Diabetes II: Goals and Treatment with Non-Insulins
/Treatment Goals for Diabetes
Once diagnosed with DM, the goal is to improve glycemic management.
A general target to start is an A1c of < 7.0%.
An A1c of 7% corresponds to an average estimated glucose of 154 mg/dL - so obviously there is room for improvement!
Why 7%, then?
An A1c drop of 1% corresponds to important improvements in microvascular outcomes, with diminishing returns once you get below 7%.
Just to provide some reference ranges for what it looks like below 7%:
A1c 6.5%: 140 mg/dL (the point at which prediabetes becomes diabetes)
A1c 6.0%: 126 mg/dL
A1c 5.7%: 117 mg/dL (the point at which we diagnose prediabetes)
A1c 5.5%: 111 mg/dL
A1c 5.0%: 96.8 mg/dL
Check out MDCalc to play with the A1c conversion calculator.
With older age, targets can become more permissive as absolute benefit is lessened.
Treatment goals should also align with other comorbid conditions that predispose to cardiovascular disease:
Smoking cessation
Reducing lipids with statin therapy
Diet
Exercise
Weight loss
Patients can have A1c checked approximately every 3-6 months, and/or engage with some form of glucose checking.
With insulin therapy, CGM or fingersticks are a must due to risk of hypoglycemia.
Self-monitoring of blood glucose is not necessary in most patients with T2DM (outside of pregnancy), but may be beneficial to provide data to patients in their lifestyle interventions.
Remember our targets for therapy in pregnancy:
Fasting: 95 mg/dL
1 hour postprandial: 140mg/dL, OR
2 hour postprandial: 120 mg/dL
Lifestyle Changes and their Importance with Diabetes Control
All patients with new diabetes should receive intensive education regarding nutrition and diet, weight management, exercise, and the potential role of surgical therapy.
Diagnosis of diabetes can be a “wake up call” for many patients who may have otherwise been in denial - and we should take advantage to help them achieve new, healthier goals.
Nutrition, Diet, and Weight Loss
Focusing on consistency in carb intake, avoiding weight gain, and balanced nutrition.
Despite importance of weight loss, few patients achieve and sustain substantial weight loss.
Benefits even at 5-10% weight loss, but most significant at > 15%.
Caloric restriction can be helpful in resolving diabetes:
DiRECT Trial - T2DM of less than 6 years and not on insulin, randomized to intensive supervised caloric restriction vs usual care.
24% of therapy group had lost 15kg or more of body weight at 1yr (vs 0% of usual care).
This was only maintained by 11% in the intervention group at 2 years.
46% of therapy group had resolved DM at one year (vs 4% in control)
This was maintained by 36% (vs 3%) at two year follow up.
Exercise
Regular exercise is beneficial, independent of weight loss!
Can also delay or reverse progression of prediabetes to T2DM
Recommendations:
30-60 mins of moderate intensity aerobic activity (40-60% VO2 max) on most days of the week (i.e., 150 mins per week, not skipping more than 2 days in a row).
Resistance training at least twice per week.
Surgical Weight Loss
Results in largest degree of sustained weight loss in those with T2DM and obesity
Appropriate for patients with:
BMI > 40, or
BMI >35 - 39.9 when hyperglycemia is inadequately managed by lifestyle measures and optimal medical therapy
Emotional Support and Psychotherapy
Many patients with these diagnoses may suffer from depression concurrently which can interfere with self care.
Psychotherapy may improve some measures of diabetes management and glycemic control based on metaanalysis of 12 trials.
Pharmacologic Therapy
When to start it?
Advised to start concurrently with diagnosis if A1c is > 7.5 - 8%, alongside lifestyle interventions.
If a highly motivated patient is near 7.5%, it is reasonable to trial 3-6 months of lifestyle modification before starting.
What med do I start?
For most patients, metformin is a reasonable first option.
However, it is getting added alongside or replaced by some newer therapies more these days!
Based on initial A1c, patient conditions, and tolerance of side effects, this is an individualized decision that likely is best decided with PCP or endocrinologists - though OB/GYNs may be writing for these meds, especially with transition out of pregnancy care.
Review of Medications:
Metformin
Biguanide medication that is standby of T2DM therapy, as it is:
Inexpensive
Efficacious at reducing hyperglycemia
Promotes modest weight loss
Well-tolerated.
A good first-line choice for most patients. Specific contraindications:
GI intolerance - can improve with slower titration or XR formulations
CKD/ESRD (GFR < 30) - concern for development of lactic acidosis
Hepatic impairment - risk of hepatotoxicity, lactic acidosis
Pregnancy and reproductive considerations
Often an excellent choice given metformin may:
Promote weight loss
Lower A1c and risk of fetal anomalies
Appears safe to continue in pregnancy (though does cross the placenta)
GLP-1 (glucagon-like peptide 1) agonists - liraglutide, semaglutide, dulaglutide
Binds GLP-1 receptors which are present in pancreatic cells, gastric mucosa, and elsewhere.
Overall effects include:
Stimulating glucose-dependent insulin release from pancreas
Slow gastric emptying
Inhibit post-meal glucagon release
Reduce food intake/appetite
Excellent therapy choice alone or as combination with metformin in patients where weight loss is desired
Semaglutide in the news lately - Ozempic (brand name) - for weight loss
Can be used in patients with significant renal impairment, unlike metformin
Low rates of hypoglycemia
Contraindications:
History of pancreatitis - postmarketing reports of hemorrhagic and nonhemorrhagic pancreatitis.
Predominantly are injectable medications - so must learn to inject SQ
Pregnancy and reproductive considerations:
Limited data on exposures and thus not recommended for use prior to, or during pregnancy
Recommended to discontinue > 2 mos prior to pregnancy
No breastfeeding data, either.
SGLT2 inhibitors - empagliflozin, canagliflozin, dapagliflozin
Inhibit SGLT2 receptors in the proximal tubule of the nephron - promoting renal excretion of glucose
Generally considered as adjunctive rather than initial therapy, but can be combined with metformin.
Good adjunctive therapy choice in T2DM with normal or mild impairment in kidney function not meeting goals with other first line agents, or with other significant comorbidities (cardiovascular disease).
Higher rates of hypoglycemia than other meds - should monitor fasting and pre-meal glucoses for a few weeks after starting meds.
Contraindications:
T1DM
CKD with eGFR < 30-45
History of prior DKA - can increase risk due to dehydration
Obtain ketones in patients with nausea, vomiting, or malaise on these meds and patient should discontinue therapy until symptoms resolve and has been evaluated.
Cause some dehydration due to free water loss with the glucosuria, so should be used with caution in patients on diuretics or other meds that may predispose to AKI
Pregnancy and reproductive considerations:
Given glucosuria, some patients may be more prone to genitourinary Candida infections - need to be monitored for this and consider discontinuing SGLT2 inhibitors in patients with recurrent bacterial UTIs or GU fungal infections
Not recommended in pregnancy due to adverse renal effects observed in animal studies.
No breastfeeding data.
Sulfonylureas - Glipizide, Glyburide, Glimepiride
Bind to a ATP-potassium channel in pancreatic beta cells, blocking them and lowering action potential of the cell → in turn allowing for increased responsiveness of cells to calcium → increasing insulin
Can be considered if contraindications to metformin exist, and may be useful in some forms of MODY
Often used in combination therapy with metformin
Should not be combined with insulin due to higher incidence of hypoglycemia
Contraindications:
Glyburide avoided in CKD - glipizide is shorter acting and has liver metabolism
No demonstrated cardiovascular benefit - so if CVD present, other agents are preferred
Patients prone to hypoglycemia - can exacerbate.
Pregnancy and reproductive considerations:
Once used in pregnancy, but now largely discontinued:
Some sulfonylureas (glyburide, glipizide) may persist and be metabolically active in newborns for 4-10 days, predisposing to hypoglycemia if exposed near delivery - advised to discontinue at least 2 weeks prior to delivery.
Can be used in breastfeeding - appears safe overall with limited passage into milk.
DPP-4 (dipeptidyl peptidase 4) inhibitors - linagliptin, saxagliptin, alogliptin, vildagliptin
Endogenous DPP-4 deactivates GLP-1 - so in principle, works like the GLP-1 agonists but increase endogenous supply (rather than providing exogenous stimulation)
Effects on GLP-1 activity though are much more modest than with GLP-1 agonists.
Generally used as add-on therapy in patients needing additional glucose lowering, as do not have protective cardiac or renal effects (compared to other agents)
Can be combined with metformin, TZDs, sulfonylureas, basal insulins, and/or SGLT2 inhibitors.
Contraindications:
History of pancreatitis
Liver disease for some agents - may worsen
Heart failure for some patients - may worsen
Pregnancy and reproductive considerations:
Limited data in pregnancy and reproduction, so are not recommended.
Thiazolidinediones - i.e., pioglitazone
Work by acting on adipose and muscular tissues to increase glucose utilization, but mechanisms are not entirely understood.
Generally an add-on therapy - may rarely be used initially in patients with contraindications to metformin and sulfonylureas, and decline injectable SGLT2 inhibitors
Contraindications:
Heart failure / any fluid overload
History of fracture, or high risk of fracture (i.e., osteoporosis or low BMD)
Active liver disease
Active or prior history of bladder cancer
Pregnancy
Macular edema
Pregnancy and reproductive considerations:
If used in reproductive-aged patients, weight loss and improvement in glycemic control has been shown to cause ovulation in anovulatory patients → unintended pregnancy
Limited pregnancy and breastfeeding data, but do cross the placenta; therefore not recommended for use.
Overview literature: NEJM 2021