CME INDIA Presentation by Dr. Santosh Malpani, MD (Medicine) Diploma Endocrin, United Diabetes and Endocrine Clinic, Nanded (Maharashtra), India.
Based on a presentation at Challenges in Diabetes (CID), Mumbai on 6th May 2023.
Many Guidelines have thrown Sulfonylureas (SUs) out of basket in 2023.
Why are we concerned about SUs?
| No uniform recommendation regarding the position of SUs (as first or second-line therapy) in both national and international diabetes management guidelines. |
| Glucose lowering effect of other compounds is less. |
| Cost of other compounds is more, availability is less. |
| Concern regarding CV safety. |
| Concern regarding Hypoglycemia. |
| Concern regarding weight gain. |
Classification of SUs
On the basis of Hierarchy of Development
| Conventional |
| Tolbutamide, Glibenclamide, Glipizide |
| Modern |
| Glimepiride, Gliclazide, Gliclazide MR, Glipizide MR |
On the basis of Duration of Action
| Short Acting | Tolbutamide |
| Intermediate Acting | Glimepiride, Gliclazide |
| Long Acting | Glibenclamide, Glimepiride, Gliclazide MR, Glipizide MR |
SUs – Mechanism of Action
- Take out available insulin.
- Viable beta cells.
- Glucose independent effect.
What Guidelines say?
| Guideline | Recommendation For Sulfonylurea |
| ADA | Third-line therapy in people with T2DM and ASCVD or CKD, following the failure of SGLT2i or GLP-1RA – in individuals without underlying cardiac or renal problems. Second-line therapy option when the cost of treatment is a major factor; if there is no risk or established CKD, ASCVD, or HF. |
| IDF | When metformin is not tolerated, SUs (except glibenclamide) can be prescribed. Metformin can be combined with SUs (except glibenclamide), SGLT2 inhibitors or DPP4 inhibitors. When starting an SU, the patient should be educated about how to prevent, recognize, and treat hypoglycemia. |
| ISPAD | SUs are not approved for use in those below 18 years of age. People on SUs should be encouraged to do self-monitoring of blood glucose to detect asymptomatic hypoglycemia. |
| Guideline | Recommendation For Sulfonylurea. |
| ADA | Third-line therapy in people with T2DM and ASCVD or CKD, following the failure of SGLT2i or GLP-1RA – in individuals without underlying cardiac or renal problems. Second-line therapy option when the cost of treatment is a major factor; if there is no risk or established CKD, ASCVD, or HF |
| IDF | When metformin is not tolerated, SUs (except glibenclamide) can be prescribed. Metformin can be combined with SUs (except glibenclamide), SGLT2 inhibitors or DPP4 inhibitors. When starting an SU, the patient should be educated about how to prevent, recognize, and treat hypoglycemia. |
| ISPAD | SUs are not approved for use in those below 18 years of age. People on SUs should be encouraged to do self-monitoring of blood glucose to detect asymptomatic hypoglycemia. |
The Indian Diabetic
Let us think about this case
Cluster of Insulin secretion defect do exist
Clinical Evidence for SUs
Legacy effect
- UKPDS 33 and ADVANCE – Reduction in the risk of microvascular disease by long term SU treatment.
- ADVANCE ON – intensive glucose control with gliclazide MR led to a 46% reduction in end-stage kidney disease (ESKD).
- The STENO-2 – intensified therapy with multiple OHAs in patients with T2DM and microalbuminuria delays the progression to nephropathy, autonomic neuropathy, and retinopathy.
Glucose lowering effect is impressive
Clinical Evidence-Glycemic Control as monotherapy
| Trial | Intervention | HbA1c Reduction |
| GUIDE | Gliclazide MR 30–120 mg OD or glimepiride 1–6 mg or glimepiride in combo (MTF or alpha glucosidase inhibitor) | HbA1c: gliclazide MR: 8.4 to 7.2% glimepiride: 8.2 to 7.2% |
| CAROLINA | Linagliptin 5 mg OD versus glimepiride 1–4 mg OD+standard of care | Linagliptin 356/3023 (11.8%) Glimepiride 362/3010 (12%) |
| UK CPRD | Gliclazide MR versus sitagliptin post metformin monotherapy | Those on gliclazide MR more likely achieved an HbA1c <7.0% (HR: 1.51) or had an HbA1c reduction≥1% from baseline (HR: 1.11) compared with patients on sitagliptin |
| GRADE | All patients continued metformin Sitagliptin (S) or Glimepiride (G) or Liraglutide (L) or Insulin glargine (I) | HbA1c>7% S 77% G 72% L 68% I 67% |
Clinical Evidence – As Third Addon
- More than five meta-analysis – adding a third drug to metformin and SU combination therapy is clinically more effective in reducing HbA1c than only dual therapy.
Clinical Evidence – SU and Insulin as Duo
- Cochrane systematic review- SU-insulin combination therapy reduced HbA1c by 1% as compared to Other SU-OAD combinations.
- Meta-analysis – SU and insulin combination had better glycemic outcomes than insulin monotherapy.
- The combination of basal insulin and glimepiride reduced the requirement of total daily insulin by almost 30%.
- SU and once-daily basal insulin were better than premixed insulin monotherapy in reducing total insulin requirement.
- A Korean study – Glimepiride add-on to insulin glargine and metformin, reduced the HbA1c by 0.49% compared to only metformin and insulin.
Bedtime insulin daytime SU (BIDS)
- Lesser requirement of insulin.
- Reduced hypoglycemia risk (associated with insulin).
- Lower the risk of weight gain.
- Lowers the risk of a rise in blood pressure.
- 24-h glycemic control.
CV and Renal safety exist
Diabetes Care 2023;46(5):1–11 testify
New findings contribute to the understanding that second-line SU for glucose lowering are
- Unlikely to increase CV risk or all-cause mortality.
- Given their potent efficacy, microvascular benefits, cost effectiveness, and widespread use, this study supports that SU should remain a part of the global diabetes treatment portfolio.
Courtsey: Ref.3
Courtsey: Sanjay Kalra, Yashdeep Gupta. Choice of Glucose-lowering Therapy— A Metabolic Fulcrum-based Approach US Endocrinology, 2015;11(2):79–80 DOI: http://doi.org/10.17925/USE.2015.11.02.79
Place of Sus in clinical Practice
| Recommendation | A1C | Gr | Evi |
| First-line initial therapy Patient cannot tolerate or contraindication to metformin | 1.5 | – | – |
| Dual therapy to start with Aim – HbA1c reduction is≥1.5% A) Consider age, life expectancy, comorbidity, risk of hypoglycemia B) In the absence of specific indications for cardio-renal protection | 0.9-1.5 | A | 1 |
| Second Add on to OHAs except for glinides Caution- With due precaution for hypoglycemia risk in patients that are elderly or have CKD | 0.8-1.5 | A | 1 |
| Second Add on to metformin monotherapy In the absence of specific indications for cardio-renal protection, cost considered With due precaution for hypoglycemia risk in patients that are elderly or have CKD | 0.9-1.62 | A | 1 |
| Third Add on to dual combination therapy In the absence of specific indications for cardio-renal protection With due precaution for hypoglycemia risk in patients that are elderly or have CKD | 0.9-1.31 | A | 1 |
| Recommendation | Grade | Evidence |
| Glibenclamide may be used in neonatal diabetes and maturity-onset diabetes mellitus of the young-3 (MODY-3) | A | 3 |
| During long-term fast periods like Ramadan and Navratri, modern SU may be cautiously used in combination with other OADs | A | 3 |
| SU (gliclazide) can be used for the management of steroid-induced mild to moderate hyperglycemia | C | 4 |
| Modern SU can be used in patients with renal impairment a) Gliclazide and glipizide – without dose adjustment in CKD stages 3, 4, 5 b) Glimepiride can be started conservatively at 1 mg daily | A | 2 |
CME INDIA Practical Tips
(By Dr. Santosh Malpani)
- Go Slow, Build slow – weekly or fortnightly intervals.
- Use only if others fail in obese diabetics.
- Don’t combine SU with other SU or Glinides.
- SUs can be prescribed as part of BIDS regime.
- Educate the patient and family members about hypoglycemia.
- Look for hypo symptoms, weight at each visit.
- Advise a 3+3 meal pattern, Avoid missing meals.
- Ask to take snack before exercise.
- Monitor CV and Renal parameters regularly.
- Prefer FDCs scored FDCs- Cost and pill burden.
CME INDIA Tail Piece
(By Dr. Santosh Malpani)
References:
- Kalra, Sanjay; Aamir, A. H.; Raza, Abbas; Das, etal. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement .Indian Journal of Endocrinology and Metabolism19(5):577-596, Sep-Oct 2015.doi: 10.4103/2230-8210.163171
- Sanjay Kalra, Yashdeep Gupta. Choice of Glucose-lowering Therapy— A Metabolic Fulcrum-based Approach US Endocrinology, 2015;11(2):79–80 DOI: http://doi.org/10.17925/USE.2015.11.02.79
- Huan Wang, Ruth L.M. Cordiner, et al., Scottish Diabetes Research Network Epidemiology Group; Cardiovascular Safety in Type 2 Diabetes With Sulfonylureas as Second-line Drugs: A Nationwide Population-Based Comparative Safety Study. Diabetes Care 1 May 2023; 46 (5): 967–977. https://doi.org/10.2337/dc22-1238
- Douros A, Dell’Aniello S, Yu OHY, Filion KB, Azoulay L, Suissa S. Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study. BMJ. 2018 Jul 18;362:k2693. doi: 10.1136/bmj.k2693. PMID: 30021781; PMCID: PMC6050517
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SUs are outdated drugs.
No further modifications after Glimepiride.ie 1996 – Twenty seven yrs.over.
After 1996- AGIs,TZDs,Gliptins,SGLT-2 i and GLP- RA.(none of them SUs)
The drugs in pipeline also Non SUs.
It may effectivley reduce A1c but effectively cause hypo.
If there is no beta cells after10 to15 yrs of duration it doesn’t have any role.
If required let us use minimum dose ie 0.5 mg to 1mg per day of Glimepiride and 40 to 80 mg of Gliclazide per day.
More the dose of SUs more the problem.
Nowadays we have better safe and cheaper drugs well studied and globally shared drugs.
May 2023 Italian guideline removed SUs and glinides.
Thanks sir for valuable input. Orphans have no support from Pharma. Still it’s prescribed even hated, proves importance in clinical practice. please have a look at the title
Very well said sir