Diabetes Core Update — March 2015

Episode Date: February 24, 2015
Hosts: Dr. Neil Skolnik & Dr. John J. Russell
Focus: SGLT2 Inhibitors — Latest Research and Clinical Insights

Episode Overview

This month’s episode centers exclusively on Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors—highlighting their development, mechanisms, clinical benefits, side effects, and the recent studies examining their use both as monotherapy and in combination therapy in diabetes management. Dr. Neil Skolnik and Dr. John Russell break down findings from six key articles, providing practicing clinicians with practical takeaways for incorporating SGLT2 inhibitors into patient care.

1. SGLT2 Inhibitors: History & Mechanism

Discussion Begins: [02:06]

Key Points

• Historical Background
  • SGLT2 inhibitors have roots tracing back to 1835 with the isolation of phlorizin from tree bark in France, initially used for other ailments before its glucosuric effects were observed.
  • Renewed interest in the 20th century after animal studies suggested utility in diabetes management.
• Mechanism of Action
  • Kidneys filter ~180g glucose daily; ~90% reabsorbed by SGLT2 in proximal tubules.
  • Inhibiting SGLT2 increases urinary glucose excretion—up to 80g/day.
  • Effect is independent of insulin and potentially useful at any stage of type 2 diabetes; research continuing in type 1.
• Benefits
  • Reduces A1C by ~0.5–1%.
  • Modest, stable weight loss (~2kg over 6-12 months).
  • Lowers systolic/diastolic BP (2–4 mmHg SBP, 1–2 mmHg DBP).
• Risks
  • Increased incidence of genital mycotic infections (esp. in women: +11% vs placebo; men: +4%).
  • Slight diuretic effect and possible volume depletion.
  • Reduced efficacy at eGFR <45–60 mL/min.
• Approved Agents (as of 2015)
  • Canagliflozin (Invokana), Dapagliflozin (Farxiga), Empagliflozin (Jardiance).

Quote:
"It's really an exciting new class of medicines... we never thought of the kidney as being instrumental for diabetes glucose control." — Dr. Skolnik [03:07]

2. Canagliflozin vs. Glimepiride Added to Metformin in Type 2 Diabetes

Study Review Begins: [06:51]

Study Details

• Design: 1,400 patients, double-blind, 104 weeks comparing canagliflozin (100mg, 300mg) vs glimepiride, all on metformin.
• Results:
  • A1C Reduction: -0.65% (100mg), -0.74% (300mg), vs -0.55% (glimepiride).
  • Weight: ~4% loss with canagliflozin, +1% gain with glimepiride.
  • BP: 2–3 mmHg decrease with canagliflozin; +1.7 mmHg increase with glimepiride.
  • Fewer hypoglycemic episodes (6–8% canagliflozin vs 40% glimepiride).
  • Higher rates of genital mycotic infections with canagliflozin, but generally mild.
• Adverse Events: Similar rates (~70%) across all arms; discontinuations low.

Quote:
"That's an impressive number—8% versus 40% [hypoglycemia]—and a slight decrease in blood pressure..." — Dr. Skolnik [08:43]

3. Canagliflozin as Add-On to Insulin in Type 2 Diabetes

Study Review Begins: [08:43]

Study Details

• Design: Randomized, double-blind, placebo-controlled; ~600 patients on insulin/adjuvant therapies; endpoints at 18 and 52 weeks.
• Results:
  • A1C Reduction: -0.62% (100mg), -0.73% (300mg) at 18 weeks; sustained at 52 weeks.
  • 2% body weight reduction; decreased BP.
  • Increased genital infections and hypovolemia.
  • More hypoglycemia than placebo, but overall incidence still favorable.

Clinical Takeaway

• Adds benefit to patients inadequately controlled on insulin alone.
• Offers weight loss, BP reduction, and good glycemic effect with manageable risks.

Quote:
"This medicine is completely insulin independent and shouldn't really be expected to have hypoglycemia." — Dr. Russell [11:19]

4. Dapagliflozin Add-On to Metformin + Sulfonylurea

Study Review Begins: [11:19]

Study Details

• Design: 24-week, double-blind, randomized; 220 patients on metformin/sulfonylurea, A1Cs 7–10.5%.
• Results:
  • A1C Reduction: -0.69% vs placebo.
  • More patients reached A1C <7% (32% dapagliflozin vs 11% placebo).
  • Weight loss: -2.1 kg; SBP drop: -3.8 mmHg.
  • Mild increases in LDL and HDL cholesterol, but stable LDL:HDL ratio.
  • Hypoglycemia (13% dapagliflozin vs 4% placebo); genital infections slightly increased.

Clinical Takeaway

• Effective as a third-line agent after metformin and sulfonylurea.
• Delivers weight/BP benefits with low-to-moderate increased hypoglycemia risk.

Quote:
"A third of the patients entering... with a mean A1C of 8 actually achieved the goal A1C of less than 7." — Dr. Skolnik [13:49]

5. Dapagliflozin in Type 1 Diabetes – Proof of Concept

Study Review Begins: [13:49]

Study Details

• Design: 2-week, dose-ranging, double-blind, proof-of-concept; 70 adults with type 1 diabetes.
• Results:
  • Dapagliflozin 10mg led to -41 mg/dL decrease in daily average glucose by day 7; mean amplitude of glycemic excursion also reduced.
  • Need for bolus insulin reduced ~20%.

Clinical Implication

• Potential to lower insulin requirements and improve glucose control in type 1 diabetes.
• Short duration; more research needed, but promising proof-of-concept.

Quote:
"To have to do less coverage with meals I think is a good thing." — Dr. Russell [17:28]

6. Empagliflozin + Linagliptin Combination as Add-On to Metformin

Study Review Begins: [17:28]

Study Details

• Design: 500+ patients on metformin; randomized to various combinations.
• Results:
  • Combination therapy superior in A1C reduction (-1.19%, -1.08%) vs either drug alone.
  • 57–61% of combination group reached A1C <7% (vs 28–36% monotherapy).
  • Low rates of hypoglycemia; tolerability similar to single agents.

Clinical Implication

• Offers a convenient, effective, and FDA-approved (as of 2015) second-line option.
• Suitable for patients requiring more than metformin alone for control.

Quote:
"A single pill combination SGLT2/DPP4 with good outcomes in this study." — Dr. Skolnik [20:04]

7. Empagliflozin + Linagliptin as Initial Therapy

Study Review Begins: [20:04]

Study Details

• Design: Patients not on prior therapy; randomized to combinations or monotherapy.
• Results:
  • Combination led to greater A1C reductions (-1.08% to -1.24%) than either drug alone.
• Takeaway:
  • Not a replacement for metformin, but a first-line alternative for those who cannot tolerate it.

Quote:
"Certainly it's an alternative [for] folks who cannot tolerate metformin as a first-line therapy." — Dr. Russell [22:56]
"Few can foresee whither their road will lead them until they come to its end. So certainly we are on the SGLT2 road..." — Dr. Russell quoting Tolkien [23:43]

Memorable Moment & Final Thoughts

• The episode closes with Dr. Russell invoking J.R.R. Tolkien to express the evolving journey of diabetes treatment:

  "Few can foresee whither their road will lead them until they come to its end. So certainly we are on the SGLT2 road. We've had a couple stops along the way in this article and we'll kind of find out where it ends." [23:43]

Key Takeaways

• SGLT2 inhibitors are a versatile and effective new class for type 2 diabetes, offering A1C reduction, weight loss, and blood pressure benefits—with favorable safety when appropriately selected.
• Now available as combination therapy with DPP-4 inhibitors, expanding options for individuals not controlled on metformin or intolerant to it.
• Early research hints at a limited but intriguing role in type 1 diabetes.
• Clinicians should monitor for genital mycotic infections, volume depletion, and adjust for renal function.

For references and article links:
Visit www.diabetesjournals.org.