Diabetes II: Goals and Treatment with Non-Insulins

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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

(c) NEJM 2021

(c) NEJM 2021