be used in renal insufficiency, eGFR 30-60 – 12,5 mg,
eGFR <30 – 6.25 mg
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TRIPLE THERAPY
If the patient’s A1C is not at target after 3 months on Mono and/or
Dual Therapy, Triple Therapy could be considered, adding a second
additional agent. When a patient is not showing improvement with
previous therapies, assessing medication adherence before adding
another agent is crucial. It is also prudent to review the patient’s recent
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medical history to ensure no other changes in health or medication
could be interfering with the current treatment regimen, or represent
potential contraindications that were not an issue under previous
regimens. Talk to your patient about how each option will affect and
be affected by their own lifestyle and medication adherence.

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COMBINATION INJECTION THERAPY
If the patient’s A1C is equal to or greater than 10%, blood glucose
is greater than or equal to 300 mg/dl, or the patient has symptoms
of hyperglycemia, then Combination Insulin Therapy should be
considered. It is not uncommon for patients to be wary of introducing
multiple daily injections. It is important to discuss the pros and cons
with your patients and be sensitive to the extra support your patients
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may need to adjusting to the idea and practice of regular injections. It
is also very important that the patient be confident in checking blood
glucose and to know how to treat hypoglycemia. The algorithm gives
you guidelines for how to start, when to adjust, and how to manage
the increased risk of hypoglycemia.
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TIP FOR LIFESTYLE MANAGEMENT
Lifestyle Management Strategies is a vital component of each therapy.
Three of the most universally helpful Lifestyle Management Strategies
include: Diabetes Patient Self-Management Education and Support
(DSMES), Medical Nutritional Therapy (MNT) and Physical Activity.
In addition, smoking cessation and psychological care may be
appropriate for some patients.
All patients should enroll in self-management education. These
educational resources equip the patient with the knowledge, skills,
and confidence to understand diabetes and be proactive in their
own treatment. Providers are encouraged to consider the burden of
treatment and patient’s level of confidence and education as well as
the level of social and family support.